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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-2 (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wistar Institute
United States
Zip Code
Kaur, Amanpreet; Webster, Marie R; Marchbank, Katie et al. (2016) sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532:250-4
Budina-Kolomets, Anna; Webster, Marie R; Leu, Julia I-Ju et al. (2016) HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors. Cancer Res 76:2720-30
Lu, Hezhe; Liu, Shujing; Zhang, Gao et al. (2016) Oncogenic BRAF-Mediated Melanoma Cell Invasion. Cell Rep 15:2012-24
Amaravadi, Ravi; Kimmelman, Alec C; White, Eileen (2016) Recent insights into the function of autophagy in cancer. Genes Dev 30:1913-30
Krepler, Clemens; Xiao, Min; Samanta, Minu et al. (2016) Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma. Oncotarget :
Grasso, Michael; Estrada, Michelle A; Ventocilla, Christian et al. (2016) Chemically Linked Vemurafenib Inhibitors Promote an Inactive BRAF(V600E) Conformation. ACS Chem Biol 11:2876-2888
Shannan, Batool; Chen, Quan; Watters, Andrea et al. (2016) Enhancing the evaluation of PI3K inhibitors through 3D melanoma models. Pigment Cell Melanoma Res 29:317-28
Jennis, Matthew; Kung, Che-Pei; Basu, Subhasree et al. (2016) An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev 30:918-30
Chatwichien, Jaruwan; Basu, Subhasree; Budina-Kolomets, Anna et al. (2016) PUMA-dependent apoptosis in NSCLC cancer cells by a dimeric β-carboline. Bioorg Med Chem Lett 26:4884-4887
Krepler, Clemens; Xiao, Min; Sproesser, Katrin et al. (2016) Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies. Clin Cancer Res 22:1592-602

Showing the most recent 10 out of 87 publications