The overall goal of project 4 is to develop novel approaches distinct from ATP mimetics to overcome resistance to BRAF inhibitors for treatment of melanoma. This project will focus on two mechanisms of resistance;BRAF dimerization leading to paradoxical MAPK activation and STATS activation which is downstream of a number of parallel signaling pathways that are activated in BRAF inhibitor resistant cells as well as in BRAF^'"^ cells. We will also determine if combination of BRAF inhibitors with the inhibition of broad cellular biological properties that sustain survival of resistant tumor cells, specifically the stress response or autophagy, can kill melanomas and prevent the emergence of drug resistance. Together, we hypothesize that targeting these pathways will overcome therapeutic resistance in a large subset of BRAF mutant melanomas, and possibly other melanoma genotypes.
The Specific Aims of the proposal are to (1) Develop inhibitors that selectively target RAF dimers. Since BRAF inhibition can lead to paradoxical MAPK activation through RAF dimers in both normal tissues and in resistant melanoma tumors, we hypothesize that targeting RAF dimers will be more effective for melanoma therapy than targeting monomeric mutant BRAF. We will employ two complementary inhibitor design strategies to target RAF dimers and evaluate the biological activity of the resulting inhibitors. (2) Develop novel STAT3 inhibitors. STATS is activated in a high proportion of melanomas and is upregulated in response to BRAF and MEK inhibition. In preliminary studies, we have developed a family of quinolol/naphthol compounds that are low-micromolar inhibitors of STATS activation through the apparent binding to the SH2 phospho-binding domain of STATS. We will now use structure-based design and medicinal chemistry to prepare more potent and selective inhibitors and evaluate the biological activity of inhibitors alone and in combination with BRAF inhibitors. (3) Determine if combination of BRAF inhibitors with HSP70 or autophagy antagonists can kill melanomas and prevent the emergence of drug resistance. HSP70 is overexpressed in BRAF mutant melanoma and HSP70 inhibitors have shown promising pre-clinical efficacy in melanoma. High autophagy levels are also common in melanoma and correlate with poor response to chemotherapy and shortened overall survival;and BRAF inhibitors can induce autophagy as a survival mechanism. We hypothesize that dual inhibition of BRAF and HSP70 or autophagy will be an effective therapeutic strategy for melanoma. Together, we anticipate that these studies will provide novel and attractive avenues to overcome resistance to BRAF inhibition in melanoma in order to provide effective long-lasting therapies for melanoma patients.

Public Health Relevance

In melanoma, the elevated activity of mutant BRAF kinase accounts for ~50% of malignant tumors. BRAF mutant selective inhibitors have extended the survival of patients in the clinic, however, most patients develop drug resistance causing the cancer to return. There is therefore a critical unmet need for novel approaches to overcome resistance to BRAF inhibitors. The goal of project 4 is to develop novel approaches to overcome resistance to BRAF inhibitors for treatment of melanoma. We anticipate that these studies will provide novel and attractive avenues to overcome resistance to BRAF inhibition in melanoma in order to provide effective long-lasting therapies for melanoma patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA114046-07
Application #
8759675
Study Section
Special Emphasis Panel (ZCA1-RPRB-2)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
7
Fiscal Year
2014
Total Cost
$401,919
Indirect Cost
$115,081
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

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