Tumors Deficient in a Specific Enzyme Are Sensitive to a New Drug 'ADI-PEG 20'
(Findings reported at AACR meeting held in Washington, DC April 17-21, 2010)
SAN DIEGO, April 21 /PRNewswire/ -- 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
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
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
Polaris Group is a privately held biopharmaceutical company.
Source: Polaris Group
CONTACT: Jim Thomson of Polaris Group, +1-858-452-6688, ext.
Web Site: http://www.polarispharma.com/
Posted: April 2010