Hypoxia-activated prodrug enhances therapeutic effect of sunitinib in melanoma
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Shujing Liu1,2, Michael T. Tetzlaff 3, Tao Wang4, Xiang Chen5, Ruifeng Yang2, Suresh M. Kumar2, Adina Vultur6, Pengxiang Li7, James S. Martin2, Meenhard Herlyn6, Ravi Amaravadi8, Bin Li1,* and Xiaowei Xu2,*
1Department of Dermatology, Yueyang Hospital, Shanghai 200437, China
2Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
3Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
4Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
5Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China
6The Wistar Institute, Philadelphia, PA 19104, USA
7Leonard Davis Institute of Health Economics, Philadelphia, PA 19104, USA
8Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
*These authors have contributed equally to this work
Xiaowei Xu, email: [email protected]
Bin Li, email: [email protected]
Keywords: TH302; sunitinib; hypoxia; melanoma; treatment
Received: March 20, 2017 Accepted: July 16, 2017 Published: December 05, 2017
Angiogenesis is a critical step during tumor progression. Anti-angiogenic therapy has only provided modest benefits in delaying tumor progression despite its early promise in cancer treatment. It has been postulated that anti-angiogenic therapy may promote the emergence of a more aggressive cancer cell phenotype by generating increased tumor hypoxia—a well-recognized promoter of tumor progression. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) which has been shown to selectively target the hypoxic tumor compartment and reduce tumor volume. Here, we show that melanoma cells grown under hypoxic conditions exhibit increased resistance to a wide variety of therapeutic agents in vitro and generate larger and more aggressive tumors in vivo than melanoma cells grown under normoxic conditions. However, hypoxic melanoma cells exhibit a pronounced sensitivity to TH-302 which is further enhanced by the addition of sunitinib. Short term sunitinib treatment fails to prolong the survival of melanoma bearing genetically engineered mice (Tyr::CreER; BRafCA;Ptenlox/lox) but increases tumor hypoxia. Long term TH-302 alone modestly prolongs the overall survival of melanoma bearing mice. Combination therapy of TH-302 with sunitinib further increases the survival of treated mice. These studies provide a translational rationale for combining hypoxic tumor cell targeted therapies with anti-angiogenics for treatment of melanoma.
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