?Project3 HSP70isakeycancer-criticalsurvivalproteinthatisnecessarytomaintainproperproteinfoldinginastressed cell.TheHSP70familycontainsmorethaneightfamilymembers.Theoneunderstudyhereisthemajorstress- inducedfamilymemberHSPA1A,hereafterHSP70.Unlikeotherfamilymembers,thisproteinisoverexpressed inover75%ofmetastaticmelanoma,andisassociatedwithdrugresistanceandpoorsurvival.Inthepastten yearswehavedevelopedaseriesofinhibitorsthattargetthestress-inducedformofHSP70butnototherfamily memberslikeHsc70andGRP75.Additionally,werecentlynotedasignificantfractionofHSP70locatedatthe mitochondriaoftumorbutnotnormalcells,andwecoupledourinhibitorstoatriphenylphosphoniummoietythat helps direct these compounds to mitochondria. In the past funding cycle we tested this compound against melanoma, and solved the crystal structure and mechanism of action. In the current funding cycle, we take newerandmorepotentderivativesofournovelmitochondria-directedHSP70inhibitorstothetoughest-to-treat subtypes of melanoma:thosethatare resistant to BRAF/MEK inhibitors, those that have wild type BRAFand NRAS (WT/WT), and those that have metastasized to the brain (melanoma brain metastases, or MBMs). Targetingthesethreecategorieshasthepotentialforsignificantclinicalimpact,andourpreliminarydatasupport the use of HSP70i for these tumor sub-types. In the proposed work we collaborate extensively with our P01 colleaguestoexploreforthefirsttimetheimpactofHSP70ionthestressedtumormicroenvironment,including cancerassociatedfibroblastsand theaged micro-environment. We alsofocuson several new HSP70 clients, including ErbB3,ID3 and GPX4. To succeed in thesegoals, we haveaccrued a team that is expert in HSP70 and proteostasis (Murphy and George), medicinal chemistry (Salvino) and the brain metastatic micro- environment(Chen).WeexpecttheproposedresearchtoyieldcandidateHSP70iforclinicaldevelopment,and toprovideanimportanttherapeuticoptionforthetoughest-to-treatmelanomasub-types.
?Project3 Metastaticmelanomacontinuestobeadevastatingdiagnosiswithpoorprognosis.Theproposedresearchwill continue to leverage the reliance of metastatic melanoma on the HSP70 chaperone, as a novel therapeutic approach. Emphasis will be placed on the ability of HSP70 inhibitors to target both the tumor and the tumor micro-environment, with focus on melanoma brain metastases (MBMs) and targeting the mitochondria in therapy-resistantmelanoma.
| 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 : |
| 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 |
Showing the most recent 10 out of 144 publications
