Cancers deficient in ASS enzyme allow ADI-PEG 20 to inhibit cancer cell growth

Apr 22 2010

Polaris Group scientists and university collaborators reported at the American Association for Cancer Research (AACR), that a number of different cancers have a deficiency in a specific enzyme, argininosuccinate synthetase (ASS), which allows pegylated arginine deiminase (ADI-PEG 20) to inhibit cancer cell growth. "Polaris has been testing this drug in melanoma patients and patients with hepatocellular carcinoma (HCC), two tumors that are ASS deficient, and we are preparing to initiate a global phase 3 clinical trial in HCC to seek regulatory approval for marketing ADI-PEG 20," said Dr. Bor-Wen Wu, CEO of Polaris. "In addition, these new results show that ADI-PEG 20 may be beneficial in a number of other tumors."

ASS is required for the production of arginine, an amino acid needed for growth and replication of cells. Normal tissue cells have normal levels of ASS and can produce sufficient arginine for their own growth and survival in the presence of ADI-PEG 20.  However, growth and replication of ASS-deficient tumor cells is inhibited by ADI-PEG 20 because arginine in these cells is degraded and depleted. The studies presented at AACR have shown that various other tumors also have a deficiency in ASS.  He et al, Polaris Group, reported that 30-60% of human breast, lung and gastric cancers were deficient in ASS.  Treatment of these and other tumor types in cell culture, including sarcoma, leukemia and plasmacytoma, showed significant inhibition of cell growth by ADI-PEG 20. He et al also established primary renal cell carcinoma cultures from fresh human tumor biopsies which were ASS-deficient.  ADI-PEG 20 inhibited growth of these cells.  These findings suggest that ASS deficiency may serve as a biomarker for selecting tumors for targeted therapy with ADI-PEG 20.

Rubin et al, Cleveland Clinic, showed that 88% of 45 different human sarcomas were ASS-deficient.  Treatment of two sarcomas, gastrointestinal stromal tumor (GIST) and malignant peripheral nerve sheath tumor (MPNST) with ADI-PEG 20 resulted in inhibition of proliferation.

Based on analysis by Jungbluth and collaborators, Ludwig Institute for Cancer Research New York Branch at Memorial Sloan-Kettering Cancer Center, demonstrating that ~50% of human small cell lung cancer (SCLC) tumor specimens were ASS-deficient, Kelly et al, showed that growth of ASS negative cell lines was inhibited by ADI-PEG 20 in cell culture.  They further showed that ADI-PEG 20 treatment of mice bearing ASS-deficient SCLC xenograft tumors caused significant and dose dependent inhibition of tumor growth in the animals.  

It has been well established that treatment of human cancer with two or more drug combinations can be much more effective than the individual drugs administered alone.  Two reports provided evidence that ADI-PEG 20 plus cisplatin treatment in cell cultures of ASS-deficient malignant pleural mesothelioma (Szlosarek et al, Barts Cancer Research UK Centre) and melanoma (Feun et al, University of Miami) resulted in synergistic cytotoxic effects on the cancer cells compared to either agent alone.  Additional evidence of inhibition of pancreatic xenograft tumors was presented by Bold et al, University of California at Davis.  Mice bearing ASS-deficient human pancreatic tumors were treated with ADI-PEG 20 plus gemcitabine and showed that the two drugs in combination inhibited tumor growth much more effectively that either drug alone.

Based on these and other findings, ADI-PEG 20 clinical trials are planned to begin in the near future for treatment of patients with malignant mesothelioma, SCLC, sarcoma, leukemia or pancreatic cancer.

SOURCE Polaris Group