?Project2 Therapyresistanceinmelanomaisamajorhurdletoimprovedsurvival.Thisprojectwilldetermineiftherapy resistance can be reversed by targeting the lysosomal enzyme protein palmitoyl thioesterase 1 (PPT1). Autophagy is a lysosome-dependent pathway that promotes tumor growth and resistance to therapy in melanoma.Autophagyinhibitionwithchloroquine(CQ)derivativesaugmentstheefficacyofmanyanticancer therapies, but has limited activity as a single agent. Clinical trials involving HCQ in melanoma show promising activity but concerns have been raised about the potency of HCQ, and its poorly understood mechanism of action. We have prepared dimeric antimalarial compounds that are 10-1000 fold more potent in vitro and in vivo than CQ or HCQ. Dimeric quinacrines (DQs) (Rebecca Cancer Discovery 2017) and dimeric chloroquines (DCs) (Rebecca Cancer Discovery in revision) look especially promising as both tool compounds and potential clinical drugs. In the current cycle, we have found that extending the linker length of these dimeric compounds increases lysosomal localization and anti-melanoma activity. These DQs and DCs with longer linkers as well as CQ were used to pull a new lysosomal target, PPT1, which is overexpressed in cancer, especially in metastatic lesions. Efforts to target the lysosome and autophagy in cancer cells have focused on the effects within cancer cells but recent literature suggests targeting this pathway in immunosuppressive cells within the TME also contributes to antitumor activity. We will leverage innovative collaborations with Projects1, 3 and4 andheavy support from the P01 cores to understand the effects of PPT1 inhibition in both tumor cells, the interaction between tumor cells and fibroblasts, tumor associatedmacrophagesandTcells.Theproposalisbasedonextensivenewpreliminarydatainresponse to the reviewers? critiques from the September 2017 submission. We will test the hypothesis that targeting PPT1 intumor cellsand macrophages overcomes therapy resistance in melanomathrough completion of3 aims:
Aim 1 will develop innovative new compounds by introducing heteroatom substitutions into the linker, and developing the first ever dimeric ferroquine derivatives that could have better penetration in the acidic TME. We willalsodevelopanovel assay forPPT1 that is compatible with live cells and animal studies.
Aim 2 will leverage collaborations within the P01 to study the role of PPT1 in blocking lipid trafficking from aged fibroblasts to melanoma cells and reversing resistance to targeted therapy.
Aim 3 will study the effects of PPT1 inhibition on tumor cell interactions with T cells and macrophages in 3D culture, immunocompetent mouse models, and a new conditional KO model of Ppt1, with the goal of reversing resistance to immunotherapy. The impact of these studies will be to unravel a deeper mechanistic understanding of the consequencesoflysosomalinhibitionwithintheTME,whichwillsupportclinicaldevelopmentoftheseagents inthefuture.Knowledgegainedwillultimatelyleadtoimprovedpatientoutcomes.
?Project2 This project will address a critical unmet need for new therapeutics for treat refractory advanced melanoma patients. We will utilize new chemical approaches to determine how best to inhibit a new target in melanoma we have identified, PPT1. We will utilize the P01 platform to study the effects of PPT1 inhibition both in the melanomacellanditsimpactonthetumormicroenvironment.
|Cañadas, Israel; Thummalapalli, Rohit; Kim, Jong Wook et al. (2018) Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med 24:1143-1150|
|Grasso, Michael; Estrada, Michelle A; Berrios, Kiara N et al. (2018) N-(7-Cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK632) Promotes Inhibition of BRAF through the Induction of Inhibited Dimers. J Med Chem 61:5034-5046|
|Noguera-Ortega, Estela; Amaravadi, Ravi K (2018) Autophagy in the Tumor or in the Host: Which Plays a Greater Supportive Role? Cancer Discov 8:266-268|
|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 :|
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