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.
|Zhang, Ying; Kurupati, Raj; Liu, Ling et al. (2017) Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. Cancer Cell 32:377-391.e9|
|Frazier, Jason P; Bertout, Jessica A; Kerwin, William S et al. (2017) Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation. Cancer Res 77:2869-2880|
|Gade, Terence P F; Tucker, Elizabeth; Nakazawa, Michael S et al. (2017) Ischemia Induces Quiescence and Autophagy Dependence in Hepatocellular Carcinoma. Radiology 283:702-710|
|Taylor, Laura A; Abraham, Ronnie M; Tahirovic, Emin et al. (2017) High ALDH1 expression correlates with better prognosis in tumorigenic malignant melanoma. Mod Pathol 30:634-639|
|Garman, Bradley; Anastopoulos, Ioannis N; Krepler, Clemens et al. (2017) Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines. Cell Rep 21:1936-1952|
|Vitiello, Marianna; Tuccoli, Andrea; D'Aurizio, Romina et al. (2017) Context-dependent miR-204 and miR-211 affect the biological properties of amelanotic and melanotic melanoma cells. Oncotarget 8:25395-25417|
|Krepler, Clemens; Sproesser, Katrin; Brafford, Patricia et al. (2017) A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma. Cell Rep 21:1953-1967|
|Whelan, K A; Chandramouleeswaran, P M; Tanaka, K et al. (2017) Autophagy supports generation of cells with high CD44 expression via modulation of oxidative stress and Parkin-mediated mitochondrial clearance. Oncogene 36:4843-4858|
|Huang, Alexander C; Postow, Michael A; Orlowski, Robert J et al. (2017) T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60-65|
|Emptage, Ryan P; Schoenberger, Megan J; Ferguson, Kathryn M et al. (2017) Intramolecular autoinhibition of Checkpoint Kinase 1 is mediated by conserved basic motifs of the C-terminal Kinase Associated-1 domain. J Biol Chem :|
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