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.
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.
|Ojha, Rani; Leli, Nektaria M; Onorati, Angelique et al. (2018) ER translocation of the MAPK pathway drives therapy resistance in BRAF mutant melanoma. Cancer Discov :
|Kugel 3rd, Curtis H; Douglass, Stephen M; Webster, Marie R et al. (2018) Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations. Clin Cancer Res 24:5347-5356
|Nicastri, Michael C; Rebecca, Vito W; Amaravadi, Ravi K et al. (2018) Dimeric quinacrines as chemical tools to identify PPT1, a new regulator of autophagy in cancer cells. Mol Cell Oncol 5:e1395504
|Nti, Akosua A; Serrano, Leona W; Sandhu, Harpal S et al. (2018) FREQUENT SUBCLINICAL MACULAR CHANGES IN COMBINED BRAF/MEK INHIBITION WITH HIGH-DOSE HYDROXYCHLOROQUINE AS TREATMENT FOR ADVANCED METASTATIC BRAF MUTANT MELANOMA: Preliminary Results From a Phase I/II Clinical Treatment Trial. Retina :
|Perego, M; Maurer, M; Wang, J X et al. (2018) A slow-cycling subpopulation of melanoma cells with highly invasive properties. Oncogene 37:302-312
|Echevarría-Vargas, Ileabett M; Reyes-Uribe, Patricia I; Guterres, Adam N et al. (2018) Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma. EMBO Mol Med 10:
|Hammerlindl, Heinz; Ravindran Menon, Dinoop; Hammerlindl, Sabrina et al. (2018) Acetylsalicylic Acid Governs the Effect of Sorafenib in RAS-Mutant Cancers. Clin Cancer Res 24:1090-1102
|Ecker, Brett L; Kaur, Amanpreet; Douglass, Stephen M et al. (2018) Age-Related Changes in HAPLN1 Increase Lymphatic Permeability and Affect Routes of Melanoma Metastasis. Cancer Discov :
|Cañadas, Israel; Thummalapalli, Rohit; Kim, Jong Wook et al. (2018) Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med 24:1143-1150
|Grasso, Michael; Estrada, Michelle A; Berrios, Kiara N et al. (2018) N-(7-Cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK632) Promotes Inhibition of BRAF through the Induction of Inhibited Dimers. J Med Chem 61:5034-5046
Showing the most recent 10 out of 144 publications