Request for Supplemental Funds aligned to CA160495

项目摘要 黑色素瘤是最致命的皮肤癌。我们的目标是了解潜在的机制 黑色素瘤的致癌信号和耐药性研究进展 选择。丝氨酸/苏氨酸激酶BRAF在约50%的黑色素瘤中发生体细胞突变， 促进MEK-ERK1/2信号的过度激活，异常生长和侵袭。而BRAF和 MEK抑制剂现在是晚期突变V600E BRAF黑色素瘤的一线治疗药物， 它们只会延缓死亡。因此，我们必须了解如何在BRAF+MEK抑制剂的基础上构建 治疗并确定如何将它们与免疫检查点代理结合，从而移除 阻断T细胞的活动。在这笔赠款的前一个周期中，我们表明FOXD3的上调- ErbB3信号是对促进药物耐受状态的BRAF抑制剂的适应性反应 在突变的BRAF黑色素瘤中。此外，我们还发现ErbB3的抑制增强了这种作用 体内突变的BRAF黑色素瘤中BRAF抑制剂的研究。在目前的提案中，我们的目标是确定 在突变的BRAF黑色素瘤中调节FOXD3的机制，测试了表观遗传学 BET/BRD抑制剂将阻断对BRAF+MEK抑制剂的适应性反应并改变肿瘤 微环境，并确定FOXD3的表达如何改变细胞的渗透/激活状态 肿瘤相关免疫细胞群与可能的免疫检查点的表达 蛋白质。在我们的实验完成后，我们预计已经确定了肿瘤和间质 靶向治疗适应性反应的标志物和知情的未来联合靶向治疗 突变型BRAF黑色素瘤的抑制物、表观遗传抑制物和基于免疫的治疗策略。

Project Summary Melanoma is the deadliest form of skin cancer. We aim to understand mechanisms underlying oncogenic signaling and drug resistance in melanoma in order to improve the current treatment options. The serine/threonine kinase, BRAF, is somatically mutated in ~50% of melanomas and drives hyper-activation of MEK-ERK1/2 signaling, aberrant growth and invasion. While BRAF and MEK inhibitors are now first-line therapy for advanced-stage mutant V600E BRAF melanomas, they only delay mortality. Thus, we must understand how to build on BRAF+MEK inhibitor treatments and determine how to combine them with immune checkpoint agents, which remove the blocks on T cell action. In the previous cycle of this grant, we showed that up-regulation of FOXD3- ErbB3 signaling is an adaptive response to BRAF inhibitors that promotes a state of drug tolerance in mutant BRAF melanoma. Furthermore, we showed that inhibition of ErbB3 enhanced the effects of BRAF inhibitors in mutant BRAF melanomas in vivo. In this current proposal, we aim to identify mechanisms regulating FOXD3 in mutant BRAF melanomas, test the possibility that epigenetic BET/BRD inhibitors will block adaptive responses to BRAF+MEK inhibitors and alter the tumor microenvironment, and determine how FOXD3 expression alters the infiltration/activation status of tumor-associated immune cell populations and the expression of putative immune checkpoint proteins. At the completion of our experiments, we expect to have identified tumor and stromal markers for adaptive responses to targeted therapy and informed future combinatorial targeted inhibitor, epigenetic inhibitor and immune-based therapeutic strategies in mutant BRAF melanoma.