SAN DIEGO, June 12, 2012 /PRNewswire/ -- Scientists from numerous institutions reported at the 2012 annual American Association for Cancer Research meeting, results from preclinical studies which showed that certain sarcomas and bladder cancers are more likely to respond to treatment with ADI-PEG 20 pegylated arginine deiminase) if they are deficient in the enzyme, argininosuccinate synthetase (ASS). This enzyme plays an important role in the synthesis of the amino acid arginine required for proteins in cell growth and function. Its deficiency in certain cancer cells requires these cells to obtain arginine from the circulation in order to survive. ADI-PEG 20 destroys arginine in circulation thereby preventing the cancers from growing. In addition, others showed that activation of a signaling pathway up regulates ASS, and that combination inhibition of that pathway together with ADI-PEG 20 overcame resistance to ADI-PEG 20 in melanoma, suggesting that ADI-PEG 20 combination therapy may be even more potent than mono-therapy.
Sowers et al from NY (Albert Einstein College of Medicine and Children's Hospital at Montefiore) (abstract No.1692) obtained osteosarcoma cell lines from primary patient tumors. Of 171 tissue slides stained with ASS antibody, 141 (66.7%) of samples had absent or negligible staining, 25.7% showed moderate staining and 7.6% showed strong staining. Results from cell cytotoxicity studies comparing ADI-PEG 20 treatment of ASS deficient cell lines and ASS positive cells showed a correlation of cell toxicity with decreased levels of ASS staining. Further studies with ADI-PEG 20 using human osteosarcoma in mouse xenograft models are ongoing.
Weich et al from Washington University in St. Louis, MO and The Cleveland Clinic, Cleveland, OH (abstract No.5629) performed ASS antibody staining analysis with sarcoma tissue samples from 701 patients and demonstrated that >85% (619 of 701) of the sarcomas did not express ASS. Studies were then carried out with ADI-PEG 20 and chloroquine, an inhibitor of autophagy, in a number of soft tissue sarcomas and osteosarcoma cell lines. A significantly lower growth rate was observed in the ASS deficient cell lines with the drug combination compared to the saline treated control samples. Studies are ongoing to further examine effects of combining arginine deprivation therapy and autophagy inhibition as a possible combined approach to clinical therapy of sarcomas.
Gupta et al from The Cleveland Clinic (abstract No. 3652) also reported on identification of ASS deficient bladder cancers. Two cancers in particular, small cell and squamous cell carcinomas, had marked reduction in levels of ASS (74-90% of 148 samples tested), suggesting that these bladder cancer subtypes may be good candidates for ADI-PEG 20 therapy.
Tsai et al from MD Anderson Cancer Center, Houston, TX and the University of Miami, Miami, FL (abstract No. 5610) showed that activation of a certain cancer signaling pathway up regulated ASS, leading to resistance to ADI-PEG 20 in melanoma cell lines. However, inhibitors of this pathway in combination therapy with ADI-PEG 20 in melanoma cell lines and in a mouse model with ASS negative melanoma yielded additive antitumor effects as compared with either agent alone. This illustrates how combining inhibitors of signaling pathways may improve ADI-PEG 20 anticancer responses. This work is now in press to Cancer Research.
"We are excited about this new information which suggests that additional tumor types are being found to be ASS deficient and may be candidates for ADI-PEG 20 treatment. Polaris is currently sponsoring a worldwide phase 3 pivotal clinical trial with single agent ADI-PEG 20 in hepatocellular carcinoma," said John Bomalaski, M.D., Executive Vice President, Medical Affairs, of Polaris. "We now also have a number of phase 1 and phase 2 clinical trials underway with ADI-PEG 20 in cancers that are ASS deficient, including small cell lung carcinoma, mesothelioma, pediatric leukemia, lymphoma and sarcoma, and prostate cancer. Our study in prostate cancer is the first to combine ADI-PEG 20 with another anticancer agent, docetaxel and we are excited with the initial results and the potential for future combination cancer therapy with ADI-PEG 20," he added.
About ADI-PEG 20
ADI-PEG 20 is a biologic being developed by Polaris to treat cancers carrying a major metabolic defect that renders them, unlike normal cells, unable to make arginine internally. Because arginine is one of the 20 amino acids that are essential for protein synthesis and survival of cells, these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI-PEG 20 works by systemically depleting the external supply of arginine, which causes these arginine-dependent cancer cells to die while leaving the normal cells unharmed.
Multiple cancers have been reported to have a high degree of arginine-dependency.
About Polaris Group
Polaris Group is a privately held multinational biopharmaceutical company that specializes in the research and development of protein drugs to treat cancer and other debilitating diseases. The company's lead therapeutic, ADI-PEG 20, is currently being evaluated in a pivotal Phase 3 trial for hepatocellular carcinoma. Polaris is also investigating ADI-PEG 20 as a treatment for other arginine-dependent cancers, such as melanoma, leukemia, lymphoma, sarcoma and pancreatic cancer. In addition to the ADI-PEG 20 project, Polaris is researching and developing other biotherapeutic agents and has a small molecule drug program that utilizes a rational structure-based approach to design novel compounds that inhibit the biological function of cancer-related protein targets.
For additional information please visit www.polarispharma.com
|SOURCE Polaris Group|
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