This project is directed toward the development of new chemotherapeutic agents for the treatment of melanoma based on the strategy of autophagy inhibition. Autophagy is an intracellular lysosome-dependent degradative process that protects cancer cells from metabolic and therapeutic stress within the tumor microenvironment. Autophagy inhibition with chloroqulne (CQ) derivatives augments the efficacy of many anticancer therapies, but has limited activity as a single agent therapy despite high levels of autophagy found in most tumors. Numerous clinical trials are testing the combination of variety of anticancer agents witJi hydroxychloroquine (HCQ), an analog of chloroqulne, but concerns have been raised about the potency of HCQ, and its pooriy understood mechanism of action. We have prepared dimeric bisaminoquinoline autophagy inhibitors that are ca. 10x more potent in vitro and in vivo than CQ or HCQ. Our hypothesis is that the new inhibitor LysOS is a more effective inhibitor of a specific unidentified target within the lysosome than standard monovalent CQ derivatives.
Our specific aims are: 1) to identify the chemical determinants that characterize the most potent bisaminoquinoline autophagy inhibitors for melanoma cells;2) to identify the molecular target of LysOS and second-generation bisaminoquinoline autophagy inhibitors in melanoma cells;and 3) to characterize the fates of melanoma cells treated with BAIs, alone and in combination with existing and novel targeted therapies for melanoma. The result of these studies will be the development of potent autophagy inhibitors with known molecular targets and mechanisms of action that will be promising drug development candidates for the treatment of melanoma.

Public Health Relevance

Autophagy is a targetable resistance mechanism to nearly all known anticancer agents, and it plays a particularly important role in melanoma. Currently there are numerous clinical trials testing autophagy inhibition in cancer patients in general and in melanoma patients in particular, coordinated by Dr. Amaravadi at the Hospital of the University of Pennsylvania, employing low potency chloroqulne derivatives as first generation autophagy inhibitors. More potent and targeted autophagy inhibitors are currently unavailable. This proposal is designed to generate a drug candidate based on LysOS, a highly potent bisaminoquinoline autophagy inhibitor that we have developed. Knowledge of the key chemical determinants of effective autophagy inhibition, the molecular target of lysosomotropic aminoquinolines and the antitumor efficacy of these compounds when combined with chemotherapy and targeted therapies will have a significant impact in the field of melanoma chemotherapy. These studies will lead to the development of drug candidates for the treatment of melanoma, with known molecular targets and mechanisms of action;based on the inhibition of autophagy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA114046-06
Application #
8589631
Study Section
Special Emphasis Panel (ZCA1-RPRB-2 (M1))
Project Start
2005-04-01
Project End
2018-08-31
Budget Start
2013-09-25
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$465,052
Indirect Cost
$148,795
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Webster, Marie R; Xu, Mai; Kinzler, Kathryn A et al. (2015) Wnt5A promotes an adaptive, senescent-like stress response, while continuing to drive invasion in melanoma cells. Pigment Cell Melanoma Res 28:184-95
Leu, Julia I-Ju; Zhang, Pingfeng; Murphy, Maureen E et al. (2014) Structural basis for the inhibition of HSP70 and DnaK chaperones by small-molecule targeting of a C-terminal allosteric pocket. ACS Chem Biol 9:2508-16
Vultur, A; Villanueva, J; Krepler, C et al. (2014) MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene 33:1850-61
Streib, Manuel; Kraling, Katja; Richter, Kristin et al. (2014) An organometallic inhibitor for the human repair enzyme 7,8-dihydro-8-oxoguanosine triphosphatase. Angew Chem Int Ed Engl 53:305-9
Ma, Xiao-Hong; Piao, Sheng-Fu; Dey, Souvik et al. (2014) Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J Clin Invest 124:1406-17
Zhang, Pingfeng; Leu, Julia I-Ju; Murphy, Maureen E et al. (2014) Crystal structure of the stress-inducible human heat shock protein 70 substrate-binding domain in complex with peptide substrate. PLoS One 9:e103518
Wang, Tao; Ge, Yingbin; Xiao, Min et al. (2014) SECTM1 produced by tumor cells attracts human monocytes via CD7-mediated activation of the PI3K pathway. J Invest Dermatol 134:1108-18
Malecka, Kimberly A; Fera, Daniela; Schultz, David C et al. (2014) Identification and characterization of small molecule human papillomavirus E6 inhibitors. ACS Chem Biol 9:1603-12
Licciulli, Silvia; Maksimoska, Jasna; Zhou, Chun et al. (2013) FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas. J Biol Chem 288:29105-14
Kastl, Anja; Dieckmann, Sandra; Wahler, Kathrin et al. (2013) Rhenium complexes with visible-light-induced anticancer activity. ChemMedChem 8:924-7

Showing the most recent 10 out of 33 publications