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Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin.

ABSTRACT: 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.

SUBMITTER: Savaraj N

PROVIDER: S-EPMC4467438 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin.

Savaraj Niramol N Wu Chunjing C Li Ying-Ying YY Wangpaichitr Medhi M You Min M Bomalaski John J He Wei W Kuo Macus Tien MT Feun Lynn G LG

Oncotarget 20150301 8

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 to ...[more]

PMID: 25749046

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Project description:Abstract BACKGROUND Patients (pts) with recurrent HGGs are usually managed with alkylating chemotherapy +/- bevacizumab. However, prognosis remains poor with an overall survival (OS) of 7–9 months. Preclinically, we showed that HGGs are a target for arginine depletion with Pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-ve HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. METHODS We expanded a phase 1 trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS), which noted activity in aggressive thoracic cancers, to pts with relapsed HGGs (clinicaltrials.gov NCT02029690). Pts with ASS1-ve recurrent HGGs were enrolled (01/16 – 06/17) to receive ADI-PEG20 weekly at the maximum tolerated dose of 36 mg/m2 i.m. plus PEM 500 mg/m2 and CIS 75 mg/m2 i.v. every 3 weeks for up to 6 cycles. Pts with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability and preliminary estimates of activity. Additional endpoints included pharmacodynamics, immunogenicity, OS, and ASS1/ASL epimutations. RESULTS 10/19 ASS1-ve heavily pre-treated pts were enrolled onto ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events (AEs) being CTCAE v4.03 grade 1–2; 7 pts (70%) had at least one grade 3 or 4 AE with neutropenia (40%) and thrombocytopenia (30%). The best response was stable disease by RECIST 1.1 and partial response (n=1; 10%) by RANO criteria. The median (95% CI) OS was 6.5 (1.8, 9.7) months. Two pts are alive and one continues 16 months on ADI-PEG20 as 3rd-line therapy for a de novo IDH-wildtype glioblastoma multiforme. Epimutations in ASS1 and/or ASL were detectable in pts’ tumours consistent with prior studies. CONCLUSIONS ADIPEMCIS was well tolerated and compares favourably to historical controls in recurrent HGG. A randomised, phase II trial comparing ADIPEMCIS with alkylating drugs at first relapse is planned (ATOMIC-G).

Project description:Arginine (Arg) deprivation is a promising therapeutic approach for tumors with low argininosuccinate synthetase 1 (ASS1) expression. However, its efficacy as a single agent therapy needs to be improved as resistance is frequently observed. Methods: A tissue microarray was performed to assess ASS1 expression in surgical specimens of pancreatic ductal adenocarcinoma (PDAC) and its correlation with disease prognosis. An RNA-Seq analysis examined the role of ASS1 in regulating the global gene transcriptome. A high throughput screen of FDA-approved oncology drugs identified synthetic lethality between histone deacetylase (HDAC) inhibitors and Arg deprivation in PDAC cells with low ASS1 expression. We examined HDAC inhibitor panobinostat (PAN) and Arg deprivation in a panel of human PDAC cell lines, in ASS1-high and -knockdown/knockout isogenic models, in both anchorage-dependent and -independent cultures, and in multicellular complex cultures that model the PDAC tumor microenvironment. We examined the effects of combined Arg deprivation and PAN on DNA damage and the protein levels of key DNA repair enzymes. We also evaluated the efficacy of PAN and ADI-PEG20 (an Arg-degrading agent currently in Phase 2 clinical trials) in xenograft models with ASS1-low and -high PDAC tumors. Results: Low ASS1 protein level is a negative prognostic indicator in PDAC. Arg deprivation in ASS1-deficient PDAC cells upregulated asparagine synthetase (ASNS) which redirected aspartate (Asp) from being used for de novo nucleotide biosynthesis, thus causing nucleotide insufficiency and impairing cell cycle S-phase progression. Comprehensively validated, HDAC inhibitors and Arg deprivation showed synthetic lethality in ASS1-low PDAC cells. Mechanistically, combined Arg deprivation and HDAC inhibition triggered degradation of a key DNA repair enzyme C-terminal-binding protein interacting protein (CtIP), resulting in DNA damage and apoptosis. In addition, S-phase-retained ASS1-low PDAC cells (due to Arg deprivation) were also sensitized to DNA damage, thus yielding effective cell death. Compared to single agents, the combination of PAN and ADI-PEG20 showed better efficacy in suppressing ASS1-low PDAC tumor growth in mouse xenograft models. Conclusion: The combination of PAN and ADI-PEG20 is a rational translational therapeutic strategy for treating ASS1-low PDAC tumors through synergistic induction of DNA damage.

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Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin.

Publications

Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin.

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