Functional precision approaches to overcome intrinsic and acquired drug resistance in melanoma

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Project Summary – Project 1 Although significant progress has been made treating melanoma, less than 30% of patients achieve long-term responses and almost 70% of patients are resistant to any approved therapies including immunotherapies and targeted therapies. Therefore, novel strategies to overcome intrinsic and acquired drug resistance are sorely needed. This Patient Derived Xenograft (PDX) Development and Trial Center (T-PDTC) research project will capitalize on our extensive collection of >500 clinically annotated and molecularly characterized PDXs to develop functional precision therapies to offset melanoma drug resistance. Our working hypothesis is that the tumor’s genomic, molecular and drug response profiles in organoids and PDXs can be leveraged to develop clinically translatable precision therapies. We also posit that our pre-clinical pipeline will identify markers to select tumors that are most likely to respond to a given treatment, offsetting drug resistance and achieving long-term responses, with no overt toxicity. We expect that our pre-clinical studies will help prioritize the clinical testing of targeted agents for the treatment of melanoma. Our melanoma PDX collection has been extensively characterized for growth properties, metastasis formation, somatic mutations through targeted and whole exome sequencing, RNA expression and expression of ~500 proteins related to signal transduction. Our models are superbly suited to investigate combination therapies to overcome or prevent drug resistance as they represent the heterogeneity of melanoma. To do this, two Specific Aims are proposed: Aim 1, will test the hypothesis that drug resistant melanomas harboring a transcriptional signature termed ‘innate anti–PD-1 resistance signature’ (IPRES+), which is associated with resistance to anti-PD1 and MAPK inhibitors, will respond to the combination of BET and MEK inhibitors. We will optimize this treatment regimen and further define markers of response and resistance. For IPRESNeg tumors, we will integrate genomic, transcriptional and proteomic analyses to pair tumors with drugs matching their molecular profile; this will allow for establishing optimal combination and dosing strategies. In aim 2, we will conduct temporal and spatial transcriptomic and proteomic analysis to identify and profile drug tolerant subpopulations. Our goal is to monitor treatment response and intervene with combinations aimed at killing both the bulk of the tumor and rare drug tolerant/persister subpopulations preventing the emergence of resistance. We anticipate that our studies will provide critical information needed to translate effective and long-lasting precision therapies from the bench to bedside and improve the outcomes of melanoma patients.