Targeted therapies in cutaneous melanoma

项目总结 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 抗体提高了晚期皮肤黑色素瘤的长期存活率，许多 患者仍然没有受益，而且药物治疗与严重的毒副作用有关。我们正在学习 黑色素瘤治疗反应的决定因素和耐药机制。从我们的 研究，我们的目标是提供临床前数据为新的组合，延迟/预防发病 获得性抵抗力，同时将患者毒性降至最低，以提高患者的存活率和 生活质量。我们的工作产生了多项临床试验(NCT03580382，NCT02012231， NCT02683395)。细胞周期调节异常是癌症的一个显著特征。黑色素瘤中的细胞 通过BRAF、NRAS和NF1突变导致MEK-ERK1/2促进周期进展 细胞周期蛋白和/或细胞周期蛋白依赖性激酶(CDK)的通路激活、扩增和/或丢失 CDK抑制蛋白。选择性CDK4/6抑制剂在ER阳性/HER2- 阴性乳腺癌，但它们在黑色素瘤中的使用需要优化组合和 日程表。我们的目标是了解如何在黑色素瘤中使用CDK4/6抑制剂并将其联合使用。 使用免疫检查点试剂，它可以消除T细胞活动的障碍。在前一个周期中 资金，我们对BRAF抑制剂的获得性耐药机制提供了新的见解 单一疗法和联合疗法。然后我们开发了新的模型并分析了 对BRAF途径抑制剂和基于CDK4/6抑制剂的组合的耐药性。我们确认了 增强S6的磷酸化作为治疗耐药的常见节点并验证我们的 使用患者试验样本的研究。在目前的提案中，我们的目标是确定和瞄准 CDK4/6抑制剂MEK抑制剂治疗慢性粒细胞白血病后残留疾病的机制 黑色素瘤。此外，我们的目的是确定CDK4/6抑制剂MEK抑制剂对细胞周期的影响。 肿瘤免疫微环境。该应用程序将利用新的模型和患者样本 从相关临床试验来衡量肿瘤的异质性和耐药机制 对CDK4/6抑制剂、MEK抑制剂耐药。确定肿瘤的内在机制和 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 跨皮肤黑色素瘤基因亚群的策略。

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.