1. Dean Lee, M.D., Ph.D., assistant professor of pediatrics from the Children's Cancer Hospital at M. D. Anderson, has found that combining the epigenetic drug MS-275 with natural killer (NK) cells makes osteosarcoma cells more sensitive to NK cells while making the NK cells more lethal to the tumor, as presented at the American Society of Pediatric Hematology/Oncology annual meeting on May 15, 2008.

2. Epeius Biotechnologies Corporation announced today that the company has taken a major step toward the commercialization of its lead product with the opening of a Phase II Registration Protocol using Rexin-G for osteosarcoma in the United States. 

2.b. Epeius Biotech Awarded Patents in Europe for Targeted Genetic Anti-Cancer Medicine: Company Expands Impressive Intellectual Property Estate

3. Combination of CP-751871, a human monoclonal antibody against the IGF-1 receptor, with rapamycin induced complete regression of established tumors. 

4. The drug RH1 was able to kill tumour cells from neuroblastoma, osteosarcoma and Ewing's sarcoma.

5. Mepact provides a significant increase in Osteosarcoma disease free survival

6. New data (May, 2008) show that L-MTP-PE in combination with other therapies is safe, well-tolerated and exhibits clear signs of disease control.

7. Rexin-G Controls Tumor Growth and Improves Survival in Chemotherapy-Resistant Soft Tissue Sarcoma and Osteosarcoma.

8. Doses of 70 Gy or higher of proton beam radiation could poosibly control unresectable osteosarcoma.

9. March 1, 2009 Researchers identify potential therapeutic target in osteosarcoma.

Vitamin D shown to be effective in interfering with osteosarcoma metastasis biochemistry

Vaccine Studies: There are several promising areas of research at the molecular level.  We present two very promising but under funded vaccine studies. 

 1. Mepact (renamed Junovan) finally produced in San Diego

2. Onyvax Reports Early Success with Osteosarcoma Cancer Vaccine

Molecular studies:

1. Chemokine Therapeutics Corporation announced on July 19, 2005 that the FDA has granted orphan-drug designation to CTCE-9908 for the treatment of Osteosarcoma.  CTCI-9908 reduced lung metastases by two thirds in clinical trials.

2. Study suggests, for the first time, the presence of CTR in patients with Osteosarcoma for whom post-operative antiangiogenic therapy may be used to prevent the post-operative progression of micro metastases.

3. S. Korean scientists find protein that helps predict spread of bone cancer

4. Danish Research Confirms Rath Discovery: Enzyme Block Stops Cancer Spread

Mouse studies:

1. Johns Hopkins scientists have shown that in mice at least, vitamin C - and potentially other antioxidants - can indeed inhibit the growth of some tumors

2. Talabostat can induce inhibition of tumor growth, independent of T-cell activity, by 60 to 90% in xenograft models of Osteosarcoma.

3. Ketoprofen reduces Osteosarcoma metastases and tumor growth rate in mouse xenograft models

4. Aerosol gemcitabine inhibits the growth of primary Osteosarcoma and Osteosarcoma lung metastases

5. Hyperthermia produces 100% regression in animal model Osteosarcoma tumors

6. Zoledronic acid suppresses lung metastases and prolongs overall survival of osteosarcoma-bearing mice

7. Zoledronic acid activates the DNA S phase checkpoint and induces osteosarcoma cell death

8. Drug MS-275 Helps Immune System Fight Osteosarcoma

9. Gene Therapy to (Ewing's Sarcoma) Bone Tumors

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Mepact, IDM's Most Advanced Product, Receives ''Orphan Medicinal Product'' Designation for the Treatment of Osteosarcoma in the European Union

PARIS, July 8, 2004 - IDM (Immuno-Designed Molecules), a biopharmaceutical company specialized in the development of immunotherapy products for the treatment and control of cancer, announces today that the European Commission has granted its product, Mepact, "orphan medicinal product" designation for the treatment of osteosarcoma. Designation was granted following the positive opinion given by the European Medicines Agency (EMEA) and its Committee for Orphan Medicinal Products (COMP). Mepact obtained "orphan drug" status in the United States in June 2001.

Mepact (L-MTP-PE) is an immune system stimulant designed to promote the destruction of cancer cells by activating macrophages present in the body. A randomized Phase III trial on Mepact administered after surgical resection of tumor, in association with chemotherapies was carried out on close to 800 patients who had recently been diagnosed with Osteosarcoma. The statistical analysis of data from the trial indicates that Mepact provides a significant increase in the disease free survival, as well as a significant increase in the overall survival of patients whose treatment includes Mepact versus treatment with chemotherapy alone. The most frequent adverse events were those typically associated with intensive chemotherapy.

Osteosarcoma is the most common form of bone cancer. It primarily occurs in children and adolescents. The incidence is approximately one thousand new cases per year both in the United States and in Europe.

The European Commission grants "orphan medicinal product" designation to medicines products targeting diseases whose prevalence in the European Union does not exceed 5 per 10,000 persons. To encourage the development of new drugs to treat rare diseases, "orphan medicinal product" designation gives companies specific financial and regulatory incentives as well as market exclusivity that, in the European Union, last for ten years after obtaining marketing authorization.

IDM is currently completing its application to regulatory authorities in order to gain approval to market Mepact in the European Union and the United States.

IDM -- The Immunogenics Company(R)

IDM is a biopharmaceutical company focused on the development of innovative products to treat and control cancer while maintaining the patient's quality of life. IDM is currently developing two lines of products: one aiming at the destruction of residual cancer cells after the use of traditional therapies, and the other to prevent tumor recurrence by triggering an immune response. IDM's most advanced product has completed a Phase III clinical trial, five other products are in clinical trials and five are in preclinical development.

For more information, please visit IDM's Web site, http://www.idm-biotech.com.

CONTACT: IDM Nadine Sciacca, +33 (0) 1 40 09 04 11 nsciacca@idm-biotech.com idm@idm-biotech.com
 

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Onyvax Reports Early Success with Osteosarcoma Cancer Vaccine

LONDON APR 19, 2005 (Agence de Presse Medicale for Reuters Health) - The private UK biotech company Onyvax on Tuesday reported positive phase l/ll clinical trial results for its cancer immunotherapy " Onyvax-105" in children and young adults with osteosarcoma.

The vaccine targets the CD55 antibody that is overexpressed in many types of cancer as part of its defence against immune system attack. The investigational drug was given to 31 pediatric and young adults with high-grade osteosarcoma who had completed best standard therapy.

The results showed that most patients receiving intensive chemotherapy for osteosarcoma could still mount an immune response to the cancer vaccine approach, the company said in a statement.

Although the trial was designed to assess feasibility of immunotherapy rather than efficacy, two patients remained tumour-free more than 4 years later.

Dr. Pritchard-Jones, Professor of Childhood Cancer at the Royal Marsden Hospital, London, and principal investigator of the study, said: "This group of patients has limited treatment options and a very poor prognosis.

"We were pleased to see a high percentage of patients developing immune responses to Onyvax-105, confirming that an immunomodulatory approach is feasible in combination with the intensive chemotherapy that these children and young adults require.

"Moreover, it is very unexpected for any patients at this stage of the disease to remain free of recurrent disease for long."

The company reported last year that its lead cancer vaccine, Onyvax-P, had doubled progression free survival time in a small nonrandomised study of men with advanced prostate cancer. Further results are expected this year.
 

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Chemokine Therapeutics reports 67% decrease in metastatic nodules with anti-cancer compound

Wednesday March 16, 7:00 am ET

- TSX symbol: CTI

VANCOUVER, March 16 /PRNewswire-FirstCall/ - Chemokine Therapeutics Corp. (the Company) (Toronto Stock Exchange: CTI), a biotechnology company developing drugs in the field of chemokines and cytokines, today announced that investigators at the National Cancer Institute (NCI) reported a two-thirds reduction in the number of visible metastatic lung nodules using the Company's investigational drug CTCE-9908 in a pre-clinical study of osteosarcoma. The study results are consistent with a pre-clinical study of CTCE-9908 conducted by researchers at Chemokine Therapeutics. CTCE-9908 is designed to inhibit the growth and spread of certain common cancers with the potential for use with existing therapies (chemotherapy, surgery, and radiation) to improve treatment outcomes. Osteosarcoma is a form of bone cancer which can spread (metastasize) to the lungs, bone marrow and liver.

The NCI findings will be the subject of a Poster Session on April 17th at the American Association for Cancer Research (AACR) 2005 Annual Meeting to be held in Anaheim, California. The abstract is available on Chemokine Therapeutics' website at www.chemokine.net. The Company will announce additional information after the poster presentation at the American Association for Cancer Research Conference.

Background on How Cancers Spread and the Potential Role of CTCE-9908

Recently, researchers discovered that the growth and spread of cancer are affected by a chemokine known as stromal cell-derived factor-1 (SDF-1). SDF-1 is produced naturally in organs such as the bone marrow, liver, and lungs and is an important regulator of stem cells. SDF-1 acts on receptors which are expressed in both stem cells and various common cancers. The presence of these receptors on cancer cells allows the cancerous cells to migrate from the original cancer site to new sites that are rich in SDF-1, such as bone marrow, liver, and lungs, where they develop new blood vessels (angiogenesis) and form new tumors (metastases).

CTCE-9908 is an analog of SDF-1 and antagonist of SDF-1 receptors developed by scientists at Chemokine Therapeutics using rational-drug design. CTCE-9908 binds competitively to the receptors on cancer cells which prevents the interaction of SDF-1 with the receptors. A recently completed Phase I study of this compound in healthy adults did not reveal any significant toxicity.

Chemokine's Research Collaboration with the NCI, Bethesda, Maryland

Chemokine has been collaborating with the National Cancer Institute's Pediatric Oncology Branch since February, 2004. The NCI continues to evaluate the oncological potential of CTCE-9908. The NCI is a component of the National Institutes of Health (NIH), one of eight agencies that compose the Public Health Service (PHS) in the Department of Health and Human Services (DHHS). The NCI, established under the National Cancer Act of 1937, is the principal agency for cancer research and training of the United States federal government.

About Chemokine Therapeutics Corp. (Toronto Stock Exchange: CTI)

Chemokine Therapeutics is a biotechnology company developing drugs in the field of chemokines and cytokines, a family of small, soluble proteins, which signal stem cell transport and growth into mature cells. These stem cells are master primitive cells, capable of producing billions of mature cells necessary for repair and regeneration. Chemokines and cytokines also play an important role in cancer and autoimmune disorders which can paradoxically contribute to the survival and growth of such diseases. The Company has two product candidates in clinical trials; CTCE-0214, for immune system recovery, and CTCE-9908, to prevent the spread of cancer and its continued growth. In addition, Chemokine maintains a drug discovery program to identify new chemokine-based drug candidates. Pharmaceutical Product Development, Inc. (PPDI) and Procter & Gamble Pharmaceuticals, Inc. have signed strategic agreements with Chemokine to collaborate on research and development. For more information, please visit our website at www.chemokine.net.

For further information contact:

Chemokine Therapeutics Corp. ---------------------------- Ian Harper, Director of Investor Relations & Corporate Development Phone: (604) 822-0305 E-mail: iharper@chemokine.net Internet: www.chemokine.net

U.S. Media Enquiries -------------------- Richard E. Cooper / Jennifer K. Zimmons, Ph.D. Strategic Growth International Phone: (212) 838-1444 Fax: (212) 838-1511 Email: jzimmons@sgi-ir.com

Canadian Media Enquiries ------------------------ Ross Marshall The Equicom Group Inc. Phone: (416) 815-0700 (Ext.238) Fax: (416) 815-0080 E-mail: rmarshall@equicomgroup.com

Source: Chemokine Therapeutics Corp.

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Effect of Ketoprofen in Topical Formulation on Vascular Endothelial Growth Factor Expression and Tumor Growth in Nude Mice With Osteosarcoma

Abstract

OST cells, a low metastatic cell line established from human osteosarcoma, were inoculated under the periosteum of the ossa cranii of nude mice. Four weeks later, tumors were percutaneously treated for an additional 4 weeks with a patch containing either placebo or ketoprofen (KP). In the placebo group, OST cells formed osteoid and invaded the cranial bone. Tumor mass weighed 3.54 g. Approximately 85% of cells within the tumor expressed proliferating cell nuclear antigen (PCNA), indicating that they were proliferating with a high mitotic activity. Many feeder vessels were located within the tumor. The majority of tumor cells expressed intensely vascular endothelial growth factor (VEGF). In the KP group, invasion of OST cells into the cranial bone was suppressed and the tumor mass was 47% of that of the placebo group. Approximately 65% of cells within the tumor were PCNA-negative, indicating that their growth was arrested. There were considerably fewer feeder vessels within the tumor in the KP group than in the placebo group. Only a small number of cells expressed VEGF. Based on these findings, we concluded that topical administration of KP to nude mice with Osteosarcoma inhibited VEGF expression, reduced the development of feeder vessels for supply of nutrients and oxygen, and suppressed tumor growth.

2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

Keywords: Osteosarcoma; Ketoprofen; Topical formulation; Tumor growth; Vascular endothelial growth factor

For the complete article, please see the Physician Web page Physician Web page

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Original Source Website

Breaking News
Point Therapeutics Reports Additional Preclinical Data Demonstrating Anti-Tumor Activity of Talabostat

Point Therapeutics, Inc. (NASDAQ: POTP) today presented preclinical data on its lead product candidate talabostat, demonstrating tumor growth suppression of several different human tumor types in mice by talabostat acting as a single agent. Results were also presented showing that when combined with docetaxel in a mouse model of human non-small cell lung cancer (NSCLC), the combination achieved greater and more sustained tumor suppression than either agent alone. These results were presented in a poster session at the 2005 American Association of Cancer Research (AACR) Annual Meeting in Anaheim, CA.

In previously published studies, talabostat was shown to elicit anti-tumor T-cell responses in mice with fully functioning immune systems. Results released today advanced this work by demonstrating that talabostat can induce inhibition of tumor growth, independent of T-cell activity, by 60 to 90% in xenograft models of B-cell lymphoma, melanoma, osteosarcoma, head-and-neck cancer, pancreatic cancer and NSCLC. The T-cell independent activity was demonstrated in mice that completely lacked functioning T-cells -- for example, severe combined immunodeficient (SCID) mice. In addition, results show that neutrophils appear to play an important role in the anti-tumor effect of talabostat independent of T-cell activity. Talabostat suppressed tumor growth for at least 30 days in SCID mice, whereas in neutrophil-depleted SCID mice, talabostat had no significant effect.

In the NSCLC immunodeficient mouse model, further results demonstrated a greatly improved anti-tumor effect when talabostat was combined with docetaxel. The anti-tumor effect of docetaxel and PT-100 was significantly (P is less than 0.0005) greater than that of either agent alone. On day 51, single agent treatment with either PT-100 or docetaxel was observed to inhibit tumor growth by 60 to 70%, whereas combination treatment resulted in 90% inhibition.

Today's results combined with previously published studies lead the authors to conclude that talabostat possesses both the potential to enhance the activity of commonly used chemotherapy regimens and the potential to treat human cancers that are refractory to T-cell immune attack. "The tumor volume reductions seen with talabostat in combination with docetaxal and other chemotherapeutic agents in animal models were significant, and clearly superior to those seen with the chemotherapy agents alone," said study author Dr. Barry Jones, Senior Vice President of Research at Point Therapeutics. "These results support our belief that talabostat has the potential to become an important treatment option for cancer patients receiving chemotherapy and further support the rationale for Point Therapeutics' four current Phase 2 clinical programs investigating the use of talabostat in combination with various chemotherapeutics agents in different cancers."

Point Therapeutics also announced today that the Company will present a poster on its Phase 2 NSCLC clinical study and will have two abstracts published on its two Phase 2 metastatic melanoma studies at the American Society for Clinical Oncology Annual Meeting, to be held May 13-17 in Orlando, FL.

About Point Therapeutics, Inc.:

Point Therapeutics, Inc. is a Boston-based biopharmaceutical company developing a family of dipeptidyl peptidase (DPP) inhibitors for a variety of cancers, certain hematopoietic disorders, type 2 diabetes and as vaccine adjuvants. Our lead product candidate, talabostat (PT-100), is a small molecule drug in Phase 2 clinical trials. Talabostat is orally-active and, through a novel mechanism of action, has the potential to inhibit the growth of malignant tumors and to accelerate the reconstitution of the hematopoietic system.

In 2004, we initiated four Phase 2 clinical trials of talabostat. The trials are studying talabostat in combination with Taxotere(R) for the treatment of advanced NSCLC, talabostat as a single agent to treat advanced metastatic melanoma, talabostat in combination with cisplatin also to treat advanced metastatic melanoma, and talabostat in combination with rituximab to treat advanced chronic lymphocytic leukemia (CLL). We are also studying talabostat in clinical trials to potentially prevent both neutropenia and anemia. In addition, our portfolio includes two other DPP inhibitors in preclinical development--PT-630 for type 2 diabetes, and PT-510 as a vaccine adjuvant.

Certain statements contained herein are not strictly historical and are "forward looking" statements as defined in the Private Securities Litigation Reform Act of 1995. This information includes statements on the prospects for our drug development activities and results of operations based on our current expectations, such as statements regarding certain milestones with respect to our clinical program and our product candidates. Forward-looking statements are statements that are not historical facts, and can be identified by, among other things, the use of forward-looking language, such as "believes," "expects," "may," "will," "should," "seeks," "plans," "schedule to," "anticipates" or "intends" or the negative of those terms, or other variations of those terms of comparable language, or by discussions of strategy or intentions. A number of important factors could cause actual results to differ materially from those projected or suggested in the forward looking statement, including, but not limited to, the ability of Point to (i) successfully develop and manufacture products, (ii) obtain external funding to finance the operations, (iii) obtain the necessary regulatory approvals, and (iv) obtain and enforce intellectual property rights, as well as the risk factors described in Point's Prospectus Supplement, filed with the Securities and Exchange Commission on March 15, 2005, and from time to time in Point's other reports filed with the Securities and Exchange Commission.

CONTACT:

Point Therapeutics, Inc. Sarah Cavanaugh, 617-933-7508 or Investor Relations The Trout Group Christine Labaree, 978-697-8463

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1: J Bone Joint Surg Br. 2004 Jan;86(1):143-7. Related Articles,

Concomitant tumour resistance in patients with osteosarcoma. A clue to a new therapeutic strategy.

Kaya M, Wada T, Nagoya S, Kawaguchi S, Isu K, Yamashita T.

Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Hokkaido, Japan.

Concomitant tumour resistance (CTR) is a unique phenomenon in which animals harbouring large primary tumours are resistant to the growth of smaller metastatic tumours by systemic angiogenic suppression. To examine this clinically, in ten patients with osteosarcoma, we investigated the effects of removal of the primary tumour on the development of pulmonary metastases, the systemic angiogenesis-inducing ability and the serum levels of several angiogenesis modulators. We found that removal of the primary tumour significantly elevated systemic angiogenesis-inducing ability in five patients who had post-operative recurrence of the tumour. Post-operative elevation of the angiogenesis-induced ability was suppressed by the addition of an angiogenic inhibitor, endostatin. Also, primary removal of the tumour decreased the serum levels of vascular endothelial growth factor and endostatin. These findings suggest, for the first time, the presence of CTR in patients with osteosarcoma for whom post-operative antiangiogenic therapy may be used to prevent the post-operative progression of micrometastases.
 

Full article (requires subscription to the Journal of Bone and Joint Surgery.)
PMID: 14765882 [PubMed - indexed for MEDLINE]

  Aerosol gemcitabine inhibits the growth of primary osteosarcoma and osteosarcoma lung metastases

^*Correspondence to Nadezhda V. Koshkina, Division Pediatrics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030

Funded by:
 Golfers against Cancer
 Legends of Friendswood

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Orphan Drug Status - a term referring to a product that treats a rare disease affecting fewer than 200,000 Americans established by the Orphan Drug Act of 1983 whereby sponsors are granted seven years of marketing exclusivity.  Tax incentives are given for research and the FDA may also award research grants for conducting clinical studies.

Mouse studies.  Most mouse (murine) studies are done by implanting human Osteosarcoma cells in mice and testing various treatments for effectiveness.  Obviously treatments that work in mice do NOT always work in humans and treatments that do NOT work in mice CAN sometimes work for humans. 

Topical ketoprofen is shown effective in reducing Osteosarcoma metastases rate and local tumor growth rate.

Hyperthermia causes 100% regression of Osteosarcoma tumors in animal models

 
Matsuoka F
Shinkai M
Honda H
Kubo T
Sugita T
Kobayashi T

.
Hyperthermia using magnetite cationic liposomes for hamster osteosarcoma
Fumiko Matsuoka1 , Masashige Shinkai1 , Hiroyuki Honda1 , Tadahiko Kubo2 , Takashi Sugita2 and Takeshi Kobayashi1
1Department of Biotechnology, School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
2Department of Orthopaedic Surgery, Hiroshima University School of Medicine, 2-3, Kasumi 1 chome, Minami-ku, Hiroshima 734-8551, Japan

BioMagnetic Research and Technology 2004, 2:3 doi:10.1186/1477-044X-2-3


© 2004 Matsuoka et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
Abstract



Background

We have developed magnetite cationic liposomes (MCLs) and applied them to local hyperthermia as a mediator. MCLs have a positive charge and generate heat under an alternating magnetic field (AMF) by hysteresis loss. In this study, the effect of hyperthermia using MCLs was examined in an in vivo study of hamster osteosarcoma.

Method

MCLs were injected into the osteosarcoma and then subjected to an AMF.

Results

The tumor was heated at over 42°C (106.7°F), but other normal tissues were not heated as much. Complete regression was observed in 100% of the treated group hamsters, whereas no regression was observed in the control group hamsters. At day 12, the average tumor volume of the treated hamsters was about 1/1000 of that of the control hamsters. In the treated hamsters, no regrowth of osteosarcomas was observed over a period of 3 months after the complete regression.

Conclusion

These results suggest that this treatment is effective for osteosarcoma.


Magnetite nanoparticles have been used in biological and medical applications, such as the separation of biological materials using magnetically labeled beads [1], drug delivery and medicine [2], or cell sorting, based on the fact that high magnetic flux density attracts magnetically labeled cells [3-5]. We previously developed "magnetite cationic liposomes" (MCLs), which are cationic liposomes containing 10-nm magnetite nanoparticles, in order to improve the accumulation of magnetite nanoparticles in target cells using the electrostatic interaction between MCLs and the cell membrane [6]. Currently, we have developed a tissue engineering technique using MCLs [7-9]. Mesenchymal stem cells (MSCs), which can differentiate into multiple mesodermal tissues, can be isolated from bone marrow in a small number. Magnetically labeled MSCs were easily prepared, because our MCLs exhibited no toxicity against the MSCs in proliferation and differentiation, and then the MSCs were enriched into the localized area that the magnetic force can reach. Cell growth was promoted and a five-fold increase in cell number was obtained at 7 days after cell seeding [7]. To establish 3D in vivo-like tissues consisting of various types of cells, we applied MCLs to the co-culture system of rat hepatocytes and human aortic endothelial cells (HAECs). Magnetically labeled HAECs accumulated onto hepatocyte monolayers by magnetic force to form a heterotypic, layered construct with tight and close contact. Albumin secretion by hepatocytes was about three times higher than that of the control co-culture system without magnetic force [8]. MCLs were also applied to construct multilayered keratinocyte sheets. On a 24-well ultra-low-attachment plate, a 5-layered keratinocyte sheet was first produced and a 10-layered epidermal sheet was formed in a high-calcium medium. The sheet formed ordinarily was detached from the bottom of the plate when the magnet was removed, and transplantation to the patient was easily performed [9]. We have termed this culture methodology as "magnetic force-based tissue engineering (Mag-TE)". We have also used MCLs as a heating mediator for cancer hyperthermia, because magnetite nanoparticles generate heat under an alternating magnetic field (AMF) [10-13].

Hyperthermia is one of the promising approaches in cancer therapy, and various methods have been employed in hyperthermia [14,15]. The most commonly used heating method in clinical settings is capacitive heating using a radiofrequency (RF) electric field [16]. However, heating tumors specifically by capacitive heating using an RF electric field is difficult, because the heating characteristics are influenced by various factors such as tumor size, position of electrodes, and adhesion of electrodes at uneven sites. From a clinical point of view, a simple heat mediator is more desirable not only for superficially located tumors but also for deep-seated tumors. Some researchers have proposed inductive heating methods, using submicron magnetic particles, for hyperthermia [17,18]. We have also developed MCLs for intracellular hyperthermia [6,10,11], which showed a ten-fold higher affinity for the tumor cells than neutrally charged magnetoliposomes [10]. Based on this feature, MCLs can be highly superior heating mediators. We previously demonstrated the efficacy of MCL-mediated hyperthermia in animals with several types of tumors, including B16 mouse melanoma [19,20], T-9 rat glioma [11,21], renal cell carcinoma [22], and VX-7 squamous cell carcinoma in rabbit tongue [23]. We also reported complete regression of mouse mammary carcinoma, larger than 15 mm in size, by frequent repeated hyperthermia [24]. Although MCL-mediated hyperthermia was found to be very effective for inducing complete regression of tumors, no studies have investigated the biodistribution of MCLs after local injection.

Osteosarcoma is a primary malignant tumor of the bone that mostly occurs in growing children and young adults [25]. Effective systemic adjuvant chemotherapy on the primary tumor and improvements in surgical resection techniques have improved the survival rate. However, these have not proved to be sufficiently effective, and a more effective protocol for the prevention and treatment of osteosarcoma is needed.

Therefore, in the present paper, our hyperthermia system was applied to hamster osteosarcoma and its hyperthermic effect was investigated.

Animals and osteosarcoma models

Three-week-old Syrian female hamsters were purchased from Japan SLC, Inc., Shizuoka, Japan, and used for the animal study.

Experimentally transplantable osteosarcoma Os515, induced by the BK virus, was used [25]. Since it was very difficult to culture the cells in a liquid medium using a dish, the osteosarcoma tissue of Os515 was maintained by the transplanting it in the Syrian hamsters.

Preparation of tumor-bearing hamsters

Minced osteosarcoma fragments (100 μ l) were transplanted into the subcutaneous layer of the back of Syrian female hamsters, which were anesthetized by an intraperitoneal injection of sodium pentobarbital (50 mg/kg body weight). Tumor size was measured every 3 days. The volume and the ratio of tumor volume were determined by the following formulas [10]:

Sarcoma volume = 0.5 × (length × width2)

Ratio of tumor volume = (sarcoma volume on each day) / (sarcoma volume before hyperthermia),

where the unit of length and width is expressed in centimeters.

Animal experiments were performed according to the principles laid down in the "Guide for the Care and Use of Laboratory Animals" prepared under the directions of the Office of the Prime Minister of Japan.

Preparation of MCLs

Magnetic particles were kindly donated by Toda Kogyo Co. (Hiroshima, Japan; average particle size of magnetite: 10 nm). MCLs were prepared using the previously described sonication method, with slight modification [6]. Briefly, 1 ml of colloidal magnetite (net 20 mg magnetite) was coated with a lipid membrane that consisted of N-(α-trimethylammonioacetyl) didodecyl-D-glutamate chloride (Sogo Pharmaceutical Co., Tokyo), dilauroylphosphatidylcholine, and dioleoylphosphatidylethanolamine (Sigma Chemical Co., St. Louis, MO, USA) in a molar ratio of 1:2:2. Magnetite concentration was measured using the potassium thiocyanate method [22].

Hyperthermia treatment

After the tumors had grown to about 10 mm in diameter, a syringe (25 G needle) containing MCLs was longitudinally inserted into each osteosarcoma nodule, subcutaneously from the nodule edge. MCLs (0.4 ml, net magnetite weight: 3 mg) were injected using an infusion pump (SP100i; World Precision Instruments Inc., Sarasota, FL, USA) for 30 min. The hamsters were then separated into control (n = 4) and treatment (n = 4) groups. The hamsters in group I (control) were not subjected to AMF. In group II (treatment group), 24 h after the injection, the hamsters were subjected to the first hyperthermia treatment after being anesthetized by an intraperitoneal injection of sodium pentobarbital (50 mg/kg body weight). A magnetic field was created using a horizontal coil (inner diameter, 7 cm; length, 7 cm) with a transistor inverter (LTG-100-05; Dai-ichi High Frequency Co., Tokyo). The magnetic field frequency was 118 kHz. The hamster was placed inside the coil such that the nodule was positioned at the center of the coil. Temperatures at the surface of the tumor tissue and in the rectum during AMF were measured by an optical fiber probe (FX-9020; Anritsu Meter Co., Tokyo). The treatment was carried out for 30 min, three times at 24 h intervals.



Figure 1 shows the temperature increase at the outside skin covering the osteosarcoma and in the rectum. The temperature of the osteosarcoma was rapidly elevated by magnetic heating and reached over 42°C (106.7°F) after 10 min; it was maintained at the same temperature by controlling the magnetic field intensity. In contrast, the temperature in the rectum remained between 37–39°C. (98.6-102.2°F.)  These results indicate that using MCLs for hyperthermia makes it feasible to heat only tumor, and not damage healthy tissues.

Monitoring tumor growth after hyperthermia

Figure 2 shows the time courses of osteosarcoma growth in the control and treatment groups. In the control group, the growth ratio of osteosarcoma in each hamster steadily increased with no evidence of regression. In contrast, complete regression of osteosarcoma was observed in 100% of the hamsters in the treatment group. In two cases, the osteosarcoma volume increased until day 4 or 10, after which it began to decrease and finally disappeared. Figure 3 shows photographs of typical hamsters from the treatment (A) and control (B) groups, at day 20 after the MCL injection. Osteosarcomas in the treatment group hamsters clearly disappeared and the skin was also quite normal.

In the treatment group, all osteosarcomas disappeared by day 15 and no regrowth of osteosarcomas was observed over a period of 3 months. As shown in Table 1, tumor volume was compared at day 12 of the MCL injection, because two control hamsters died on day 12. At day 12 of the MCL injection, 75% of the osteosarcomas disappeared, and the average tumor volume of the treated hamsters was about 1/1000 that of the control hamsters. Although there were only four hamsters in each group, it has been proven that our hyperthermia was a significantly effective treatment for osteosarcoma.



The treatment of osteosarcoma usually involves the administration of anticancer drugs or surgery or a combination of both. In such cases, several side effects of drugs and the mutilation of arms or legs cause patients additional pain. Hyperthermia is a promising approach for the treatment of osteosarcoma. Although radiofrequency capacitive heating has performed well as a heating method, electric waves cannot be focused on the tumor tissue and may affect, and thereby damage, normal bone tissue. Therefore, although several researchers have proposed simulation of heating to prevent such side effects [26,27], it is not a fundamental solution. Inductive heating has a great advantage of hyperthermia for osteosarcoma in bone because the magnetic field used in this therapy does not cause bone decay. Takegami et al. have proposed a ferromagnetic bone cement as a thermoseed to generate heat by hysteresis loss under an AMF [28]. The heat-generating ability was investigated using rabbit and human cadaver tibiae in which this thermoseed was implanted. By applying a magnetic field with a maximum of 300 Oe and 100 kHz, it was found that the temperature increase of the thermoseed implanted bone was beyond 50°C. However, implanted magnetic cement remains in patient bone. Therefore, it should be carefully investigated whether long-term deposits of magnetite affects patient health, that is, acute and/or chronic toxicity by excess absorption of Fe ions, e.g., hemochromatosis [29]. In our previous study, the magnetic particles administered were completely cleared from the body within 10 days in the case of mice [30].

We have performed hyperthermia using magnetic particles against brain tumor, tongue cancer, kidney cancer, and a malignant melanoma. In the present study, the effect of hyperthermia was investigated against a hamster osteosarcoma. Although it is an elementary investigation using subcutaneous tumor, the anti-tumor effect against the osteosarcoma was confirmed. Moreover, it should be noted that the treatment temperature was only 42°C (107.6°F.) In the case of melanoma-bearing mice, a more efficient treatment effect was observed when the treatment at 46°C (115°F) was carried out and complete regression was obtained [19]. In addition, mouse mammary carcinoma, larger than 15 mm in size, was also completely regressed. Furthermore, all large tumors disappeared within 70 days when frequent repeated treatment involving MCL injection was carried out, whereas all control mice died within 52 days [24]. Therefore, sufficient treatment effect can be also expected for large osteosarcomas and/or malignant invasive orteosarcoma.

From the present results, it can also be stated the essential advantage of hyperthermia, i.e., the fact that the hyperthermic effect is independent of the type of cancer cell, was reconfirmed. We succeeded in demonstrating the hyperthermic effect using a hamster model in addition to mouse, rat, and rabbit. The present results prove that hyperthermia is a reliable and effective cancer therapy across species.

In future work, it is necessary to study the medical effects against osteosarcomas that originate in bone cells, such as in the femur. In this case, it will be necessary to monitor the distribution of magnetic particles in the tumor and/or bone marrow. When a dense magnetic particle solution is flowed to the bone marrow, the toxic effect to the systemic immune system should be carefully investigated. If particles are localized into the tumor tissues in the bone, it will be easy to heat the tumor because heat quenching by the blood flow is ignored and a high hyperthermic effect will be expected.


Acknowledgments



This work was supported in part by Grants-in-Aid for Scientific Research (No. 13853005, 12558106) from the Ministry of Education, Science, Sports and Culture of Japan.



1. Safarikova M, Safarik I: The application of magnetic techniques in biosciences.
Magn Electr Sep 2001, 10:223-252. OpenURL
Return to citation in text: [1]

2. Saiyed ZM, Telang SD, Ramchand CN: Application of magnetic techniques in the field of drug discovery and biomedicine.
BioMagn Res Technol 2003, 1:2. [PubMed Abstract] [BioMed Central Full Text] OpenURL
Return to citation in text: [1]

3. Miltenyi S, Muller W, Weichel W, Radbruch A: High gradient magnetic cell separation with MACS.
Cytometry 1990, 11:231-238. [PubMed Abstract] OpenURL
Return to citation in text: [1]

4. Radbruch A, Mechtold B, Thiel A, Miltenyi S, Pfluger E: High-gradient magnetic cell sorting.
Methods Cell Biol 1994, 42:387-403. [PubMed Abstract] OpenURL
Return to citation in text: [1]

5. Safarik I, Safarikova M: Use of magnetic techniques for the isolation of cells.
J Chromatogr Biomed Sci Appl 1999, 722:33-53. [Publisher Full Text] OpenURL
Return to citation in text: [1]

6. Shinkai M, Yanase M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T: Intracellular hyperthermia for cancer using magnetite cationic liposomes: in vitro study.
Jpn J Cancer Res 1996, 87:1179-1183. [PubMed Abstract] OpenURL
Return to citation in text: [1] [2] [3]

7. Ito A, Hibino E, Honda H, Hata K, Kagami H, Ueda M, Kobayashi T: A new methodology of mesenchymal stem cell expansion using magnetic nanoparticles.
Biochem Eng J 2004, in press. OpenURL
Return to citation in text: [1] [2]

8. Ito A, Takizawa Y, Honda H, Hata K, Kagami H, Ueda M, Kobayashi T: Tissue engineering using magnetite nanoparticles and magnetic force: heterotypic layers of co-cultured hepatocytes and endothelial cells.
Tissue Eng 2004, in press. OpenURL
Return to citation in text: [1] [2]

9. Ito A, Hayashida M, Honda H, Hata K, Kagami H, Ueda M, Kobayashi T: Construction and harvest of multilayered keratinocyte sheets using magnetite nanoparticles and magnetic force.
Tissue Eng 2004, in press. OpenURL
Return to citation in text: [1] [2]

10. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T: Intracellular hyperthermia for cancer using magnetite cationic liposomes: ex vivo study.
Jpn J Cancer Res 1997, 88:630-632. [PubMed Abstract] OpenURL
Return to citation in text: [1] [2] [3] [4]

11. Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T: Intracellular hyperthermia for cancer using magnetite cationic liposomes: an in vivo study.
Jpn J Cancer Res 1998, 89:463-469. [PubMed Abstract][Publisher Full Text] OpenURL
Return to citation in text: [1] [2] [3]

12. Ito A, Matsuoka M, Honda H, Kobayashi T: Antitumor effects of combined therapy of recombinant heat shock protein 70 and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma.
Cancer Immunol Immunother 2004, 53:26-32. [PubMed Abstract][Publisher Full Text] OpenURL
Return to citation in text: [1]

13. Ito A, Matsuoka F, Honda H, Kobayashi T: Heat shock protein 70 gene therapy combined with hyperthermia using magnetic nanoparticles.
Cancer Gene Ther 2003, 10:918-925. [PubMed Abstract][Publisher Full Text] OpenURL
Return to citation in text: [1]

14. Stauffer PR, Cetas TC, Jones RC: System for producing localized hyperthermia in tumors through magnetic induction heating of ferromagnetic implants.
Natl Cancer Inst Monogr 1982, 61:483-487. OpenURL
Return to citation in text: [1]

15. Brezovich IA, Atkinson WJ, Lilly MB: Local hyperthermia with interstitial techniques.
Cancer Res 1984, 44(Suppl 10):4752s-4756s. [PubMed Abstract] OpenURL
Return to citation in text: [1]

16. Ikeda N, Hayashida O, Kameda H, Ito H, Matsuda T: Experimental study on thermal damage to dog normal brain.
Int J Hyperthermia 1994, 10:553-561. [PubMed Abstract] OpenURL
Return to citation in text: [1]

17. Lin JC, Wang YJ: Interstitial microwave antennas for thermal therapy.
Int J Hyperthermia 1987, 3:37-47. [PubMed Abstract] OpenURL
Return to citation in text: [1]

18. Stauffer PR, Cetas TC, Fletcher AM, DeYoung DW, Dewhirst MW, Oleson JR, Roemer RB: Observations on the use of ferromagnetic implants for inducing hyperthermia.
IEEE Trans Biomed Eng 1984, 31:76-90. [PubMed Abstract] OpenURL
Return to citation in text: [1]

19. Suzuki M, Shinkai M, Honda H, Kobayashi T: Anti-cancer effect and immune induction by hyperthermia of malignant melanoma using magnetite cationic liposomes.
Melanoma Res 2003, 13(2):129-135. [PubMed Abstract][Publisher Full Text] OpenURL
Return to citation in text: [1] [2]

20. Ito A, Tanaka K, Kondo K, Shinkai M, Honda H, Matsumoto K, Saida T, Kobayashi T: Tumor regression by combined immunotherapy and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma.
Cancer Sci 2003, 94:308-313. [PubMed Abstract][Publisher Full Text] OpenURL
Return to citation in text: [1]

21. Shinkai M, Yanase M, Suzuki M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T: Intracellular hyperthermia for cancer using magnetic cationic liposomes.
J Magn Magn Mater 1999, 194:176-184. [Publisher Full Text] OpenURL
Return to citation in text: [1]

22. Shinkai M, Le B, Honda H, Yoshikawa K, Shimizu K, Saga S, Wakabayashi T, Yoshida J, Kobayashi T: Targeting hyperthermia for renal cell carcinoma using human MN antigen-specific magnetoliposomes.
Jpn J Cancer Res 2001, 92:1138-1145. [PubMed Abstract][Publisher Full Text] OpenURL
Return to citation in text: [1] [2]

23. Matsuno H, Thonai I, Mitsudo K, Hayashi Y, Ito M, Shinkai M, Kobayashi T, Yoshida J, Ueda M: Interstitial hyperthermia using magnetite cationic liposomes inhibit to tumor growth of VX-7 transplanted tumor in rabbit tongue.
Jpn J Hyperthermic Oncol 2001, 17:141-149. OpenURL
Return to citation in text: [1]

24. Ito A, Tanaka K, Honda H, Abe S, Yamaguchi H, Kobayashi T: Complete regression of mouse mammary carcinoma with a size greater than 15mm by frequent repeated hyperthermia using magnetite nanoparticles.
J Biosci Bioeng 2003, 96:364-369. OpenURL
Return to citation in text: [1] [2]

25. Sekiguchi M, Satomura T, Saegusa M, Takeuchi H, Asanuma K, Shimoda T: An experimental transplantable osteosarcoma with spontaneous pulmonary metastasis in hamsters.
Int J Exp Pathol 1994, 75:51-60. [PubMed Abstract] OpenURL
Return to citation in text: [1] [2]

26. Ohura K, Ikenaga M, Nakamura T, Yamamuro T, Ebisawa Y, Kokudo T, Kotoura Y, Oka M: A heat-generating bioactive glass-ceramic for hyperthermia.
J Appl Biomater 1991, 2:153-159. [PubMed Abstract] OpenURL
Return to citation in text: [1]

27. Luderer AA, Borrelli NF, Panzarino JN, Mansfield GR, Hess DM, Brown JL, Barnett EH, Hahn EW: Glass-ceramic-mediate, magnetic-field-induced localized hyperthermia: response of a murine mammary carcinoma.
Radiat Res 1983, 94:190-198. [PubMed Abstract] OpenURL
Return to citation in text: [1]

28. Takegami K, Sano T, Wakabayashi H, Sonoda J, Yamazaki T, Morita S, Shibuya T, Uchida A: New ferromagnetic bone cement for local hyperthermia.
J Biomed Mater Res 1998, 43:210-214. [PubMed Abstract][Publisher Full Text] OpenURL
Return to citation in text: [1]

29. Pippard MJ: Iron deficiency and overload. In: Oxford Textbook of Medicine.
Oxford University Press, England 1990, 19.83-19.91. OpenURL
Return to citation in text: [1]

30. Ito A, Nakahara Y, Tanaka K, Kug Honda H, Kobayashi T: Time course of biodistribution and heat generation of magnetite cationic liposomes in mouse model.
Jpn J Hyperthemic Oncol 2004, 19:131-139. OpenURL
Return to citation in text: [1]




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 IDM Successfully Manufactures First Lot of Junovan(TM) to Support Filing for Marketing Authorization

SAN DIEGO, Sept. 22 /PRNewswire-FirstCall/ -- IDM Pharma, Inc.
(Nasdaq: IDMI) today announced that it has produced a first lot of Junovan
(previously known as L-MTP-PE or MEPACT) that meets current specifications as
well as the prior specifications for the product used in the conduct of the
Phase III study in patients with high grade non-metastatic osteosarcoma, the
indication for which IDM will be seeking marketing authorization. The Company
achieved this important milestone with its key contract manufacturers, Genzyme
Pharmaceuticals, Liestal, Switzerland; NOF Corporation, Tokyo, Japan; Ben
Venue Laboratories, Cleveland, Ohio and Solvias AG, Basel, Switzerland.
"We are pleased to be working with world-class contract manufacturers as
this is an essential step for IDM to ensure we have GMP product that not only
meets current requirements, but that will also be sufficiently comparable to
the previous product utilized during clinical development so that the
development data can be used to support approval," said Jean-Loup
Romet-Lemonne, IDM's Chairman and CEO. "We intend to initiate comparability
studies with the new IDM product immediately. A proposed protocol for
demonstration of comparability is currently under review by the FDA."

About Junovan(TM)
Junovan is a liposomal formulation of MTP-PE (Muramyl Tripeptide
Phosphatidylethanolamine) specifically designed for in vivo targeting of
macrophages by intravenous infusion. It is a fully synthetic derivative of
muramyl dipeptide, a naturally occurring component of bacterial cell walls.
Junovan has been evaluated in Phase II and Phase III clinical trials for the
treatment of osteosarcoma. The IDM Phase III trial was the largest ever
published in osteosarcoma and demonstrated improvement in disease-free and
overall survival among patients with non-metastatic, resectable osteosarcoma,
who were treated with L-MTP-PE, corresponding to a relative reduction in the
risk of recurrence of 25% and a relative reduction in the risk of death of
30%. Adverse events associated with the use of Junovan are generally mild to
moderate and thought to be associated with its biological activity. Severe
adverse events in the Phase III study were those typically associated with
high dose multiple-drug chemotherapy, which was used together with Junovan in
the Phase III trial.
Junovan for the treatment of osteosarcoma is IDM's lead product candidate.
Junovan has received Orphan Drug Status in both the U.S. and EU, and the
Company is working with U.S. and EU regulatory agencies regarding the
appropriate pathway for product marketing approval. The Company expects to
receive regulatory approval for Junovan in the U.S. and EU in 2007.


About IDM Pharma
IDM is a biopharmaceutical company focused on the development of
innovative products that activate the immune system to treat cancer and
infectious disease. IDM is currently developing three types of products: the
first is designed to destroy cancer cells by activating innate immunity, the
second to prevent tumor recurrence by triggering a specific adaptive immune
response, and the third to treat chronic infectious disease with therapeutic
vaccines.
IDM currently has 7 products in clinical development. The most advanced
product, Junovan(TM), has completed a Phase III clinical trial in
osteosarcoma. Three products are in Phase II clinical trials in bladder
cancer, melanoma and non-small cell lung cancer, and three are in Phase I in
colorectal cancer, hepatitis B and HIV infection.
IDM has major product development partnerships with SANOFI-AVENTIS in
cancer immunotherapy, and with INNOGENETICS in vaccine development for the
treatment of chronic hepatitis B and C and papilloma virus infection. MEDAREX
and SANOFI-AVENTIS are corporate partners and shareholders of IDM or its
affiliate since 1993 and 2001 respectively.

For more information, visit http://www.idm-pharma.com.



SOURCE IDM Pharma, Inc.
Issuers of news releases and not PR Newswire are solely responsible for the accuracy of the content.
Terms and conditions, including restrictions on redistribution, apply.
 

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Zoledronic acid suppresses lung metastases and prolongs overall survival of osteosarcoma-bearing mice

Benjamin Ory, M.D. 1, Marie-Françoise Heymann, M.D. 2, Akira Kamijo, M.D., Ph.D. 3, François Gouin, M.D., Ph.D. 1, Dominique Heymann, Ph.D. 1 *, Françoise Redini, Ph.D. 1

1Universite de Nantes EA 3822; INSERM ERI 7, Physiopathologie de la Resorption Osseuse et Therapie des Tumeurs Osseuses Primitives, Faculte de Medecine, Nantes, France 2Departement de Pathologie, Hopital Nord Laennec, St. Herblain, France 3Department of Orthopedic Surgery, Yokohama City University, School of Medicine, Yokohama, Japan

email: Dominique Heymann (dominique.heymann@univ-nantes.fr)

^*Correspondence to Dominique Heymann, Universite de Nantes EA 3822; INSERM ERI 7, Physiopathologie de la Resorption Osseuse et Therapie des Tumeurs Osseuses Primitives, Faculte de Medecine, 1 rue Gaston Veil, 44035 Nantes cedex 1, France

Fax: (011) 33 2 40 41 28 60

Funded by:
 Ministere de la Recherche; Grant Number: ACI TS/0220044
 Comite des Pays de Loire de la Ligue Contre le Cancer

BACKGROUND

Although there is no doubt that bisphosphonates (BPs), specific inhibitors of osteoclasts, are beneficial for the treatment of bone metastases, their effects on visceral metastases are unclear. The effect of zoledronic acid (ZOL) was examined in vivo on lung metastasis progression and animal survival, and in vitro on the cellular mechanisms involved.

METHODS

An animal model of lung metastasis was developed in C3H/He mice inoculated intravenously with a spontaneous murine osteosarcoma POS-1 cell line. Lung metastasis was determined at the time of autopsy. ZOL was assessed in vitro on POS-1 cell proliferation, cell cycle progression, and caspase-1 and -3 activities.

RESULTS

The overall survival in five independent experiments (two series treated with ZOL 0.1 mg/kg twice a week, and three series with 0.1 mg/kg five times a week) showed a significant increase of the actuarial survival: 0.422 ± 0.07 in ZOL-treated animals versus 0.167 ± 0.07 in controls (P = 0.036). Lung metastases were absent in all ZOL-treated mice that survived more than 21 days postinjection as revealed by macroscopic and histologic analysis. In vitro, a 48-hour incubation with 10 M ZOL inhibited POS-1 cell line proliferation associated with cell cycle arrest in S-phase. In addition, ZOL induced a weak increase of caspase-3 activity, but not caspase-1.

CONCLUSION

We demonstrate that ZOL exerts a direct antitumor effect on POS-1 cells in vitro, significantly diminishes osteosarcoma-induced lung metastasis in vivo, thereby prolonging survival of POS-1-inoculated animals. Cancer 2005. © 2005 American Cancer Society.

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S. Korean scientists find protein that helps predict spread of bone cancer

SEOUL, April 26 (Yonhap) -- South Korean scientists on Thursday said they have found a method to predict the spread of bone cancer to internal organs that could help saves lives.

Kim Min-suk and Jeon Dae-geun at the Korea Institute of Radiological and Medical Sciences said clinical observations on 64 patients over three years have shown a close correlation between the presence of ezrin protein and bone cancer metastasis.

Bone cancer, also called osteosarcoma, is a rare form of cancer that usually strikes teenagers. The cancer is hard to treat because while surgery can remove malignant tumors, there is a chance that the cancer can metastasize and invade distant tissues and organs. The mortality rate for a person who has contracted the illness is 40 percent.

"Of the 33 people who tested positive for the ezrin protein, 21 suffered from cancerous tumors invading distant tissues and organs," said Kim. In the 31 cases where no ezrin protein was detected, only one patient had to undergo treatment after the cancer metastasized.

The findings, released in the Journal of Clinical Orthopedics and Related Research, represent the first time that scientists have found a direct link between the protein and the spread of bone cancer. In the past, ezrin was used to determine if cancer cells had been completely destroyed after surgery or other forms of treatment.

The scientists also said that the newly discovered link could help prevent relapse among patients who have already been treated for cancer.

yonngong@yna.co.kr

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Received for publication July 13, 2006.
Revised October 18, 2006.
Accepted for publication October 18, 2006.

Zoledronic acid activates the DNA S phase checkpoint and induces osteosarcoma cell death characterized by AIF and EndoG translocation independently of p53 and Rb status

Abstract

The molecular mechanisms responsible for the cellular effects of the nitrogen containing bisphosphonate Zoledronic acid (Zol) was assessed on several osteosarcoma cell lines differing in their p53 and Rb status. Zol inhibited cell proliferation and increased atypical apoptosis. The Zol-effects on proliferation were due to cell cycle arrest in S and G2/M phases subsequent to the activation of the intra S DNA damage checkpoint with an increase of P-ATR, P-chk1, Wee1, P-cdc2 levels and a decrease of cdc25c, regardless of the p53 and Rb status. In addition, the atypic apoptosis induced by Zol was independent of caspase activation and was characterized by nuclear alterations, increased Bax expression and reduced Bcl2 level. Furthermore, mitochondrial permeability was also upregulated by Zol, independently of p53 in association with the translocation of Apoptosis Inducing Factor (AIF) and Endonuclease-G (EndoG). Zol also disturbed cytoskeletal organization, cells junctions, inhibited cell migration and phosphorylation of focal adhesion kinases. The main difficulty encountered in treating cancer relates to mutations in key genes such as p53, Rb or proteins affecting caspase signalling carried by many tumor cells. We have demonstrated for the fisrt time that Zoledronic acid activated the DNA damage S phase checkpoint, the mitochondrial pathway via AIF and EndoG translocation, inhibited cell proliferation and induced cell death bypassing these potentials mutations. Therefore Zoledronic acid may be considered as an effective therapeutic agent in clinical trials of osteosarcoma in which mutation for p53 and Rb very often occur, and where current treatment with traditional chemotherapeutic agents are ineffective.

Key words: Mechanisms of cell killing/apoptosis, Pharmacokinetics, metabolism and activation, Tumor suppressors, Cholesterol metabolism/lipoproteins

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'Promising drug' for child cancer
Laboratory tests suggest a new drug may prove effective in tackling three types of childhood cancer, a scientific conference has heard.

The drug RH1 was able to kill tumour cells from neuroblastoma, osteosarcoma and Ewing's sarcoma, all of which can be resistant to current treatment.

In a pre-clinical study, University of Manchester scientists found the drug could boost cancer cell death by 50%.

They now want to hold a clinical trial involving children with cancer.

RH1 effectively encourages cancer cells to kill themselves.

All cells have an inbuilt suicide mechanism which becomes active when they become damaged or grow uncontrollably, but in cancer cells this mechanism either switches off or stops working properly.

From adult to child

The first stage of a clinical trial of RH1 in adult cancer patients has been completed, and has been found to be particularly effective in tumours with a certain sort of enzyme - DT-diaphorase - found in cancers of the lung, liver and breast.

In many cases, patients become resistant to their drugs and need new options
Dr Bruce Morland
CCLG

Dr Guy Makin, the study's lead researcher at Cancer Research UK's Paterson Institute, said it was "very exciting" to be able to work with a drug for children that had only just completed the first stage of adult trials.

"We hope that this will be just the first of many new agents that we can show are useful for treating childhood cancer," he told the National Cancer Research Institute Conference in Birmingham.

According to Cancerbacup, some 100 children develop neuroblastoma and around 60 children develop osteosarcomas or Ewing's sarcoma in the UK each year.

"Survival rates for children with cancer are high at 75%," said Dr Bruce Morland, chairman of the Children's Cancer and Leukaemia Group (CCLG).

"But in many cases, patients become resistant to their drugs and need new options."

One parent of a child who had been blinded by neuroblastoma at 18 months old welcomed the news.

"We were devastated to hear that Louis had neuroblastoma, and finding out that he had been blinded by the disease was really hard to deal with," said Michael Moorhouse, from Bradford.

"He's now doing well and is like any other six-year-old boy, enjoying life and pursuing his passion for drumming.

"It's really encouraging to see new research like this that could help children like Louis in the future."

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November 28, 2004

Danish Research Confirms Rath Discovery: Enzyme Block Stops Cancer Spread

Research done at Copenhagen University and published in the International Journal of Cancer confirms a discovery made by Dr. Mathias Rath, the controversial founder of a new direction in health care called Cellular Medicine. The Danish study found that the enzyme urokinase plasminogen activator plays a critical role in the spread of cancer. Absence of the enzyme prevents the forming of metastases.

While the Danish researchers are now looking for a medication capable of eliminating the enzyme, Dr. Rath and his researchers have already found that our bodies have a natural mechanism that blocks the enzyme, which can be reinforced by abundantly supplying certain nutrients: vitamin C and the aminoacids lysine and proline.

Notorious "quackbuster" Stephen Barrett put his foot in his mouth when he cited a comment from the Swiss Study Group for Complementary and Alternative Methods in Cancer (SKAK) and the Swiss Cancer League (SCL) that Rath's discovery was not somehing to be reckoned with, as it had "never been scientifically tested". A very lazy way of making nothing of someone else's discovery, to be sure, but one that is widely used by the current pharma/medical establishment when it comes to "warning" of natural cures that could significantly cut into pharma profits by using non-patentable substances such as simple nutrients to fight disease.

Matthias Rath Institute

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How Vitamin C Stops Cancer

Science Daily — Nearly 30 years after Nobel laureate Linus Pauling famously and controversially suggested that vitamin C supplements can prevent cancer, a team of Johns Hopkins scientists have shown that in mice at least, vitamin C - and potentially other antioxidants - can indeed inhibit the growth of some tumors ¯ just not in the manner suggested by years of investigation.
The conventional wisdom of how antioxidants such as vitamin C help prevent cancer growth is that they grab up volatile oxygen free radical molecules and prevent the damage they are known to do to our delicate DNA. The Hopkins study, led by Chi Dang, M.D., Ph.D., professor of medicine and oncology and Johns Hopkins Family Professor in Oncology Research, unexpectedly found that the antioxidants' actual role may be to destabilize a tumor's ability to grow under oxygen-starved conditions. Their work is detailed this week in Cancer Cell.

"The potential anticancer benefits of antioxidants have been the driving force for many clinical and preclinical studies," says Dang. "By uncovering the mechanism behind antioxidants, we are now better suited to maximize their therapeutic use."

"Once again, this work demonstrates the irreplaceable value of letting researchers follow their scientific noses wherever it leads them," Dang adds. (Yessss.)

The authors do caution that while vitamin C is still essential for good health, this study is preliminary and people should not rush out and buy bulk supplies of antioxidants as a means of cancer prevention.

The Johns Hopkins investigators discovered the surprise antioxidant mechanism while looking at mice implanted with either human lymphoma (a blood cancer) or human liver cancer cells. Both of these cancers produce high levels of free radicals that can be suppressed by feeding the mice supplements of antioxidants, either vitamin C or N-acetylcysteine (NAC).

However, when the Hopkins team examined cancer cells from cancer-implanted mice not fed the antioxidants, they noticed the absence of any significant DNA damage. "Clearly, if DNA damage was not in play as a cause of the cancer, then whatever the antioxidants were doing to help was also not related to DNA damage," says Ping Gao, Ph.D, lead author of the paper.

That conclusion led Gao and Dang to suspect that some other mechanism was involved, such as a protein known to be dependent on free radicals called HIF-1 (hypoxia-induced factor), which was discovered over a decade ago by Hopkins researcher and co-author Gregg Semenza, M.D., Ph.D., director of the Program in Vascular Cell Engineering. Indeed, they found that while this protein was abundant in untreated cancer cells taken from the mice, it disappeared in vitamin C-treated cells taken from similar animals.

"When a cell lacks oxygen, HIF-1 helps it compensate," explains Dang. "HIF-1 helps an oxygen-starved cell convert sugar to energy without using oxygen and also initiates the construction of new blood vessels to bring in a fresh oxygen supply."

Some rapidly growing tumors consume enough energy to easily suck out the available oxygen in their vicinity, making HIF-1 absolutely critical for their continued survival. But HIF-1 can only operate if it has a supply of free radicals. Antioxidants remove these free radicals and stop HIF-1, and the tumor, in its tracks.

The authors confirmed the importance of this "hypoxia protein" by creating cancer cells with a genetic variant of HIF-1 that did not require free radicals to be stable. In these cells, antioxidants no longer had any cancer-fighting power.

The research was funded by the National Institutes of Health.

Authors on the paper are Dean Felsher of Stanford; and Gao, Huafeng Zhang, Ramani Dinavahi, Feng Li, Yan Xiang, Venu Raman, Zaver Bhujwalla, Linzhao Cheng, Jonathan Pevsner, Linda Lee, Gregg Semenza and Dang of Johns Hopkins.

Note: This story has been adapted from a news release issued by Johns Hopkins Medical Institutions.

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Ways To Teach Approved Drugs New Tricks: How To Combat Cancer

ScienceDaily (Oct. 30, 2007) — Although all cancers are not alike, most share common causes, whether it is the result of a genetic mutation or faulty biochemical signaling pathway. For that reason, drugs developed specifically for one disease might have an impact on many others. Increasingly, researchers are discovering ways of combining new and existing drugs to fight cancer -- broadening the targets of already-approved targeted therapeutics.

At the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, researchers present the results of some of these investigations, whether it is finding a new use for the immunosuppressant rapamycin or adapting the use of approved antibodies to reach the same targets within different cancers.

Combination of CP-751871, a human monoclonal antibody against the IGF-1 receptor, with rapamycin results in a highly effective therapy for xenografts derived from childhood sarcomas: Abstract C172.

Researchers at St. Jude Children's Research Hospital in Memphis, Tennessee, have discovered that an engineered antibody, in combination with rapamycin, may offer treatment for rhabdomyosarcoma, osteosarcoma, and Ewing's' sarcoma -- three rare childhood cancers. The antibody, called CP-751871, is currently in a Phase III trial by its developer, Pfizer, Inc., while rapamycin, an approved immunosuppressant, is also under study for its anti-cancer properties.

Combined, the researchers believe, the two therapeutics act in a way that helps to promote apoptosis, a series of internal signals within a cell that cause its self-destruction. CP-751871 binds to -- and thereby blocks the action of -- a cell surface protein called insulin-like growth factor receptor (IGF-1R), which research has shown to be a part of a process that limits apoptosis. Rapamycin has been shown to inhibit mTOR, a protein involved in regulation of cell growth, proliferation and survival. There is increasing evidence that activation of cellular proteins upstream or downstream of mTOR is critical in the process of cancer progression.

"Together, the two therapeutics seem to have a synergistic effect in human sarcomas, combined they function more strongly than either drug alone," said Raushan T. Kurmasheva, Ph.D., a post-doctoral fellow at St. Jude. "We are looking to extend our studies to include more sarcoma models, but we believe this looks like a promising clinical application for these drugs."

Ways to Teach Approved Drugs New Tricks

According to Kurmasheva, the combined therapy could be a breakthrough in treatment of human sarcomas in general and childhood sarcomas, in particular. Both Ewing's sarcoma and osteosarcoma are cancers of the bone and connecting tissue that are most frequently diagnosed in teens. Rhabdomyosarcoma is a rare disease that primarily affects children between the ages of one and five, but which can also strikes adolescents. While prognosis for childhood sarcomas is generally good, if caught early, children with these diseases face a grim prognosis if the cancer metastasizes, Kurmasheva says.

With support from the National Cancer Institute and Pfizer, the St. Jude researchers began their study in cell cultures of both cancer types. The antibody, alone, significantly retarded cell growth, they found. In animal models of sarcoma, both drugs curbed tumor growth. The two drugs combined, however, induced complete regression of established tumors. Due to the encouraging results, Kurmasheva and her colleagues are looking to expand their research to other animal models as well as look for biomarkers that could indicate positive response to treatment in a clinical setting.

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Epeius Biotechnologies Corporation announced today that the company has taken a major step toward the commercialization of its lead product with the opening of a Phase II Registration Protocol using Rexin-G for osteosarcoma in the United States. Following the accelerated approval of Rexin-G for the treatment of all solid tumors by the Bureau of Food and Drugs in the Philippines, Epeius opened a number of Phase I/II clinical trials in the United States for pancreatic cancer, breast cancer and all types of sarcoma in the summer of 2007.

Caption: EpeiusBased on the exceptional safety profile of Rexin-G in the first 18 patients who participated in these U.S.-based clinical trials, and the profound demonstration of single agent efficacy in metastatic osteosarcoma, the FDA approved a Phase II Registration Protocol using intravenous Rexin-G for recurrent or metastatic osteosarcoma that is refractory to known therapies. The study will recruit 20-30 patients in 12-18 months. Children who are at least 10 years of age or older are eligible to participate in the study. The adaptive trial design of this advanced Phase II registration protocol incorporates (i) a dosing schedule based on the patient's estimated tumor burden and not on standard dosing per kilogram body weight or body surface area, and (2) a tumor response evaluation process that is unique to the manner in which osteosarcoma responds favorably to therapy, i.e., with necrosis and increasing calcification in metastatic tumors and decreased glucose utilization using PET-CT imaging studies.

Rexin-G is a tumor-targeted gene medicine that seeks out and destroys both primary tumor and metastatic cancers that have spread throughout the body. Delivered by simple intravenous infusion, Rexin-G has demonstrated unprecedented single-agent efficacy against a broad spectrum of solid tumors where chemotherapy, radiotherapy and other targeted therapies have failed. With more than three years of clinical experience with Rexin-G in an increasing number of otherwise intractable cancers in the Philippines, Japan and the U.S., we have gained valuable insights into the general safety, optimal dosing parameters, and best treatment regimens that provide the greatest benefits for the cancer patient without compromising safety.

The on-going clinical trials of Rexin-G are centered in San Marino CA, where Epeius Biotechnologies Corporation has its headquarters, and in Santa Monica CA at the Sarcoma Oncology Center. Dr. Sant P. Chawla, M.D., who trained at the University of Texas M.D. Anderson Cancer Center, is a renowned expert on malignant sarcomas, and serves as Principal Investigator (PI) for these clinical trials.

About Epeius Biotechnologies
Epeius Biotechnologies Corporation is a privately held biopharmaceutical company dedicated to the advancement of genetic medicine with the development and commercialization of its proprietary targeted delivery systems. Credited with innovations ranging from oncogene discovery, to designer therapeutic genes, to pathotropic (disease-seeking) targeting, to high-performance vector engineering, to advanced biopharmaceutical manufacturing and bioprocess development, Epeius Biotechnologies is well positioned to "launch" its enabling platform technologies for the benefit of cancer patients worldwide. Rapid advances in clinical drug development provide Epeius with a unique opportunity for early revenues from the exportation and sale of its lead product to the Philippines and reciprocating Southeast Asian countries-thus demonstrating the high growth potential of a small biotechnology company while maintaining the lowered risk profile of a biopharmaceutical company with a high-value, late-stage product.

To learn more about Rexin-G and Epeius' pipeline of proprietary compounds currently available for partnership or clinical trials, please visit us at

epeiusbiotech.com

For information about clinical trials:

Clinical Trials for Rexin-G

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Drug Therapy To Bolster Immune System Cells Found Effective Toward Osteosarcoma and other Childhood Cancer

ScienceDaily (May 15, 2008) — Researchers from The University of Texas M. D. Anderson Cancer Center have found a possible approach to therapy that may make cancer cells more sensitive to attack by immune system cells while making the immune system cells more powerful.

The combination has the potential to treat different types of childhood cancer, including osteosarcoma, leukemia and neuroblastoma, while possibly sparing young patients from more difficult therapies such as stem cell transplant or more toxic chemotherapy.

Dean Lee, M.D., Ph.D., assistant professor of pediatrics from the Children's Cancer Hospital at M. D. Anderson, has found that combining the epigenetic drug MS-275 with natural killer (NK) cells makes osteosarcoma cells more sensitive to NK cells while making the NK cells more lethal to the tumor, as presented at the American Society of Pediatric Hematology/Oncology annual meeting on May 15, 2008.

"Traditional chemotherapy drugs kill any fast-growing cells like cancer, but they also killed healthy fast-growing cells like hair, bone marrow and mucous membranes, making the drugs very toxic," says Lee, senior investigator on the study. "There's a new class of drugs that takes cells that aren't properly regulated and makes them behave. In our study, we found that these drugs make tumor cells more recognizable and vulnerable to natural killer cells."

Osteosarcoma is a rare pediatric cancer, but the most common bone cancer found in children. According to the American Cancer Society, it affects approximately 400 children, adolescents and young adults under the age of 20 in the United States each year, and nearly a third of those relapse. Relapsed and metastatic osteosarcomas are rarely sensitive to treatment with chemotherapy or radiation, but several studies have suggested these tumors may be immunologically responsive.

Lee's study of human tissue cultures shows the synergistic effect of combining NK cells with histone deacetylase (HDAC) inhibitors such as MS-275 to fight childhood cancer, which Lee hopes will lead to a clinical trial for patients. When added to a human tissue culture, MS-275 heightened the amount of the NKG2D receptor on the NK cell's surface to pick up signals from stressed cells, such as tumor cells. In addition, the MS-275 simultaneously caused the stress signals of the tumor cells to increase, making it easier for NK cells to detect them and kill them.

Trials are currently open using HDAC and proteasome inhibitors as well as NK cells to treat patients, but not as a combination therapy.

"By applying what we've found from our study, we hope to improve our treatment for many cancers, but not by giving more NK cells or by giving more toxic chemotherapy," says Lee. "Instead, we want to marry the two therapies to improve each other and provide a more effective, less toxic treatment for our patients."

Lee's study found similar responses from acute myelogenous leukemia (AML) and neuroblastoma, but using different inhibitors. For neuroblastoma and AML, the proteasome inhibitors Bortezomib and NPI-0052 were found to have the greatest effect on sensitizing tumor cells to NK cells. Additional research is being conducted on acute lymphocytic leukemia, the most common cancer in children, and medulloblastoma, the most common brain cancer in children.

Other investigators on the study include Shiguo Zhu, Ph.D, and Laurence Cooper, M.D., Ph.D. from the Children's Cancer Hospital at M. D. Anderson. Funding for the study came from M. D. Anderson and the For Julie Foundation.

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IDM Pharma Announces Updated Data From Mifamurtide (L-MTP-PE) Compassionate Access Program

- Data Presented at the 21st Annual Meeting of The American Society of
Pediatric Hematology/Oncology (ASPHO) Meeting -

IRVINE, Calif., May 15 /PRNewswire-FirstCall/ -- IDM Pharma, Inc. (the
Company) (Nasdaq: IDMI) today announced the presentation of updated data
from a compassionate access program evaluating mifamurtide (L-MTP-PE) in
patients with lung metastases as a result of the progression of
osteosarcoma, a rare and often fatal bone tumor that typically affects
children and young adults. The data show that L-MTP-PE in combination with
other therapies is safe, well- tolerated and exhibited signs of disease
control.

The compassionate access program provides L-MTP-PE treatment to
patients who have either failed or cannot tolerate treatment with existing
therapies compared to the Phase 3 pivotal study, which evaluated newly
diagnosed patients.

"The results that we have seen to date from the Phase 3 clinical trial
in patients with non-metastatic osteosarcoma are being supported in
patients with lung metastases as the L-MTP-PE compassionate access
experience continues to be encouraging," said Peter Anderson, M.D., Ph.D.,
principal investigator and professor of pediatrics, Children's Cancer
Hospital at The University of Texas M. D. Anderson Cancer Center in
Houston. "With a formalized protocol now in place, we can address the
increasing number of requests for compassionate access to L-MTP-PE and meet
the unmet needs of certain patients by providing this much needed treatment
option."

Study design and findings

Twenty-nine high-risk osteosarcoma patients (ages 10 - 21) were
enrolled and 27 have been treated with L-MTP-PE in the compassionate access
program to date (May 8, 2008). Patients in the program had documented
diagnosis of high grade osteosarcoma with relapsed or recurrent disease
(locally or metastatic) with resectable or not completely resectable
disease, or who are unable to complete recommended chemotherapy due to
toxicity.

L-MTP-PE (2 mg/m2 IV over 1 hour) was administered twice a week for 12
weeks followed by once a week for 24 weeks. In addition, some patients in
the program were also treated with other agents including aerosol
recombinant granulocyte monocyte colony stimulating factor (GM-CSF) an
immune stimulating agent (n=20), ifosfamide (n=4), and/or gemcitabine
(n=2).

Results to date are as follows:
-- Nine patients are alive with disease.
-- Nine patients have no evidence of disease.
-- Nine patients have died.
-- There are two patients for whom the status is unknown.
Treatment with L-MTP-PE combined with other agents including aerosol
GM- CSF was generally well tolerated. Patients treated with chemotherapy
had no unexpected toxicities and toxicity from L-MTP-PE infusions was
minimal. There were no reports of grade 3 or 4 drug-related toxicities with
the exception of fever grade 3 and flu-like symptoms with the first dose.
This was prevented with ibuprofen and acetaminophen after subsequent doses.
One patient developed pleural and pericardial effusion that was possibly
L-MTP-PE and/or GM-CSF related and the patient was removed from the study.

In March, the Company announced that it had formalized a clinical
protocol with the FDA, which provides L-MTP-PE to eligible, high-risk
osteosarcoma patients through a compassionate access study. The
compassionate access study is being conducted initially at M. D. Anderson
and Memorial-Sloan Kettering Cancer Center in New York.

"Patients are our first priority and we are committed to providing
L-MTP- PE to those who desperately need treatment," said Timothy P.
Walbert, president and chief executive officer, IDM Pharma. "The potential
survival and quality of life benefits for patients treated with L-MTP-PE
continue to be supported through physician experience and we remain
committed to advancing L- MTP-PE through the European and U.S. regulatory
processes to bring this important treatment to market."

Update on L-MTP-PE Regulatory Status

In January 2008 the Company announced that following presentation of
data at an oral explanation hearing before the Committee for Medicinal
Products for Human Use (CHMP) of the European Medicines Agency, the CHMP
determined in a non-binding opinion that L-MTP-PE suggested a possible
clinical benefit in terms of survival and granted the Company a clock stop,
or time extension. The clock stop allows the Company additional time to
respond to all the remaining questions regarding the marketing
authorization application for L-MTP-PE (MAA). The CHMP has requested
clarification of the existing data in order to gain assurance about the
quality of the data before drawing any final conclusions from the data
presented. In addition, the Company is required to address a number of
remaining questions relating to chemistry, manufacturing and controls (CMC)
and the Company expects to provide responses and data regarding these
issues to the CHMP in advance of its meeting scheduled for June 23-26,
although the CHMP may have additional questions or require additional
information regarding these issues. In April, the European regulatory
authorities conducted an inspection of the Children's Oncology Group (COG)
to assess the quality of the overall survival data from the 2006
confirmatory database included in our applications for regulatory approval,
and to review Good Clinical Practices compliance of COG in terms of patient
randomization and stratification, overall survival data collection, and
study monitoring. The Company supported the COG in this effort.

The Company expects to receive a final opinion from the CHMP in the
third quarter and a final decision from the European Commission in the
fourth quarter of 2008.

As previously announced, in the United States the Company continues to
work with the COG as well as external experts and advisors to gather
patient follow up data from the Phase 3 clinical trial of L-MTP-PE and to
respond to other questions in the non-approvable letter the Company
received from the U.S. Food and Drug Administration (FDA). The Company
expects to submit the amended New Drug Application (NDA) in the fourth
quarter of 2008.

L-MTP-PE was granted orphan drug status in the United States in 2001
and in Europe in 2004. In Europe, the MAA was filed in November 2006 and in
the U.S, the NDA was submitted to FDA in October 2006 and was accepted for
review in December 2006.

About Osteosarcoma

Between two and three percent of all childhood cancers are
osteosarcoma. Because osteosarcoma usually develops from osteoblasts, it
most commonly affects children and young adults experiencing their
adolescent growth spurt. Boys and girls have a similar incidence rate until
later in their adolescence, when boys are more commonly affected. While
most tumors occur in larger bones, such as the femur, tibia, and humerus,
and in the area of the bone that has the fastest growth rate, they can
occur in any bone. The most common symptom is pain, but swelling and
limited movement can occur as the tumor grows.

Osteosarcoma is an orphan disease with fewer than 1,000 new cases
diagnosed in the United States each year. A similar incidence of the
disease exists in Europe. According to the Children's Oncology Group, the
survival of children with osteosarcoma has remained at 60-65 percent since
the mid-1980s. The standard treatment for osteosarcoma is tumor resection
with combination chemotherapy before and after surgery.

About IDM Pharma

IDM Pharma is focused on the development of innovative cancer products
that either destroy cancer cells by activating the immune system or prevent
tumor recurrence by triggering a specific adaptive immune response. IDM
Pharma is dedicated to maximizing the full therapeutic and commercial
potential of each of its innovative products to address the needs of
patients and the physicians who treat these patients.

For more information about the company and its products, visit
http://www.idm-pharma.com.

Forward-Looking Statements

This press release includes forward-looking statements that reflect
management's current views of future events including the objectives of the
compassionate access study, the Company's plans to address the remaining
questions with respect to the MAA for L-MTP-PE during the clock-stop
granted by the CHMP, and the expected timing of a final opinion from the
CHMP and of a final regulatory decision regarding the MAA in the European
Union, as well as the Company's plans to collect, analyze and submit
additional Phase 3 data in an amended NDA for L-MTP-PE, including the
expected timing for such amended NDA, and to respond to other matters
raised by the FDA. Actual results may differ materially from the
forward-looking statements due to a number of important factors, including,
but not limited to, whether the Company will be able to respond to the
remaining issues with regard to the MAA, including verification of data
quality and CMC items, to the satisfaction of the CHMP, whether the CHMP
will ask the Company for further information at or following the June 2008
meeting to address remaining issues with regard to the MAA, which would
delay the timing of a final opinion from the CHMP, whether the final
opinion of the CHMP will be consistent with the non-binding opinion of the
CHMP, whether the European Commission will follow the final opinion of the
CHMP once issued, whether the timing for the final opinion of the CHMP and
the regulatory decision in Europe will occur as expected by the Company,
the possibility that additional data from the Phase 3 clinical trial of
L-MTP-PE and other information in any amendment to the NDA for L-MTP-PE
submitted by the Company may not provide adequate support for regulatory
approval of L-MTP- PE in the United States within the timeframe expected by
the Company, if at all, and whether the Company will be able to manufacture
and commercialize L- MTP-PE even if it is approved by regulatory
authorities, and whether the cash resources of the Company will be
sufficient to fund operations as planned. These and other risks affecting
the Company and its drug development programs, intellectual property
rights, personnel and business are more fully discussed in the Company's
Quarterly Report on Form 10-Q filed with the SEC for the quarter ended
March 31, 2008 and other periodic reports filed with the SEC. The Company
expressly disclaims any intent or obligation to update these
forward-looking statements, except as required by law.

SOURCE IDM Pharma, Inc.

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Drug MS-275 Helps Immune System Fight Osteosarcoma
Therapy May Help Children Avoid Harsh Treatment

Combining natural killer (NK) cells that help defend the body against disease with a new class of drugs may help the immune system fight cancer, according to a laboratory study of pediatric cancer cells.

Significance of results

Dean Lee, M.D., Ph.D.The hope is that this combination could be added with little additional toxicity as an adjunct to other therapies, such as stem cell transplant or high-dose chemotherapy, says Dean Lee, M.D., Ph.D., assistant professor in the Children's Cancer Hospital at M. D. Anderson and principal investigator on the study. Lee presented the findings in May at the American Society of Pediatric Hematology/Oncology annual meeting.

“Chemotherapy drugs are often very toxic to children,” Lee says. “While they kill unhealthy fast-growing cells like cancer, they also destroy healthy fast-growing cells like hair, bone marrow and mucous membranes. We discovered that this new class of drugs, which regulates certain cells, makes cancer cells more vulnerable to the body’s natural defenses against cancer.”

Research methods

The study involved MS-275, part of a class of drugs called histone deacetylase inhibitors known to affect cancerous cells. Researchers added MS-275 to human NK cells and osteosarcoma cells. Osteosarcoma is the most common pediatric bone cancer.

Primary results

The addition of MS-275 made osteosarcoma cells more sensitive to NK cells and also made the NK cells more lethal to the tumor. This suggests pediatric cancers may be amenable to treatment with NK cells, and treatment may be greatly enhanced if NK cells are combined with certain other drugs, Lee says.

Lee's study found similar responses using different inhibitors in acute myelogenous leukemia, a common blood cancer in children and adults, and neuroblastoma, one of the most common solid tumors in children, usually found in the adrenal gland.

Background

Several studies have suggested NK cells may have an effect on osteosarcoma tumors that have metastasized (spread to other parts of the body) or relapsed (returned after treatment), Lee says.

Approximately 400 young patients are diagnosed with the rare disease each year, and about one-third of these patients relapse, according to the American Cancer Society. When osteosarcoma does come back, it’s often resistant to treatment.

What’s next?

Lee hopes this preliminary study will lead to a clinical trial: "Incorporating the lessons from this study, we hope we can improve treatment for many cancers and make treatment less toxic.”

Additional research is being conducted on acute lymphocytic leukemia, the most common cancer in children, and medulloblastoma, the most common brain cancer in children.

— Adapted by Dawn Dorsey from an M. D. Anderson news release.

M. D. Anderson resources:

Osteosarcoma

Dean Lee, M.D., Ph.D.

Children’s Cancer Hospital at M. D. Anderson

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Rexin-G Controls Tumor Growth and Improves Survival in Chemotherapy-Resistant Soft Tissue Sarcoma and Osteosarcoma
Edited by Debra Tone
Thu, 20 Nov 2008, 19:28:29 EST

Phase I/II & Confirmatory Phase II Studies

SAN MARINO, Calif., Nov. 20 (SEND2PRESS NEWSWIRE) -- Epeius Biotechnologies announced today the results of Phase I/II and II studies of Rexin-G in chemotherapy-resistant metastatic soft tissue sarcoma and osteosarcoma, as presented by Dr. Sant P. Chawla, principal investigator, at the CTOS 14th annual meetings held in London UK on November 13-15, 2008. Patients received repeated infusions of Rexin-G i.v. over a period up to 9 months. Analysis of safety and efficacy data showed no major toxicity, while documenting significant control of tumor growth.

epeiusAnalysis of efficacy in 42 patients with bone and soft tissue sarcoma showed a dose-response relationship between overall survival and Rexin-G which was highly significant. A confirmatory Phase II study in 17 osteosarcoma patients showed a median overall survival greater than seven months; that is, after failing standard chemotherapies.

Two patients are disease-free greater than 6 months after surgical resection of residual tumors and Rexin-G given as both neoadjuvant and adjuvant monotherapy.

These studies indicate that (i) intravenous Rexin-G is safe and well-tolerated, and (ii) Rexin-G controls tumor growth and improves survival in a dose-dependent manner in patients with chemotherapy-resistant metastatic soft tissue sarcoma and osteosarcoma.

About Epeius Biotechnologies

Epeius Biotechnologies Corporation is a privately held biopharmaceutical company dedicated to the advancement of genetic medicine with the development and commercialization of its proprietary targeted delivery systems.

To learn more about Rexin-G® and Epeius Biotechnologies' pipeline of proprietary compounds currently available for clinical development, please visit us at www.epeiusbiotech.com.

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Stem Cells Deliver Gene Therapy to Bone Tumors in Preclinical Test Targeted Approach Could Minimize Side Effects While Reducing Tumor Growth

 HOUSTON, Dec. 8, 2008--Researchers from The University of Texas M. D. Anderson Cancer Center have potentially found a way to use stem cells to deliver a gene therapy that fights pediatric bone tumors. The preclinical study in mice could lead to a therapy that avoids systemic toxicity from chemotherapy by directly targeting the tumor.
The study, published in the latest issue of Cancer, tested mesenchymal stem cells (MSCs) from mouse bone marrow to see if they could deliver the gene therapy, interleukin-12 (IL-12), directly to Ewing’s sarcoma tumors. The stem cells were infused with the IL-12 gene and then administered intravenously into the mouse. A series of experiments confirmed that the stem cells delivered IL-12 to the tumor and that the gene therapy significantly inhibited tumor growth.
Eugenie Kleinerman, M.D, division head for the Children’s Cancer Hospital at M. D. Anderson has done extensive research on pediatric bone tumors such as Ewing’s sarcoma and osteosarcoma. Kleinerman’s previous research has shown the ability of IL-12 to inhibit tumor growth in Ewing’s sarcoma and osteosarcoma. IL-12 is a gene that prevents tumors from forming new blood vessels that allow them to grow.
In August, Kleinerman had research findings published in the International Journal of Cancer, which reported that bone marrow cells migrated to Ewing's sarcoma tumors and helped form the new blood vessels that support tumor growth.
“We already knew that IL-12 had a significant impact on tumor growth of bone cancers,” Kleinerman says. “When we discovered that some bone marrow cells are attracted to tumors, we looked into finding the specific stem cells that could function to deliver the gene therapy to the tumor and hopefully avoid systemic toxicity.”
Currently, patients with Ewing’s sarcoma receive multi-agent chemotherapy with surgery and/or radiation. According to a study by Douglas Hawkins, M.D., from the University of Washington School of Medicine, the two-year disease-free survival rate for patients with localized disease receiving this aggressive treatment has remained at 60 to 70 percent. For patients whose Ewing’s sarcoma has metastasized, their two-year disease-free survival rate drops to 10 to 30 percent. The cure rate for patients who are diagnosed with metastasis is less than 10 percent.
“There is a great need for new therapeutic approaches for treating Ewing’s sarcoma patients, especially those who have relapsed or who have metastases,” Kleinerman says. “Plus, the long-term effects and secondary cancers associated with intensive chemotherapy and radiation validate the need for more effective and less toxic therapies for young patients.”
Laurence Cooper, M.D., Ph.D. associate professor and head of the Cell Therapy Program at the Children’s Cancer Hospital, has already initiated clinical trials using cell therapy to treat children with relapsed cancer. Currently, he is investigating how to standardize the production of cells infused with various genes. Once this is achieved, cell-based gene therapy, like Kleinerman’s IL-12 gene therapy, can be used in clinical trials for patients.
Funding for Kleinerman’s study came from a National Institutes of Health R01 grant. Xiaoping Duan, M.D., Hui Guan, Ph.D., and Ying Cao, Ph.D., also contributed to the study.

________________________________
About M. D. Anderson The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 41 Comprehensive Cancer Centers designated by the National Cancer Institute. For four of the past six years, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News and World Report.
About the Children’s Cancer Hospital at M. D. Anderson The Children’s Cancer Hospital at The University of Texas M. D. Anderson Cancer Center has been serving children, adolescents and young adults for more than 50 years. In addition to the ground breaking research and quality of treatment available to pediatric patients, the Children’s Cancer Hospital provides its patients with comprehensive programs that help the children lead more normal lives during and after treatment. For further information, visit the Children’s Cancer Hospital Web site at www.mdanderson.org/children.
Contact: Sara Farris 713-792-9133 | sfarris@mdanderson.orgsfarris@mdanderson.org
Contact Us
M. D. Anderson External Communications Office Media Hotline: (713) 792-0655 If you have questions or need assistance with the subscription, contact Kim Nathanknathan@mdanderson.org>
(c)2008 The University of Texas M. D. Anderson Cancer Center

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Posted December 10, 2008
Proton beam therapy: Is it the future of radiation?
There is great enthusiasm for proton beam therapy, but it has not yet been proven better than existing treatments.

Proton beam therapy may be the next great leap forward in radiation oncology.

Supporters say the technology allows physicians to treat a broad spectrum of cancers with few adverse effects, while more precisely targeting tumor cells with higher doses of radiation. Detractors say proton beam therapy is hugely expensive and has not been shown to be superior to conventional radiation treatment.

With proton beam therapy, physicians use a cyclotron to accelerate protons and fire them directly into tumor cells with submillimeter precision. Because healthy tissue is largely spared, oncologists can, in theory, deliver much higher doses of radiation, while improving local control and reducing the risk for recurrence and morbidities.

Anthony L. Zietman, MD
Anthony L. Zietman, MD, uses proton beam therapy in his practice at the Francis H. Burr Proton Therapy Center.

Courtesy of Massachusetts General Hospital

Proton beam therapy can be used to treat any disease that can be treated with radiation, though it is most often associated with head and neck cancers, pediatric cancers and prostate cancer. The James M. Slater, M.D. Proton Treatment and Research Center at Loma Linda University Medical Center focuses on prostate, lung and brain cancer treatment. Physicians at the massive Hampton University Proton Therapy Institute under construction in Hampton, Va., plan to begin treating 2,000 patients annually for prostate, breast, lung and pediatric cancers in 2010.

Leonard Arzt is the executive director of National Association for Proton Therapy. The association is a nonprofit corporation that promotes the clinical benefits of proton beam radiation therapy for cancer patients.

Leonard Arzt
Leonard Arzt

Arzt has been a supporter of the therapy for 20 years. Proton beam therapy, he said, is simply superior to conventional radiotherapy.

“There are no drawbacks that I know of in terms of the modality itself,” Arzt said, speaking from his office in Silver Spring, Md. “It’s the best medically accepted radiation that can control cancer and do minimal to no harm to surrounding healthy cells, tissues or organs. It provides higher doses for better control.”

Anthony L. Zietman, MD, a professor of radiation oncology at Massachusetts General Hospital and the Francis H. Burr Proton Therapy Center, believes that proton beam therapy, however, can cause side effects.

“It’s a misconception,” he said. “I see a lot of patients with side effects. I wish I didn’t, but I do with all the therapies. There’s no such thing as the perfect therapy.”

Jerry M. Slater, MD, medical director at the Loma Linda’s proton clinic, does not go so far as Arzt, though he did say the side effects of proton beam are minimal.

DISCUSS IN OUR FORUM What is your position on proton beam therapy?

“The published reports are out there showing there are always some morbidities, but we’re looking at making them less than we would have otherwise,” he told HemOnc Today.

The first use of proton therapy to attack tumor cells dates back to the 1950s, but the treatment began gaining in popularity in 1990 after Loma Linda opened the first hospital-based proton therapy center. Like all emerging therapies, proton beam therapy faces two important questions: Is it any better than current treatments? And if so, is it worth the price? Two articles published in The Journal of Clinical Oncology last year suggest the answers to both questions could be “no.”

As good or better?

Brada et al searched as far back as 1966 for publications on clinical applications of protons and found only two phase-3 trials. Both of those trials looked at prostate cancer patients and neither made a direct comparison between photons and protons.

Upon conducting a systemic analysis of those articles, they found that there was not enough evidence to conclude proton therapy was superior to conventional radiotherapy at treating chordomas and chondrosarcomas of the skull base, ocular tumors, prostate cancer, head and neck cancer, or a host of other cancers.

They went on to say that protons may in fact be a useful treatment, but the therapy requires more research, especially appropriately designed and powered clinical studies. Slater argued that proton beam has been proven safe and effective time and time again.

“It’s a well-known fact that there’s no other form of radiation that I can put into a patient, give the maximum dose to the target and [give] less to normal tissue with every single beam I use,” he said. “X-rays will never do that. There’s no other technology that will ever allow you to maximize every beam into the target. Protons can do that.”

Arzt said it was a well-established fact that there are few clinical trials evaluating proton beam therapy, but added that the lack of scientific evidence is not slowing the demand for the treatment.

“It’s true; there could be more studies out there to prove to the scientific community, if that’s what they’re looking for,” he said. “There is a lot of anecdotal evidence, there is a lot of experience, there are a lot of testimonials from patients.”

For some physicians, that lack of hard clinical evidence is a huge problem, but Cynthia Keppel, PhD, scientific and technical director at the Hampton University Proton Therapy Institute, among others, says that clinical trials will be informative but should not be necessary in this case. She compared the adoption of proton beam to the move from analog X-rays to digital or from hand-calculated treatment planning to computerized simulation codes.

“They didn’t have to go through a big multicenter trial,” she said. “The technological improvements were just so obviously better that, while they did have to be FDA approved, they were adopted immediately. There is a long history of that, from digital X-rays to treatment planning to new imaging devices. Proton therapy has taken this path. The fundamental proton dose deposition is so obviously an improvement on what’s done now that the devices have received FDA approval and we as a community have started treating.”

Theodore Lawrence, MD, PhD
Theodore Lawrence

“All new approaches need clinical trials,” said Theodore Lawrence, MD, PhD, chair of radiation oncology at the University of Michigan Medical School and a member of the physician leadership group of the Particle Therapy Institute of Michigan. “We can discuss what kind of clinical trial, but all new approaches need to be rigorously evaluated in human beings.”

Lawrence said it is still unknown exactly how proton beams act in the body, and added that there is evidence suggesting that proton beam therapy has “as much as 4 mm of inaccuracy about where the beam actually stops.”

“I’m not against proton therapy,” he said. “I’m against blindly accepting a new, expensive therapy without rigorous testing. ... I don’t think we are incapable of testing new technology. I just think we have to have the will.”

Worth the cost?

Konski et al conducted a cost-benefit analysis of proton beam therapy and concluded that it would not be cost effective for most patients with adenocarcinoma of the prostate. The results, published in The Journal of Clinical Oncology, showed proton beam therapy only had a 49% chance of being cost-effective at 15 years for a 70-year-old patient. For a 60-year-old patient, the treatment had a 54% chance of being cost-effective at 15 years.

However, as Lawrence points out, that study is based on an as-yet-unproven assumption about proton beam therapy.

“He assumed you could give 10 Gy more with protons than you could with photons,” Lawrence said. “There’s no proof of that at all. There’s no proof you can give even one more Gy with protons than with photons.”

On the other hand, a 2005 study published in Cancer showed that protons had a lifetime cost savings of €23,600 and added 0.68 quality-adjusted life-years per patient for childhood medulloblastoma. The analysis found that reductions in IQ loss and growth hormone deficiency contributed to the greatest part of the cost savings and were the most important parameters for cost-effectiveness.

The experts who spoke with HemOnc Today felt that proton beam therapy was likely to have the most benefit for children with cancer. Children are much more radiosensitive than adults and are at far greater risk for secondary cancers and late effects.

Results of a study published in 2003 in the International Journal of Radiation Oncology-Biology-Physics showed that the dose to 90% of the cochlea was reduced from 101.2% of the prescribed posterior fossa boost dose from conventional X-rays to 2.4% for photons and 33.4% IMRT in a patient with pediatric medulloblastoma. Dose to 50% of the heart volume was reduced from 72.2% for conventional X-rays to 0.5% for protons compared with 29.5% for IMRT.

Other studies have shown proton therapy provides better target coverage with excellent sparing of orbital bone compared with IMRT or 3D-conformal radiotherapy for retinoblastoma, and that protons were superior at treating pediatric orbital rhabdomyosarcoma because of reduced exposure to orbital structures, the pituitary gland and the brain.

In a 2007 review published in Cancer, Greco and Wolden concluded that doses of 70 Gy or higher could possibly control unresectable osteosarcoma and non-rhabdomyosarcoma soft-tissue sarcomas and that protons were the “most feasible means” to achieve that level of radiation.

Mody et al reported the results a 25-year follow-up on survivors of childhood acute lymphoblastic leukemia in Blood earlier this year. The researchers found that, compared with their siblings, survivors suffered more multiple chronic medical conditions and more severe or life-threatening chronic medical conditions. Survivors were also more likely to report functional impairment, activity limitations and poorer mental and physical health. Survivors were also less likely to marry, graduate from college or have a job or health insurance.

Rajen Mody, MD, an assistant professor in the department of pediatrics and communicable diseases at University of Michigan Medical School and one of that study’s co-authors, told HemOnc Today in June that only the survivors who had undergone radiotherapy or relapsed suffered those late effects. He added that those negative outcomes were a direct result of radiation delivered to the cranial-spinal axis.

Proton beam therapy may be able to spare survivors of childhood cancers a lifetime of suffering.

“Young children are incredibly sensitive to radiation. If irradiated early in life, they may experience a lot of growth and development problems,” Mody said. “They are also at a high risk for developing treatment-induced cancers down the line. If radiation is deemed absolutely necessary for treatment during early years, newer modalities like proton beam therapy should be studied to see if they cause fewer long-term side effects.”

Setup costs

It takes a colossal, hugely expensive set-up to deliver proton beam therapy, and one of the chief arguments against the procedure is its massive cost. The University of Florida Proton Therapy Institute opened in 2006 at a cost of $125 million. It is a three-story, approximately 98,000-square-foot building housing a 220-ton cyclotron, three gantry-fitted treatment rooms, a fixed-beam room, a milling shop for the fabrication of patient-specific devices, an anesthesia and infusion suite and a patient library.

Hampton’s facility, or HUPTI, is slated to cost $225 million, and the university deems it will be the world’s largest free-standing proton therapy institute. Keppel said the expense was well-justified.

“The university has made a focused effort to expand cancer research,” she said. “The proton center represents the largest movement of the university in this direction, but it has been the university’s vision to look at cancer research.”

Keppel added that HUPTI is part of a larger investment that will put the school at the forefront of cancer research and treatment.

“It’s a new step. The university is ready to play a more prominent role on the national scene,” she said. “This project has already raised the visibility of the university and we hope to show the country and the world what we can do at Hampton.”

Hampton is an historically black university and Keppel hopes that minorities will be more willing to trust a historically black institution. She notes that there are devastatingly large minority health disparities associated with many types of cancers, most notably prostate cancer. The national death rate for black men is more than twice that of white men.

She added that although the cost for proton beam therapy will be greater than conventional radiotherapy for patients, it will still cost less than some forms of chemotherapy.

“It is more expensive than conventional radiotherapy, but it is not 10 or 100 times more expensive for the patient, even though putting up a center is 10 to 100 times more expensive for an institution willing to make this investment in improved health care.”

In a 2007 article published in Oncology Issues, Nancy Price Mendenhall, MD, medical director at The University of Florida Proton Therapy Institute, estimated that these centers can cost 10 times as much to build compared with a similarly sized conventional facility. She added that proton beam centers also face higher costs for treatment planning, quality assurance, machine operation and maintenance, though these centers are designed to last three times as long as conventional clinics.

In a 2003 study published in Clinical Oncology, Goiten and Jermann estimated the costs for proton beam therapy as 2.4 times that of conventional therapy, though the authors suggested that could drop to as low as 1.7 times higher as more facilities open. They estimated that if construction costs could be “forgiven” somehow, proton beam could cost 1.3 times as much as X-ray therapy.

Mendenhall wrote that if proton beam therapy lives up to its promise of lowering rates of toxicity and recurrence, the treatment could cost less than conventional radiotherapy over time. However, the initial outlays are huge and the treatment is at least somewhat more expensive to patients.

Arzt, however, points out that the cost is worth it for many patients.

“How can you put a price tag on quality of life? How can you put a price tag on outcomes?” he said. “How do you put a price tag on men who fear they’ll have to wear a diaper or be impotent? It’s hard to put a price tag on that.”

FAST FACTS: Issues at Hand

Slater argues that looking at current costs is short-sighted. All new therapies are expensive at the outset, but the cost drops over time.

“Ultimately you have to create something that can become efficient enough so that the costs are not exorbitant,” he said. “That’s directly the way proton therapy is going. The cost is, over time, going to become less and less for the patient. In the long term, some things we will be able to do will be cheaper than other forms of radiotherapy,” he said, adding that nothing is cheaper when it’s first developed.

Zietman, who uses proton beam in his clinical practice, said about 85% of patients who are treated at Francis H. Burr Proton Therapy Center have pediatric or brain cancers. Approximately 15% of patients are treated for prostate cancer compared with as much as 50% of patients at some centers. But, he adds, his facility is largely free of financial pressures because the proton beam center there is paid off.

His fear is that the only path to survival for a proton center coming online now is to see a lot of men with relatively easy to treat prostate cancers, and there is some question as to whether proton beam is the best treatment for that disease.

“If these centers were being established to treat children and brain tumors, I would have absolutely no problem with them,” Zietman said. “My problem is not with proton beam therapy and not with the good use of proton beam therapy. My problem is with the most common use of proton beam therapy, which is to treat prostate cancer.

“I worry that the new centers will have these financial pressures. The only business model that makes any sense is treating a lot of prostate cancer,” he said.

Construction costs could drop sooner rather than later. Still River Systems of Littleton, Mass., has announced plans to build more smaller proton beam clinics in St. Louis and Mandarin, Fla. The Siteman Cancer Center at Barnes-Jewish Hospital and Washington University has broken ground on The Kling Center, which it bills as what will be the world’s first miniature proton beam clinic. The $25 million project is expected to open next summer.

First Coast Oncology-Mandarin in Jacksonville, Fla., is planning to open a clinic at an estimated cost of $20 million to $35 million. The FDA, however, has not yet approved these compact systems.

Ultimately, careful science and fiscal sense are keystones for proton beam therapy moving forward. “Proton beam therapy can potentially be a good form of treatment in many clinical situations,” Mody said. “It needs to be prospectively studied, established carefully and used wisely.” – by Jason Harris

POINT/COUNTER
Is it wise to invest in proton beam therapy?

For more information:

* Beck M. A prostate-cancer therapy stirs debate on cost, efficacy. Wall Street Journal. Available at: http://online.wsj.com/article/SB122212195470764853.html. Accessed November 6, 2008.
* Bjöjk-Erikkson T, Glimelius B. The potential of proton beam therapy in paediatric cancer. Acta Oncol. 2005;44:871-875.
* Brada M, Pijls-Joannesma M, De Reysscher D. Proton therapy in clinical practice: Current clinical evidence. J Clin Oncol. 2007;doi:10.102/JCO.2006.10.0131.
* Goiten M, Cox J. Should randomized clinical trials be required for proton radiotherapy? J Clin Oncol.2008;doi:10.1200/JCO.2007.14.4329.
* Goitein M, Jermann M. The relative costs of proton and X-ray radiation therapy. Clinical Oncology. 2003;doi:10.1053/clon.2002.0174.
* Greco, C. Wolden S. Current status of radiotherapy with proton and light ion beams. Cancer. 2007;doi:10.1002/cncr.22542.
* Konski A, Speier W, Anlon A, et al. Is proton beam therapy cost effective in the treatment of adenocarcinoma of the prostate? J Clin Oncol. 2007;doi:10.1200/JCO.2006.09.0811.
* Levin W, Kooy H, Loeffler JS, DeLaney TF. Proton beam therapy. Br J Cancer. 2005;93:849-854.
* Mendenhall N. The promise of proton therapy is two-fold — Less toxicity and higher cure rates than achievable with x-ray therapy. Oncology Issues. 2007;38-41.
* Mody R. Li S, Dover D, et al. Twenty-five year follow-up among survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study. Blood. 2008;111:5515-5523.
* Pollack A. Cancer fight goes nuclear, with heavy price tag. New York Times. Available at: http://www.nytimes.com/2007/12/26/health/25cnd-proton.html?_r=1&scp=5&sq=proton%20beam&st=cse&oref=slogin. Accessed November 7, 2008.
* Voiland A. The promise of proton-beam therapy. U.S. News & World Report. Available at: http://health.usnews.com/articles/health/cancer/2008/04/16/the-promise-of-proton-beam-therapy.html. Accessed November 4, 2008.
* Zietman A, DiSilvio M, Slater J, et al. Comparison of conventional-dose vs. high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: A randomized controlled trial. JAMA. 2005;294;1233-1239.

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Epeius Biotech Awarded Patents in Europe for Targeted Genetic Anti-Cancer Medicine: Company Expands Impressive Intellectual Property Estate

Posted 16 December 2008 @ 12:13 pm EST

SAN MARINO, Calif., Dec. 16 /PRNewswire/ -- Epeius BiotechnologiesCorporation, a leader in tumor-targeted gene delivery systems, has receivedtwo additional European patents for the platform targeting technologies andmolecular designs that enable precision gene delivery to primary cancers andmetastatic lesions that have spread throughout the body. With profounddemonstrations of clinical benefit and single-agent-efficacy, as well asoverall safety, Epeius Biotech continues to lead the field of clinical genemedicine with the advent of pathotropic (or disease-seeking) targeting. Theselatest EU patents follow on the heels of a major clinical patent that wasrecently awarded in the USA for targeted gene delivery in vivo. Togetherthese clinical patents provide additional intellectual property protection forthe platform of highly advanced biotechnologies embodied in the company'sleading anti-cancer agent Rexin-G(R) -- the first and so far onlytumor-targeted gene delivery system that has been successfully validated inthe clinic.

Based on recent breakthroughs in tumor-targeting and nanotechnology, a newgeneration of powerful biological anti-cancer agents that are exceedinglyprecise and highly selective for diseased tissues is currently in clinicaldevelopment. Anti-cancer agents such as Rexin-G(R) can be delivered by simpleintravenous infusion, yet are programmed to seek-out and accumulateselectively in primary and metastatic lesions that have spread throughout thebody, delivering a tumor-killing gene while sparing normal cells and tissues.Representing the world's first targeted genetic medicine proven to be bothsafe and effective in the clinic, Rexin-G(R) is commercially available in thePhilippines -- for use in all solid tumors that are refractory to standardchemotherapy -- and is currently in clinical trials in the USA for severaltypes of cancer.

About Epeius Biotechnologies

Epeius Biotechnologies Corporation is a privately held biopharmaceuticalcompany dedicated to the advancement of genetic medicine with the developmentand commercialization of its proprietary targeted delivery systems. To learnmore about our pipeline of proprietary biotechnologies currently available forclinical development and/or new product development, please visit us athttp://www.epeiusbiotech.com.

For more information about Rexin-G(R), on-going clinical trials in the USAand abroad, and/or Epeius pathotropic (disease-seeking) gene delivery systems,please contact Erlinda M. Gordon, M.D., at egordon@epeiusbiotech.com.

*(LOGO 72dpi: Send2press.com/mediaboom/08-0421-Epeius_72dpi.jpg)

This release was issued on behalf of the above organization bySend2Press(R), a unit of Neotrope(R). http://www.Send2Press.com

SOURCE Epeius Biotechnologies

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Researchers identify potential therapeutic target in osteosarcoma
M. D. Anderson findings suggest a key role for interleukin-11 receptor alpha

IMAGE: Valerae O. Lewis, M.D., associate professor and chief of Orthopedic Oncology at M. D. Anderson.
Click here for more information.

HOUSTON-A receptor known to be active in bone metastases, but previously unexplored in primary bone tumors, is a potential therapeutic target in osteosarcoma, investigators from The University of Texas M. D. Anderson Cancer Center report in the March 1 issue of Cancer Research.

The researchers found that the protein - interleukin-11 receptor alpha (IL-11Ra) - is highly expressed in primary osteosarcoma and in lung metastases from these tumors. Their research suggests the possibility of delivering therapeutic agents directly to osteosarcoma cells by targeting the receptor with circulating particles that display a peptide mimic of the natural ligand that binds IL-11Ra.

Osteosarcoma is the most common primary malignant tumor of bone. "Existing treatment has not changed the prognosis for osteosarcoma for the last 20 to 30 years," said lead investigator Valerae O. Lewis, M.D., associate professor and chief of Orthopedic Oncology at M. D. Anderson. "About 30 percent of patients still relapse and die of their disease. New therapeutic strategies and agents are needed."

The effectiveness of the current chemotherapy regimens for osteosarcoma is limited by toxic side effects, including damage to the heart and nerves, kidney failure and hearing loss, Lewis noted. Identification of a target specific for osteosarcoma cells opens the door for the development of therapies that can shut down the tumor cells without inflicting the collateral damage caused by conventional osteosarcoma treatments.

IL-11Ra is a target in bone metastasis; far less is known about its attributes, if any, in primary tumors of bone. To address IL-11R? as a potential molecular target in osteosarcoma, the authors confirmed the protein expression and localization of IL-11Ra in several mouse and human osteosarcoma cell lines.

In an orthotopic mouse model of human osteosarcoma, the investigators found that the IL-11Ra not only was markedly present in the primary osteosarcoma and in its metastases but was absent from normal bone marrow and lungs.

To evaluate the accessibility of IL-11Ra as a target, the researchers intravenously administered small, virus-like particles called phages equipped with a peptide that mimics IL-11, the receptor's natural ligand. After 24 hours in circulation, the ligand-directed particles were taken up in the tumors but showed little or no accumulation in several control organs.

"Connecting therapeutic agents to this ligand-directed system might result in improved, targeted drugs," said co-senior author Renata Pasqualini, Ph.D., Professor of Medicine and Cancer Biology in the David H. Koch Center at M. D. Anderson.

"It is conceptually unexpected that a receptor would be over-expressed not only in metastatic tumors to bone but also in primary bone tumors; this is quite important because human osteosarcoma is a malignant tumor with very few targets at the protein level," said co-senior author Wadih Arap, M.D, Ph.D., also Professor of Medicine and Cancer Biology in the David H. Koch Center.

Immunohistochemical staining analysis of IL-11Ra expression in primary and metastatic human osteosarcoma samples provided further evidence of the potential value of IL-11Ra as a therapeutic target. All primary human osteosarcoma samples exhibited moderate-to high-intensity staining of tumor cells. More than half of tumor blood vessels also showed moderate-to-high-intensity staining. All pulmonary metastases were positive for IL-11Ra expression, while normal, control lung tissue was negative.

"This indicates that therapeutic targeting of IL-11Ra may yield anti-tumor, anti-metastasis and anti-angiogenesis effects in osteosarcoma," Lewis said.

Phase I trial of IL-11R for bone metastasis

The U.S. Food and Drug Administration recently issued "safe to proceed" status for an M. D. Anderson-sponsored investigational new drug based on a cell-death-inducing therapy directed at IL-11R. The drug is defined as BMTP-11 (Bone Metastasis Targeting Peptide 11). The first clinical trial, in which BMTP-11 will be evaluated in prostate cancer patients, will soon be activated.

Lewis noted that the research group has initiated pre-clinical studies to measure potential anti-tumor effects of BMTP-11 in osteosarcoma models. If successful, such efforts may lead to a rapid evolution of BMTP-11 toward the management of osteosarcoma.

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Research was funded by an M. D. Anderson Institutional Research Grant and a Robert Wood Johnson Foundation grant to Lewis and grants from the National Institutes of Health, the U.S. Department of Defense, the Gillson-Longenbaugh Foundation, and the Marcus Foundation, to Arap and Pasqualini.

Co-authors with Lewis, Arap and Pasqualini are Michael G. Ozawa, in the David H. Koch Center M. D. Anderson and an M.D./Ph.D. student in the Graduate School of Biomedical Sciences, operated jointly by The University of Texas Health Science Center at Houston and M. D. Anderson; Guiyang Wang, of the Department of Orthopedic Oncology; Michael T. Deavers, M.D. of M. D. Anderson's Department of Pathology; and Tamaki Shintani, D.D.S., Ph.D., of M. D. Anderson's Department of Radiation Oncology.

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 41 Comprehensive Cancer Centers designated by the National Cancer Institute. For six of the past nine years, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News and World Report.

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Vitamin D’s Anti-tumorigenic Properties in Bone Involve Upregulation of MAPK and AP-1/p21waf1

Cancer Lett. 2007 Aug 28;254(1):75-86, Wei Wu, Xiaoyu Zhang, Laura P. Zanello

The molecular mechanisms underlying antiproliferative actions of the steroid 1α,25-dihydroxy vitamin D (1,25D) in human osteosarcoma cells are known only partially. To better understand the signaling involved in 1,25D anti-tumorigenic properties in bone, we stably silenced vitamin D receptor (VDR) expression in the human osteosarcoma SaOS-2 cell line. We found that 1,25D treatment reduced cell proliferation by approximately 25% after 3 days only in SaOS-2 cells expressing native levels of VDR protein, and involved activation of MAPK/AP-1/p21 pathways. Both sustained (3 days) and transient (15 min) 1,25D treatment activated JNK and ERK1/2 MAPK signaling in a nongenomic VDR-dependent manner. However, only sustained exposure to hormone led to upregulation of p21 and subsequent genomic control of the cell cycle. Specific blockade of MEK1/MEK2 cascade upstream from ERK1/2 abrogated 1,25D activation of AP-1 and p21, and subsequent antiproliferative effects, even in the presence of a nuclear VDR. We conclude that 1,25D-induced inhibition of human osteosarcoma cell proliferation occurs via sustained activation of JNK and MEK1/MEK2 pathways downstream of nongenomic VDR signaling that leads to upregulation of a c-Jun/c-Fos (AP-1) complex, which in turn modulates p21 gene expression. Our results demonstrate a cross-talk between 1,25D/VDR nongenomic and genomic signaling at the level of MAP kinase activation that leads to reduction of cell proliferation in human osteosarcoma cells.

Go to OncologySTAT for pdf file: Vitamin D Anti-tumorigenic properites in Bone

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