Targeted therapies in cutaneous melanoma

项目摘要 皮肤黑色素瘤的发病率正在上升。虽然靶向抑制剂和免疫检查点 抗体增加了晚期皮肤黑色素瘤的长期生存，许多 患者仍然没有受益，并且治疗方案与显著的毒性相关。我们正在研究 黑色素瘤治疗反应的决定因素和耐药机制。从我们 研究，我们的目标是提供新的组合，延迟/预防发作的临床前数据 获得性耐药，同时最大限度地减少患者毒性，以提高患者生存率， 生活质量多项临床试验源自我们的工作（NCT 03580382，NCT 02012231， NCT 02683395）。异常的细胞周期调节是癌症的标志性特征。在黑色素瘤中， 通过BRAF、NRAS和NF 1突变促进周期进展，导致MEK-ERK 1/2 途径活化、细胞周期蛋白和/或细胞周期蛋白依赖性激酶（CDK）的扩增和/或细胞周期蛋白的缺失。 CDK抑制蛋白。选择性CDK 4/6抑制剂是FDA批准用于ER阳性/HER 2- 阴性乳腺癌，但它们在黑色素瘤中的使用需要优化组合， 时间表。我们的目标是了解如何利用CDK 4/6抑制剂在黑色素瘤和联合收割机， 免疫检查点试剂，消除T细胞作用的障碍。的前一循环中 我们提供了对BRAF抑制剂获得性耐药机制的新见解， 单一疗法和联合疗法。然后，我们开发了新的模型， 对BRAF通路抑制剂和基于CDK 4/6转运蛋白的组合的抗性。我们确定 增强S6磷酸化作为治疗抗性的共同节点，并验证了我们的研究结果。 使用患者试验样本进行研究。在目前的建议中，我们的目标是确定和针对 CDK 4/6抑制剂+ MEK抑制剂治疗后残留疾病的潜在机制 黑素瘤此外，我们的目的是确定CDK 4/6抑制剂+ MEK抑制剂对细胞增殖的影响。 肿瘤免疫微环境该应用程序将利用新的模型和患者样本 从相关的临床试验中测量肿瘤的异质性和药物耐受性机制 对CDK 4/6抑制剂+ MEK抑制剂耐药。确定肿瘤的内在机制， 对肿瘤相关免疫微环境的影响将为潜在的新治疗提供信息 皮肤黑色素瘤的遗传亚群的策略。

PROJECT SUMMARY The incidence of cutaneous melanoma is rising. While targeted inhibitors and immune checkpoint antibodies have increased long-term survival in advanced-stage cutaneous melanoma, many patients still do not benefit and regimens are associated with significant toxicities. We are studying the determinants of treatment response and mechanisms of resistance in melanoma. From our studies, we aim to provide pre-clinical data for new combinations that delay/prevent the onset of acquired resistance while minimizing patient toxicities in order to improve patient survival and quality of life. Multiple clinical trials have emanated from our work (NCT03580382, NCT02012231, NCT02683395). Aberrant cell cycle regulation is a hallmark feature of cancer. In melanoma, cell cycle progression is promoted through mutations in BRAF, NRAS and NF1 leading to MEK-ERK1/2 pathway activation, amplification of cyclins and/or cyclin-dependent kinases (CDK) and/or loss of CDK inhibitor proteins. Selective CDK4/6 inhibitors are FDA-approved in ER-positive/HER2- negative breast cancer but their use in melanoma requires optimization of combinations and schedules. We aim to understand how to utilize CDK4/6 inhibitors in melanoma and combine them with immune checkpoint agents, which remove the blocks on T cell action. In the previous cycle of funding, we provided new insights into mechanisms of acquired resistance to BRAF inhibitor monotherapy and combination therapy. We then developed novel models and to analyze resistance to BRAF pathway inhibitors and CDK4/6 inhibitor-based combinations. We identified enhanced phosphorylation of S6 as a common node of therapy resistance and validated our studies using patient trial samples. In this current proposal, we aim to identify and target mechanisms underlying residual disease following CDK4/6 inhibitor + MEK inhibitor treatment in melanoma. Additionally, we aim to determine effects of CDK4/6 inhibitor + MEK inhibitor on the tumor immune microenvironment. The application will utilize novel models and patient samples from relevant clinical trials to measure heterogeneity of tumors and mechanisms of drug tolerance and resistance to CDK4/6 inhibitor + MEK inhibitor. Identifying the tumor intrinsic mechanisms and effects on the tumor-associated immune microenvironment will inform potential new treatment strategies across genetic subset of cutaneous melanoma.