Metastatic melanoma is one of the fastest growing tumor types in the US and also is one of the most challenging malignancies to treat once metastasis occurs. Though several new therapeutic approaches are available for melanoma patients, mean overall survival with these therapies remains in the 12 month range. Clearly, better treatments are needed and excellent targets for therapy are found within the pathways regulated by products of the CDKN2A gene which is mutated or deleted in 43% of melanomas. Two products of the CDKN2A gene are INK4A/p16 (an inhibitor of the cyclin-dependent kinases, CDK4/6) and ARF (a suppressor of the E3 ubiquitin ligase MDM2 that mediates ubiquitination and degradation of p53). When p16 binds to CDK4/6, it inhibits the CDK4/6 mediated hyper-phosphorylation of RB1, thus allowing RB to block entry into S- phase of the cell cycle. When p16 is deleted or mutated this regulation of cell cycle is compromised. Deletion or mutation of ARF results in the unbridled MDM2 mediated ubiquitination and degradation of p53, resulting in a loss of p53-mediated transcription of regulators of cell cycle and apoptosis. Since p53 is seldom mutated in melanoma, restoring its function is key for inducing apoptosis in tumor cells. Recently, drugs that target CDK4/6 and HDM2 have moved into clinical trials. We have preliminary data that combining a CDK4/6 inhibitor with an HDM2 antagonist induces marked inhibition of melanoma growth. This important finding, coupled with our recent success in preclinical models of melanoma with MDM2/HDM2 inhibitors combined with agents that block cell cycle and induce senescence, form the basis for this proposal. Hypothesis: We postulate that melanoma patient tumors that are RB1WT/ TP53WT will be inhibited by therapy that combines CDK4/6 inhibitors (CDK4/6i) with agents that disrupt MDM2/p53 interaction. There are three aims for this proposal: 1) To compare the senescence associated secretory program (SASP) in melanocytes of oncogene induced senescence (OIS) to that of therapy induced senescence pathways in vitro and in vivo and evaluate the effectiveness of MDM2 (MDM2i) and CDK4/6 inhibitors (CDK4/6i) on melanoma tumor growth, senescence, SASP, and apoptosis, and on recruitment of immune cells into the tumor microenvironment (TME) in immune competent mice with focus on BRAFWT/NRASWT or NRASmut melanoma; 2) To characterize the benefit of combining an HDM2 antagonist with CDK4/6 inhibitors for treatment of metastatic melanoma using patient derived xenografts (PDX) from BRAFWT/NRASWT and NRASmut tumors that are RBWT/TP53WT and to characterize gene mutation/expression signatures that will predict response to this therapy; 3) To characterize the effectiveness of CDK4/6 inhibitor combined with HDM2 inhibitor in the treatment of RBWT/TP53WT melanoma tumors that progressed on therapy. PDX models will be utilized and coordinated with biopsy from patient tumor at the time of progression from 3 ongoing clinical trials at Vanderbilt involving patients with tumors that are BRAFWT/NRASmut or BRAFWT/NRASWT.
This proposal will utilize preclinical models to evaluate very relevant new therapies for BRAFWT metastatic melanoma patients who currently have few options for treatment. By targeting the CDKN2A pathway which is disrupted in 43% of the melanomas, we hope to block tumor growth and prolong the lives of these patients.
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|Vilgelm, Anna E; Johnson, Douglas B; Richmond, Ann (2016) Combinatorial approach to cancer immunotherapy: strength in numbers. J Leukoc Biol 100:275-90|
|Nichols, Erin E; Richmond, Ann; Daniels, Anthony B (2016) Disparities in Uveal Melanoma: Patient Characteristics. Semin Ophthalmol 31:296-303|
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