Polaris Group Lead Therapeutic Candidate ADI-PEG 20 Induces Alterations in Gene Expression and Demonstrates Potential Anticancer Activity in Non-Small Cell Lung Cancers, Malignant Pleural Mesothelioma and Melanomas, Cancers That Are Deficient in Key Metabolic Protein Polaris Group Scientific Colleagues from Several University Cancer Centers Present Data at 2014 AACR Meeting in San Diego, CA
SAN DIEGO, April 29, 2014 /PRNewswire/ -- Polaris Group collaborating scientists from numerous institutions reported results from preclinical studies at the 2014 annual American Association for Cancer Research (AACR) meeting, which showed that certain non-small cell lung cancers (NSCLC), malignant pleural mesothelioma (MPM) and melanomas are more likely to respond to treatment with ADI-PEG 20 (pegylated arginine deiminase) if they are deficient in the enzyme argininosuccinate synthetase (ASS1). This enzyme plays an important role in the synthesis of the amino acid arginine required for proteins in cell growth and function. ASS1 deficiency in certain cancer cells requires these cells to obtain arginine from the circulation in order to survive. ADI-PEG 20 is designed to deplete arginine in the circulation and thereby prevent cancers from growing. Results of research on gene expression of ASS1 loss and the effects of ADI-PEG 20 in MPM showed that patients who have lost ASS1 have a worse prognosis, and differentially regulates various genes compared to those with high ASS1 levels. In addition, other studies showed that resistance to cisplatin in NSCLC, and resulting worse prognosis, results in loss of ASS1 and sensitivity to arginine depletion with ADI-PEG 20. Lastly, melanoma resistance to BRAF inhibition, a treatment used in approximately 50% of melanoma patients, confers sensitivity to ADI-PEG 20, suggesting that ADI-PEG 20 could be an effective therapy in such patients who have relapsed on this first-line treatment.
Treating ASS1-deficient NSCLC with ADI-PEG 20 inhibited cancer cell growth and resulted in cancer cell death.
You et al from the University of Miami and Miami Veterans Affairs Medical Center (abstract No.1435) found that 6 of 12 NSCLC cell lines were ASS1 deficient. They next tested 72 NSCLC tissue slides stained with anti-ASS antibody, and approximately 80% were ASS1 deficient. Treatment of ASS1 deficient cells with ADI-PEG 20 resulted in tumor growth inhibition with induction of autophagy and eventually apoptosis. In two cell lines, the cause of ASS1 gene silencing was ASS1 methylation. Further studies with ADI-PEG 20 using human NSCLC in mouse xenograft models are ongoing.
ASS1-deficiency resulted in more aggressive MPM; ADI-PEG 20 treatment may increase effectiveness of chemotherapeutic agents.
Cutts et al from Barts Cancer Institute and other centers in the United Kingdom (abstract No.1431) used pathway analysis tools on microarray to evaluate gene expression data from human MPM cell lines. They found that ASS1 loss was linked to several pro-tumorigenic functions, including increased cell invasiveness and migration. They also detected a large number of enriched pathways connected to the immune response. Furthermore, ASS1 deficiency was linked to worse outcome with a median overall survival of 6 months for low ASS1 expressers compared to 12 months for ASS1 high expressers using a retrospective data set of 41 MPM patients. Next, they determined that ADI-PEG 20 treatment modulated numerous pathways in ASS1 deficient cells. Furthermore, Connectivity mapping revealed that arginine depletion with ADI-PEG 20 potentiated several chemotherapeutic agents. Their work shows that ASS1 loss results in a more aggressive mesothelioma phenotype and identifies several potential combination strategies with ADI-PEG 20 that are being taken into clinical trials.
Cisplatin resistant NSCLC may be susceptible to ADI-PEG 20 treatment.
Wangpaichitr et al from the University of Miami and Miami Veterans Affairs Medical Center and MD Anderson Cancer Center (abstract No. 1428) reported that cisplatin resistant NSCLC lost ASS1 expression and were sensitive to arginine deprivation, suggesting that cisplatin resistant NSCLC may be good candidates for ADI-PEG 20 therapy.
BRAF mutation common in many cutaneous melanoma patients indicates ADI-PEG 20 as a potential next-line therapy.
Li et al from the University of Miami and Miami Veterans Affairs Medical Center and MD Anderson Cancer Center (abstract No. 3701) showed that BRAF inhibitor resistant cells are sensitive to arginine deprivation with ADI-PEG 20. Approximately 50% of cutaneous melanoma patients harbor the BRAF mutation, and thus are candidates for BRAF inhibition. However, virtually all eventually relapse, and next-line therapy is needed. Such therapy could be ADI-PEG 20 monotherapy or combination therapy with a BRAF downstream inhibitor such as a MEK inhibitor.
"We are excited about this new information which suggests that additional tumor types are ASS1 deficient and may be candidates for ADI-PEG 20 treatment," said John Bomalaski, M.D., Executive Vice President, Medical Affairs of Polaris Pharmaceuticals, Inc. "Polaris is currently sponsoring a worldwide phase 3 pivotal clinical trial with single agent ADI-PEG 20 in hepatocellular carcinoma. We now also have a number of phase 1 and phase 2 clinical trials underway with ADI-PEG 20 in cancers that are ASS1 deficient, not only as monotherapy, but also combined with one or two other agents. We are excited with these results and the potential for future combination cancer therapy with ADI-PEG 20."
About ADI-PEG 20
ADI-PEG 20 is a biologic being developed by Polaris Group to treat cancers, especially those carrying a major metabolic defect that renders such cancer cells, unlike normal cells, unable to internally synthesize arginine. Because arginine is one of the 20 amino acids that are essential for protein synthesis and survival of cells, it is believed that these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI-PEG 20 is designed to systematically deplete 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 Group is also investigating ADI-PEG 20 as a treatment for other cancers, such as melanoma, mesothelioma, NSCLC, breast, ovarian, leukemia, lymphoma, sarcoma and pancreatic cancer. In addition to the ADI-PEG 20 program, Polaris Group is researching and developing other biotherapeutic agents and is advancing 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