Malignant melanoma is usually resistant to drug therapy which historically has been non-selective in action and often very toxic. A novel approach is to target a specific defect found in melanoma cells. We and others have shown that exposure of melanoma cells to arginine deiminase (ADI), an enzyme that catalyzes the hydrolysis of arginine to citrulline, results in apoptotic cell death. This unique sensitivity to ADI is primarily due to the fact that melanoma cells, unlike normal cells, do not express argininosuccinate synthetase (ASS) and hence are unable to synthesize arginine. Transfection of ASS cDNA confers resistance to AD1, further confirming that lack of ASS expression is critical for ADI sensitivity. We formulated a pegylated form of ADI (ADI-PEG20) to reduce immunogenicity and to increase the half-life. ADI-PEG20 has shown significant antitumor activity in vivo with low toxicity. We have completed a Phase I trial of ADI-PEG20 in advanced melanoma. Remarkably, 5/10 patients had partial response when treated at a dose >160 IU/m2, a dose that depleted plasma arginine to non detectable levels for >7 days. No > grade 2 toxicity was observed. Interestingly, two patients who did not respond had ASS expression in their tumors. In this application, we plan to conduct a Phase II trial to confirm the antitumor activity in advanced melanoma as outlined in specific aim 1.
In specific aim 2, we will assay ASS in tumor samples by immunohistochemistry and RT-PCR prior and after treatment to assess whether ASS expression can be a predictor for tumor response, and whether de-repression of ASS occurs at relapse.
In specific aim 3, we will investigate the possible mechanism of apoptotic cell death by ADI-PEG20. In addition, the possible mechanism(s) of resistance will be examined by using an in-vitro cell line made resistant to ADI-PEG20 and by using de-novo resistant cell lines derived from tumors at time of treatment failure. In order to optimize future use of ADI-PEG20, we will investigate whether pharmacological manipulation can induce/repress ASS expression. Our goal is to improve the treatment outcome of melanoma while minimizing toxicity by targeting a specific defect in melanoma cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA109578-01
Application #
6816878
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Xie, Heng
Project Start
2004-08-06
Project End
2007-07-31
Budget Start
2004-08-06
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$204,525
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
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Li, Ying-Ying; Feun, Lynn G; Thongkum, Angkana et al. (2017) Autophagic Mechanism in Anti-Cancer Immunity: Its Pros and Cons for Cancer Therapy. Int J Mol Sci 18:
Li, Ying-Ying; Wu, Chunjing; Chen, Shu-Mei et al. (2016) BRAF inhibitor resistance enhances vulnerability to arginine deprivation in melanoma. Oncotarget 7:17665-80
Savaraj, Niramol; Wu, Chunjing; Li, Ying-Ying et al. (2015) Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin. Oncotarget 6:6295-309
You, Min; Savaraj, Niramol; Kuo, Macus T et al. (2013) TRAIL induces autophagic protein cleavage through caspase activation in melanoma cell lines under arginine deprivation. Mol Cell Biochem 374:181-90
Feun, L G; Marini, A; Walker, G et al. (2012) Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase. Br J Cancer 106:1481-5
Wangpaichitr, Medhi; Sullivan, Elizabeth J; Theodoropoulos, George et al. (2012) The relationship of thioredoxin-1 and cisplatin resistance: its impact on ROS and oxidative metabolism in lung cancer cells. Mol Cancer Ther 11:604-15
You, Min; Savaraj, Niramol; Wangpaichitr, Medhi et al. (2010) The combination of ADI-PEG20 and TRAIL effectively increases cell death in melanoma cell lines. Biochem Biophys Res Commun 394:760-6
Kuo, Macus Tien; Savaraj, Niramol; Feun, Lynn G (2010) Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes. Oncotarget 1:246-51
Savaraj, N; You, M; Wu, C et al. (2010) Arginine deprivation, autophagy, apoptosis (AAA) for the treatment of melanoma. Curr Mol Med 10:405-12

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