-Overall The clinical landscape of melanoma is evolving rapidly, however, a significant fraction of individuals fail to respond to frontline therapy, and another significant fraction of melanoma patients develop resistance. In order to improve the response to frontline therapies, we have previously focused on inhibiting survival pathways, including autophagy, senescence and proteostasis. In the new funding cycle, we extend this focustowardtargetingthemelanomamicroenvironment. Targeted therapies designed to inhibit tumor-intrinsic signaling do not contemplate the influences of the microenvironment, and the recent success of immunotherapy is a reminder of how important the consideration of the microenvironment is. Our data are revealing that the normal aging of stromal cells creates a microenvironment that promotes the activation of signaling pathways that circumvent those targeted by therapies such as vemurafenib, making the one gene, one drug approach less likely to be successful. Additionally, the crosstalkbetweenstromal and immunecells in the tumor microenvironment is vastly underexplored. We believe that genetic drivers in the tumor cell, or specific checkpoints on immune cells cannot be effectively targeted, without the consideration of the crosstalk between thosecellpopulationsandothercellsinthemicroenvironment. TheProgram consistsoffour well-integratedprojects, fromateam thathas workedextremely welltogether over the last five years, publishing numerous high-impact collaborative papers. The evolution of this P01 into its new form is truly a reflection of these concerted efforts, evolving from targeting cell fate, to a realization that cell fate can be differentially affected by its microenvironment. The four Projects are designed in order to achieve a fully coordinated understanding of how multiple factors (but with a focus on aging) in the tumor microenvironment contribute to therapy resistance. The alteration of lipid profiles in stromal, immune and tumor cells isemerging asa keydriverof resistance. TheProjects will worktogether to understand the impact of lipid production, accumulation, uptake, metabolism and catabolism in tumor cells. Using the novel compounds developed within the current funding cycle of the grant, we will target tumor/TMEcrosstalk,andexplorenovelwaysinwhichtodisruptit.
-Overall This program project is a renewal from a highly productive team of investigators, which produced 107 publications, >70% of which are collaborations among the team. Overall, our findings in the 2013-2018 cycle have led to a natural evolution of our studies, where we found that the aged microenvironment is a key contributortotherapyresistance,andthatlipidmetabolismisacriticalregulatorofbothtumorcellandimmune cell response, resulting in forms of cell death such as ferroptosis. Using the tools we have developed in the current funding cycle (dimeric quinacrines, HSP70 inhibitors) and our new understanding of the role of the tumor microenvironment in therapy resistance, this Program focuseson how toovercome resistance and lack ofresponsetotherapybytargetingnotjustthetumor,butalsothemicroenvironment.
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| Jenkins, Russell W; Aref, Amir R; Lizotte, Patrick H et al. (2018) Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Cancer Discov 8:196-215 |
| Emptage, Ryan P; Lemmon, Mark A; Ferguson, Kathryn M et al. (2018) Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain. Structure 26:1137-1143.e3 |
| Barnoud, Thibaut; Budina-Kolomets, Anna; Basu, Subhasree et al. (2018) Tailoring Chemotherapy for the African-Centric S47 Variant of TP53. Cancer Res 78:5694-5705 |
| Liu, Shujing; Zhang, Gao; Guo, Jianping et al. (2018) Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis. Nat Commun 9:5426 |
| Pathria, Gaurav; Scott, David A; Feng, Yongmei et al. (2018) Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival. EMBO J 37: |
| Reyes-Uribe, Patricia; Adrianzen-Ruesta, Maria Paz; Deng, Zhong et al. (2018) Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma. Oncogene 37:4058-4072 |
| Rebecca, Vito W; Nicastri, Michael C; Fennelly, Colin et al. (2018) PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. Cancer Discov : |
| Kaur, Amanpreet; Ecker, Brett L; Douglass, Stephen M et al. (2018) Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility. Cancer Discov : |
| Chen, Gang; Huang, Alexander C; Zhang, Wei et al. (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560:382-386 |
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