Preclinical Studies in Pancreatic Cancer and Melanoma Demonstrated ADI-PEG 20 Works Synergistically With Inhibitors of Autophagy

Data Presented at the 102nd Annual Meeting of the American Association for Cancer Research

SAN DIEGO, April 11, 2011 /PRNewswire/ -- Polaris Group (Polaris) announced today that data from preclinical studies of ADI-PEG 20, the Company's pegylated arginine deiminase therapeutic, is synergistic with hydroxychloroquine (ChQ) in a human pancreatic cancer cell line and with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in human melanoma cell lines. Both ChQ and TRAIL are known inhibitors of autophagy. These results support the commencement of Phase 1/2 clinical studies in these cancer types to investigate the combination of ADI-PEG 20 with autophagy inhibitors.

"We are excited to learn that ADI-PEG 20 can potentially be used in combination with yet another class of chemotherapeutic agents," commented John Bomalaski, M.D., executive vice president, medical affairs of Polaris. "ADI-PEG 20 has already demonstrated apparent efficacy and remarkable safety in clinical trials as a single agent. We are now making plans to initiate clinical studies to test the efficacy and safety of ADI-PEG 20 when used in combination with antitumor agents and other compounds."  

A summary of the abstracts follows:

Chloroquine induces defective autophagic flux and enhances pancreatic cancer cell death induced by pegylated-arginine deiminase

Rouebeh Daylami et. al. (AACR Abstract # 3782)

A majority of human pancreatic adenocarcinomas are deficient in argininosuccinate synthase (ASS) and are therefore sensitive to arginine deprivation by ADI-PEG 20. ASS-deficient cell lines undergo cell death when deprived of arginine, but also undergo autophagy. It is hypothesized that autophagy is protective in the setting of arginine deprivation and that inhibition of autophagy by hydroxychloroquine (ChQ) would increase cell death. The human pancreatic cancer cell line MIA-PaCa2 was treated in vitro and in vivo with ADI-PEG 20 alone or in the presence of ChQ. In vitro treatment with ADI-PEG 20 induced caspase-dependent cell death as well as autophagy. ChQ at low doses inhibited autophagy induced by ADI-PEG 20, but increased cell death. In xenografts, addition of ChQ to a sub-therapeutic dose of ADI-PEG 20 increased tumor suppression, decreased autophagy and increased cell death compared to either treatment alone. Arginine deprivation by ADI-PEG 20 induces autophagy and cell death in cell lines deficient in ASS1. Autophagy appears to play a protective role, and its inactivation by ChQ enhances tumor suppression. Combining ChQ with ADI-PEG 20 in pancreatic cancer may increase the cell death induced by ADI-PEG 20 by blocking ADI-PEG 20-induced autophagy.

TRAIL enhances cytotoxicity of arginine depletion therapy in argininosuccinate synthetase-negative melanoma cells through interruption of autophagy via activation of caspases

Min You et. al. (AACR Abstract # 4096)

Melanomas that do not express the gene that codes for ASS (ASS1) cannot make arginine from citrulline; thus arginine depletion caused by ADI-PEG 20 results in growth inhibition and eventually leads to cell death. However, autophagy does take place during arginine deprivation in melanoma which prevents death in some melanoma cells. During this period, certain melanoma cells can turn on the ASS1 gene and hence become resistant to ADI-PEG 20. It has previously been shown that combining tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with ADI-PEG 20 can accelerate the cell death (apoptosis) process and hence greatly enhance cytotoxicity. In this study, further data from combination treatment confirm that the enhancement effect of the combination needs the participation of both the extrinsic and intrinsic pathways of apoptosis. This finding suggests that the combination treatment turns off the autophagic process during arginine deprivation, possibly through caspase activation, and allows the apoptotic process to take place. Overall, these findings indicate that autophagy is a pro-survival mechanism in melanoma cells under nutritional stress, and interfering with this pathway may achieve greater efficacy with ADI-PEG 20 treatment.

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. Phase 2 clinical trials have yielded positive results in patients with hepatocellular carcinoma or metastatic melanoma, and Phase 2 trials for small cell lung cancer and mesothelioma are currently ongoing. Polaris also plans to initiate clinical studies in prostate cancer, pancreatic cancer, leukemia, lymphoma and sarcoma this year.

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 advancing into 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, prostate cancer, 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

Posted: April 2011

View comments

Hide
(web2)