The long-term goal of this P01 is to promote research to better understand the biology of melanomas and to translate this research to better therapies with the ultimate goal of achieving cures. Our overarching hypothesis is that intrinsic resistance to signaling inhibitors can be overcome if we take into account the genetic signatures of melanoma cells and the biological properties that are driven by intrinsic and extrinsic signals. For this competitive renewal, we will shift our focus away from the traditional targeting of kinase active sites that control canonical growth factor signaling. To achieve our goals we have developed three overarching aims, which require close coordination of projects and cores:
In Aim 1 we will define cell fates for therapy of melanoma. While cell death due to apoptosis or necrosis is widely regarded to be the ultimate goal of any cancer therapy, in melanoma we now take into account two additional cell states that emerging data indicate are critical: autophagy (Projects 2 and 3) and senescence (Project 1). Our goal is to block cells from entering dormant survival states such as quiescence or pseudo-senescence and force them to die as a result of apoptosis or necrosis.
In Aim 2, we will investigate the mechanism of action of signaling inhibitors. Project 4 will generate a series of novel targeted inhibitors to prevent dimer formatio of BRAF or CRAF and investigate a novel STAT3 inhibitor that resulted from recent screens. Under this aim we will combine the expertise of chemists, structural biologists and cell biologists to develop a new generation of compounds that promise a major impact on melanoma therapy in the future.
In Aim 3, we will develop combination strategies for melanoma therapy. Since melanomas evolve through genetic alterations of multiple driver genes and are highly responsive to signals from the tumor microenvironment, the field has learned that single agents cannot cure by killing all malignant cells. In each project we will explore synergy among signaling inhibitor therapies using unique models for selection. The Cores for this P01 are essential for our progress in the coming funding cycle. To account for the increased needs for compound synthesis and modification, we have added a Medicinal Chemistry Core (D) in this renewal application.
This P01 focuses on understanding the biology of melanoma and on developing new therapeutic strategies against this disease. Our goal is to eliminate all tumor cells and avoid the survival of any small subpopulation of resistant cells that could repopulate the patient and give rise to more aggressive and resistant tumors. This program consists of four projects and five cores. One of the four projects extends from our previous proposal but now additionally focuses on the design of novel inhibitors that target mutant and wild type BRAF, as well as the related CRAF protein which allows cells to escape BRAF signal inhibition. The other three projects move beyond RAF inhibition to target new processes and pathways based on our decades-long experience in signaling in melanoma. Autophagy (self-digestion due to stress), proper protein assembly (heat shock proteins), and senescence (aging and quiescence) are novel areas to focus on and target in melanoma.
|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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