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 #
5P01CA114046-10
Application #
9334558
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2008-05-16
Project End
2019-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Noguera-Ortega, Estela; Amaravadi, Ravi K (2018) Autophagy in the Tumor or in the Host: Which Plays a Greater Supportive Role? Cancer Discov 8:266-268
Jenkins, Russell W; Aref, Amir R; Lizotte, Patrick H et al. (2018) Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Cancer Discov 8:196-215
Emptage, Ryan P; Lemmon, Mark A; Ferguson, Kathryn M et al. (2018) Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain. Structure 26:1137-1143.e3
Barnoud, Thibaut; Budina-Kolomets, Anna; Basu, Subhasree et al. (2018) Tailoring Chemotherapy for the African-Centric S47 Variant of TP53. Cancer Res 78:5694-5705
Liu, Shujing; Zhang, Gao; Guo, Jianping et al. (2018) Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis. Nat Commun 9:5426
Pathria, Gaurav; Scott, David A; Feng, Yongmei et al. (2018) Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival. EMBO J 37:
Reyes-Uribe, Patricia; Adrianzen-Ruesta, Maria Paz; Deng, Zhong et al. (2018) Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma. Oncogene 37:4058-4072
Rebecca, Vito W; Nicastri, Michael C; Fennelly, Colin et al. (2018) PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. Cancer Discov :
Kaur, Amanpreet; Ecker, Brett L; Douglass, Stephen M et al. (2018) Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility. Cancer Discov :
Chen, Gang; Huang, Alexander C; Zhang, Wei et al. (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560:382-386

Showing the most recent 10 out of 144 publications