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Preclinical Studies in Pancreatic Cancer and Melanoma Demonstrated ADI-PEG 20 Works Synergistically With Inhibitors of Autophagy
Date:4/11/2011

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 induce
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