Targeted therapies in cutaneous melanoma

皮肤黑色素瘤的靶向治疗

基本信息

批准号：
10395432
负责人：
Andrew Eric Aplin
金额：
$ 36.31万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-14 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10395432
关键词：
Address Agonist Antibodies Antigen-Presenting Cells BRAF gene CD8-Positive T-Lymphocytes CDK4 gene Cell Cycle Progression Cell Cycle Regulation Clinical Clinical Data Clinical Trials Clonal Evolution Combined Modality Therapy Cutaneous Melanoma Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Cyclins Data Drug Tolerance Drug resistance ERBB2 gene Estrogen receptor positive Evolution FDA approved Funding Genetic Genotype Goals Heterogeneity Immune system Immunization Immunocompetent Immunooncology Incidence Leukocytes MAPK3 gene MEKs Malignant Neoplasms Measures Mediating Melanoma Cell Mesenchymal Modeling Mus Mutation NF1 gene NF1 mutation OX40 PIK3CA gene Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Pre-Clinical Model Publishing Quality of life Regimen Reporter Residual Tumors Resistance Ribosomal Protein S6 Role Sampling Schedule Signal Transduction T-Lymphocyte TNFSF4 gene Testing Therapeutic Toxic effect Treatment Protocols Up-Regulation Vimentin Work anti-PD1 therapy base clinically relevant immune checkpoint improved in vivo in vivo Model inhibitor inhibitor therapy insight malignant breast neoplasm melanoma mutant novel patient derived xenograft model pre-clinical prevent protein kinase inhibitor resistance mechanism response single cell analysis small molecule inhibitor targeted treatment treatment response treatment strategy tumor tumor heterogeneity tumor-immune system interactions

项目摘要

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.

项目概要皮肤黑色素瘤的发病率正在上升。同时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率，许多患者仍然没有受益，并且治疗方案与显着的毒性相关。我们正在学习黑色素瘤治疗反应和耐药机制的决定因素。来自我们的研究，我们的目标是为延迟/预防发作的新组合提供临床前数据获得耐药性，同时最大限度地减少患者的毒性，以提高患者的生存率和生活质量。我们的工作已经开展了多项临床试验（NCT03580382、NCT02012231、 NCT02683395）。异常的细胞周期调节是癌症的一个标志特征。在黑色素瘤中，细胞 BRAF、NRAS 和 NF1 突变导致 MEK-ERK1/2，从而促进周期进展途径激活、细胞周期蛋白和/或细胞周期蛋白依赖性激酶 (CDK) 扩增和/或缺失 CDK 抑制剂蛋白。选择性 CDK4/6 抑制剂已获得 FDA 批准用于治疗 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时间表。我们的目标是了解如何在黑色素瘤中利用 CDK4/6 抑制剂并将它们结合起来与免疫检查点药物一起使用，可以消除 T 细胞活动的障碍。在上一个周期中资金，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。然后我们开发了新颖的模型并进行分析对 BRAF 通路抑制剂和基于 CDK4/6 抑制剂的组合的耐药性。我们确定了 S6 的磷酸化增强作为治疗耐药的常见节点，并验证了我们的研究使用患者试验样本进行研究。在当前的提案中，我们的目标是确定并瞄准 CDK4/6 抑制剂 + MEK 抑制剂治疗后残留疾病的机制黑色素瘤。此外，我们的目标是确定 CDK4/6 抑制剂 + MEK 抑制剂对肿瘤免疫微环境。该应用程序将利用新颖的模型和患者样本从相关临床试验中测量肿瘤的异质性和耐药机制以及对CDK4/6抑制剂+MEK抑制剂的耐药性。识别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遗传子集的策略。