-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.

Public Health Relevance

-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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA114046-12
Application #
10019466
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Forry, Suzanne L
Project Start
2008-04-01
Project End
2024-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
12
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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:

Showing the most recent 10 out of 144 publications