Transcriptional Silencing of ASS1 Suggests the Potential Use of ADI-PEG 20 to Treat AML, Glioblastoma and Bladder Cancer
Data Presented at the 102nd Annual Meeting of the American Association for Cancer Research
SAN DIEGO, April 8, 2011 /PRNewswire/ -- Polaris Group (Polaris) announced today that data from preclinical studies suggest ADI-PEG 20, the Company's pegylated arginine deiminase therapeutic, may be effective in treating acute myeloid leukemia (AML), glioblastoma multiforme (GBM) and bladder cancer. These cancers have a high incidence of deficiencies of the arginine synthesis enzyme argininosuccinate synthetase (ASS) due to hypermethylation at the promoter of the gene that codes for ASS (ASS1). Lack of expression of ASS1 causes the tumor cells to rely on externally supplied arginine for survival and thus become susceptible to arginine-degrading enzymes such as ADI-PEG 20.
"We are excited that AML, bladder cancer and glioblastoma multiforme have been identified as cancers that may be responsive to arginine deprivation therapy with ADI-PEG 20," said John Bomalaski, M.D., executive vice president, medical affairs of Polaris. "Polaris has completed Phase 2 clinical testing of ADI-PEG 20 in hepatocellular carcinoma (HCC) and melanoma and is about to initiate a pivotal Phase 3 trial in HCC. We are hopeful that the positive clinical results already observed in HCC and melanoma will be reproduced in these new potential indications."
A summary of the abstracts follows:
Pegylated arginine deiminase (ADI-PEG 20) as a potential novel therapy for argininosuccinate synthetase-deficient acute myeloid leukemia
Peter Szlosarek, et.al. (AACR Abstract # 467)
AML is the most common leukemia in adults and the second most common leukemia in children. A lack of ASS1 protein was identified in three of seven leukemic cell lines and in all nine samples acquired from AML patients. Methylation of the ASS1 promoter correlated with reduced levels of ASS1 mRNA and absence of ASS1 expression. Bone marrow trephines from patients with AML revealed absence of ASS1 protein in 87 percent (46/53) of samples by immunohistochemistry, indicating that ASS1 expression may be a biomarker of response to ADI-PEG 20 in vivo. ADI-PEG 20 significantly reduced the viability of ASS1-negative AML lines, whereas the ASS1-positive control lines were resistant to drug-induced arginine deprivation.
Epigenetic silencing of argininosuccinate synthetase renders human bladder cancer cells sensitive to pegylated arginine deiminase
Michael Allen, et.al. (AACR Abstract # 76)
Based on reports of instability at 9q34, in bladder cancer, the ASS1 status was investigated using a variety of molecular and genetic techniques, and the impact of arginine deprivation on the viability of bladder cancer cell lines in vitro and in vivo was assessed. Very low mRNA levels and no ASS1 protein were found in three of seven bladder cancer cell lines. The ASS1-negative cell lines were all hypermethylated at the ASS1 promoter, compared with the ASS1-positive cell lines, which were hypomethylated. There was no evidence for ASS1 mutations by gene sequencing or loss of heterozygosity by fluorescence in situ hybridization and single nucleotide polymorphism arrays. An analysis of 48 patients with bladder cancer revealed 65 percent were ASS1-negative by immunohistochemistry, with evidence for ASS1 methylation as the mechanism for ASS1 inactivation. The arginine depleting agent ADI-PEG 20 triggered caspase-dependent and independent apoptosis of ASS1-negative cell lines, whereas ASS1-positive control bladder cell lines were resistant to ADI-PEG 20. In addition, down-regulation of ribonucleotide reductase M2 (RRM2) has been identified as a biomarker of ADI-PEG 20 activity, and ongoing work is focused on combining ADI-PEG 20 with cisplatin-doublet chemotherapy in vivo.
Transcriptional silencing disrupts two levels of arginine biosynthesis in glioblastoma multiforme: a novel, targeted therapeutic strategy for high grade gliomas
Nelofer Syed, et. Al. (AACR Abstract # LB 260)
Both ASS1 and argininosuccinate lyase (ASL) are down-regulated in glioblastoma multiforme (GBM). Down-regulation correlates with aberrant, neoplasia-specific methylation in each gene, and expression is restored by demethylation. Arginine starvation produced by exposure to ADI-PEG 20 induces an adaptive transcriptional up-regulation of both ASS1 and ASL that is blocked in GBM cells by methylation. Cells lacking ASS or ASL are sensitive to arginine deprivation and die by apoptosis when treated with ADI-PEG 20. In de novo GBM treated by surgical debulking, ASS1 was silenced in 13/60 (21.7 percent) cases and ASL in 3/60 (5 percent). These cases had no expression of the proteins, as seen by immunohistochemistry, as well as aberrant gene methylation.
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