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PubMed | Polaris Group, University of Texas M. D. Anderson Cancer Center, University of Miami and Miami VA Healthcare System
Type: Journal Article | Journal: Oncotarget | Year: 2015

Loss of argininosuccinate synthetase (ASS) expression in melanoma makes these tumor cells vulnerable to arginine deprivation. Pegylated arginine deiminase (ADI-PEG20) which degrades arginine to citrulline and ammonia has been used clinically and partial responses and stable disease have been noted with minimal toxicity. In order to improve the therapeutic efficacy of ADI-PEG20, we have combined ADI-PEG20 with a DNA damaging agent, cisplatin. We have shown that the combination of the two drugs together significantly improved the therapeutic efficacy when compared to ADI-PEG20 alone or cisplatin alone in 4 melanoma cell lines, regardless of their BRAF mutation. In-vivo study also exhibited the same effect as in-vitro with no added toxicity to either agent alone. The underlying mechanism is complex, but increased DNA damage upon arginine deprivation due to decreased DNA repair proteins, FANCD2, ATM, and CHK1/2 most likely leads to increased apoptosis. This action is further intensified by increased proapoptotic protein, NOXA, and decreased antiapoptotic proteins, SURVIVIN, BCL2 and XIAP. The autophagic process which protects cells from apoptosis upon ADI-PEG20 treatment also dampens upon cisplatin administration. Thus, the combination of arginine deprivation and cisplatin function in concert to kill tumor cells which do not express ASS without added toxicity to normal cells.


SAN DIEGO, Nov. 9, 2016 /PRNewswire/ -- Polaris Group announced today that ADI-PEG 20, arginine deiminase formulated with polyethylene glycol, can selectively enhance the effect of radiation in argininosuccinate synthetase (ASS1) deficient pancreatic tumors according to results presented by researchers from MD Anderson Cancer Center at the annual meeting of the American Society for Radiation Oncology (ASTRO). The researchers reported that pre-treatment of ADI-PEG 20 sensitizes ASS1-deficient pancreatic tumor cells to radiation both in vitro and in vivo, resulting in enhanced cell killing in tissue culture and significantly delayed tumor growth in an animal model. It is well known that radiation-associated cellular damage induces endoplasmic reticulum (ER) stress signals, which leads to disruption of cell cycle and apoptosis. The results revealed that ADI-PEG 20 treatment increased the expression level of multiple proteins involved in ER stress induced by radiation, providing insight into the mechanism behind radio-sensitization by ADI-PEG 20. ADI-PEG 20 was designed to deplete arginine in the circulation. Tumor cells deficient in ASS1, a key enzyme in the arginine biosynthesis loop, are expected to be more sensitive to ADI-PEG 20 treatment. "We are intrigued by the discovery that ADI-PEG 20 radio-sensitizes ASS1-deficient pancreatic cancer by upregulating proteins involved in ER stress, thereby expanding its mechanism of action and the scope of its potential use as an oncology therapeutic," said John Bomalaski, M.D., Executive Vice President of Medical Affairs at Polaris Pharmaceuticals, Inc. ADI-PEG 20 is a biologic being developed by Polaris Group to treat cancers, especially those carrying a major metabolic defect that renders such cancer cells, unlike normal cells, unable to internally synthesize arginine. Because arginine is one of the 20 amino acids that are essential for protein synthesis and survival of cells, it is believed these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI-PEG 20 is designed to deplete the external supply of arginine, which causes arginine-dependent cancer cells to die while leaving the patient's normal cells unharmed. Multiple cancers have been reported to have a high degree of arginine dependency. Polaris Group is a multinational biotechnology company specializing in the research and development of novel pharmaceuticals to treat cancer. The company's lead therapeutic, ADI-PEG 20, is a novel biologic in late stage clinical development. It has been tested in more than twenty clinical trials globally for a wide variety of cancers, including hepatocellular carcinoma, mesothelioma, pancreatic cancer, non-small cell lung cancer, melanoma, acute myeloid leukemia and others. As a fully integrated company, Polaris is engaged in applying protein structure-based drug design technology to develop novel drug candidates for cancers, conducting clinical studies at top-tier cancer centers worldwide, and manufacturing all clinical materials at its certified cGMP facilities in northern California.


SAN DIEGO, Nov. 8, 2016 /PRNewswire/ -- Polaris Group announced today that ADI-PEG 20, arginine deiminase formulated with polyethylene glycol, can selectively enhance the effect of radiation in argininosuccinate synthetase (ASS1) deficient pancreatic tumors according to results presented by researchers from MD Anderson Cancer Center at the annual meeting of the American Society for Radiation Oncology (ASTRO). The researchers reported that pre-treatment of ADI-PEG 20 sensitizes ASS1-deficient pancreatic tumor cells to radiation both in vitro and in vivo, resulting in enhanced cell killing in tissue culture and significantly delayed tumor growth in an animal model.  It is well known that radiation-associated cellular damage induces endoplasmic reticulum (ER) stress signals, which leads to disruption of cell cycle and apoptosis.  The results revealed that ADI-PEG 20 treatment increased the expression level of multiple proteins involved in ER stress induced by radiation, providing insight into the mechanism behind radio-sensitization by ADI-PEG 20. ADI-PEG 20 was designed to deplete arginine in the circulation. Tumor cells deficient in ASS1, a key enzyme in the arginine biosynthesis loop, are expected to be more sensitive to ADI-PEG 20 treatment. "We are intrigued by the discovery that ADI-PEG 20 radio-sensitizes ASS1-deficient pancreatic cancer by upregulating proteins involved in ER stress, thereby expanding its mechanism of action and the scope of its potential use as an oncology therapeutic," said John Bomalaski, M.D., Executive Vice President of Medical Affairs at Polaris Pharmaceuticals, Inc. ADI-PEG 20 is a biologic being developed by Polaris Group to treat cancers, especially those carrying a major metabolic defect that renders such cancer cells, unlike normal cells, unable to internally synthesize arginine. Because arginine is one of the 20 amino acids that are essential for protein synthesis and survival of cells, it is believed these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI-PEG 20 is designed to deplete the external supply of arginine, which causes arginine-dependent cancer cells to die while leaving the patient's normal cells unharmed. Multiple cancers have been reported to have a high degree of arginine dependency. Polaris Group is a multinational biotechnology company specializing in the research and development of novel pharmaceuticals to treat cancer. The company's lead therapeutic, ADI-PEG 20, is a novel biologic in late stage clinical development. It has been tested in more than twenty clinical trials globally for a wide variety of cancers, including hepatocellular carcinoma, mesothelioma, pancreatic cancer, non-small cell lung cancer, melanoma, acute myeloid leukemia and others. As a fully integrated company, Polaris is engaged in applying protein structure-based drug design technology to develop novel drug candidates for cancers, conducting clinical studies at top-tier cancer centers worldwide, and manufacturing all clinical materials at its certified cGMP facilities in northern California.


PubMed | Washington University in St. Louis, Polaris Group and Cleveland Clinic
Type: Journal Article | Journal: Cell death & disease | Year: 2016

Sarcomas comprise a large heterogeneous group of mesenchymal cancers with limited therapeutic options. When treated with standard cytotoxic chemotherapies, many sarcomas fail to respond completely and rapidly become treatment resistant. A major problem in the investigation and treatment of sarcomas is the fact that no single gene mutation or alteration has been identified among the diverse histologic subtypes. We searched for therapeutically druggable targets that are common to a wide range of histologies and hence could provide alternatives to the conventional chemotherapy. Seven hundred samples comprising 45 separate histologies were examined. We found that almost 90% were arginine auxotrophs, as the expression of argininosuccinate synthetase 1 was lost or significantly reduced. Arginine auxotrophy confers sensitivity to arginine deprivation, leading temporarily to starvation and ultimately to cell survival or death under different circumstances. We showed that, in sarcoma, arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20) maintains a prolonged state of arginine starvation without causing cell death. However, when starvation was simultaneously prolonged by ADI-PEG20 while inhibited by the clinically available drug chloroquine, sarcoma cells died via necroptosis and apoptosis. These results have revealed a novel metabolic vulnerability in sarcomas and provided the basis for a well-tolerated alternative treatment strategy, potentially applicable to up to 90% of the tumors, regardless of histology.


Kelly M.P.,Sloan Kettering Cancer Center | Jungbluth A.A.,Sloan Kettering Cancer Center | Wu B.-W.,Polaris Group | Bomalaski J.,Polaris Group | And 2 more authors.
British Journal of Cancer | Year: 2012

Background: Some cancers have been shown to lack expression of argininosuccinate synthetase (ASS), an enzyme required for the synthesis of arginine and a possible biomarker of sensitivity to arginine deprivation. Arginine deiminase (ADI) is a microbial enzyme capable of efficiently depleting peripheral blood arginine. Methods: Argininosuccinate synthetase expression was assessed in human small cell lung cancer (SCLC) by immunohistochemistry (IHC), with expression also assessed in a panel of 10 human SCLC by qRT-PCR and western blot. Proliferation assays and analyses of apoptosis and autophagy assessed the effect of pegylated ADI (ADI-PEG20) in vitro. The in vivo efficacy of ADI-PEG20 was determined in mice bearing SCLC xenografts. Results: Approximately 45% of SCLC tumours and 50% of cell lines assessed were negative for ASS. Argininosuccinate synthetase-deficient SCLC cells demonstrated sensitivity to ADI-PEG20, which was associated with the induction of autophagy and caspase-independent cell death. Arginine deiminase-PEG20 treatment of ASS-negative SCLC xenografts caused significant, dose-dependent inhibition of tumour growth of both small and established tumours. Conclusion: These results suggest a role for ADI-PEG20 in the treatment of SCLC, and a clinical trial exploring this therapeutic approach in patients with ASS-negative SCLC by IHC has now been initiated. © 2012 Cancer Research UK All rights reserved.


Feun L.G.,University of Miami | Marini A.,University of Miami | Walker G.,University of Miami | Elgart G.,University of Miami | And 10 more authors.
British Journal of Cancer | Year: 2012

Background: Arginine-depleting therapy with pegylated arginine deiminase (ADI-PEG20) was reported to have activity in advanced melanoma in early phase I-II trial, and clinical trials are currently underway in other cancers. However, the optimal patient population who benefit from this treatment is unknown. Methods: Advanced melanoma patients with accessible tumours had biopsy performed before the start of treatment with ADI-PEG20 and at the time of progression or relapse when amenable to determine whether argininosuccinate synthetase (ASS) expression in tumour was predictive of response to ADI-PEG20.Results:Twenty-seven of thirty-eight patients treated had melanoma tumours assessable for ASS staining before treatment. Clinical benefit rate (CBR) and longer time to progression were associated with negative expression of tumour ASS. Only 1 of 10 patients with ASS-positive tumours (ASS) had stable disease, whereas 4 of 17 (24%) had partial response and 5 had stable disease, when ASS expression was negative (ASS), giving CBR rates of 52.9 vs 10%, P=0.041. Two responding patients with negative ASS expression before therapy had rebiopsy after tumour progression and the ASS expression became positive. The survival of ASS patients receiving at least four doses at 320 IU m -2 was significantly better than the ASS group at 26.5 vs 8.5 months, P=0.024. Conclusion: ADI-PEG20 is safe and the drug is only efficacious in melanoma patients whose tumour has negative ASS expression. Argininosuccinate synthetase tumour positivity is associated with drug resistance and tumour progression. © 2012 Cancer Research UK All rights reserved.

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