Personalized targeting of anti-apoptosis pathways to overcome therapeutic resistance in melanoma

项目摘要-项目2 黑色素瘤是一种侵袭性皮肤癌，在每种癌症的生命损失年数中仅次于 在美国的相关死亡事件。尽管联合使用BRAF和MEK抑制剂进行靶向治疗 (BRAFi+Meki)在BRAFV600突变黑色素瘤中取得了非常高的临床缓解率，最终~80% 患者会产生抵抗力。值得注意的是，目前还没有针对BRAFWT黑色素瘤患者的靶向治疗方法。 此外，只有约40%的转移性黑色素瘤对免疫检查点抑制剂有持久的反应。因此， 有一个重要的临床需求尚未得到满足，那就是确定新的策略来预防/抵消临床耐药。 已批准的BRAFV600突变黑色素瘤患者的靶向治疗，并开发有效的治疗方法 BRAFWT皮肤和非皮肤黑色素瘤如肢端黑色素瘤的手术入路 在临床研究中具有代表性。黑色素瘤的治疗耐药性主要是由阻止 促进肿瘤细胞的凋亡，促进其存活。因此，为了解决黑色素瘤的未得到满足的需求 治疗，我们将开发针对异常抗细胞凋亡途径驱动的个性化治疗方法 抗药性。我们假设靶向治疗耐药的抑制生存机制 黑色素瘤会使它们对细胞凋亡敏感，导致肿瘤消退。我们将对此进行测试 假设有两个目的。目的1，是基于我们的初步结果显示BRAFV600-突变黑色素瘤 高MCL1的PDX对BRAFi+Meki具有抵抗力。我们的初步研究还表明，MCL1Hi肿瘤是 对MCL1抑制敏感。我们将优化MCL1抑制与MAPKi结合以克服药物 抵抗。在目标2中，我们将利用DNA损伤修复(DDR)基因中存在的体细胞突变 BRAFwt黑色素瘤，并将确定DDR抑制剂在基于 DDR基因。重要的是，由于很大比例的肢端黑色素瘤是BRAFWT，并且对电流具有抵抗力 治疗，我们将在这项研究中包括肢端黑色素瘤PDX，并确定DDR的治疗价值 抑制剂。为了达到这两个目的，我们将使用一种新的体外微有机球体平台(Xilis Inc.)和体内肿瘤 在我们收集的大量分子表征的PDX中进行生长抑制研究，以确定最有效的 可以转化为未来临床试验的治疗方法。然后我们将进行整个肿瘤/空间/单个细胞的手术 对应答者和无应答者进行分子分析，以确定应答者和抗药性的生物标志物。至 为了实现这些目标，我们组建了一支优秀的调查团队，他们具有多样性和互补性 专业知识。我们的专业知识和资源将共同促进最佳方案的优化和优先 有效地解决黑色素瘤患者的两个未得到满足的紧急需求的联合治疗。

Project Summary – Project 2 Melanoma is an aggressive skin cancer and is only second in the number of life-years lost per cancer- related death in the US. Although targeted therapies with combinations of BRAF and MEK inhibitors (BRAFi+MEKi) achieve very high clinical response rates in BRAFV600-mutant melanoma, ultimately ~80% of patients develop resistance. Notably, there are no approved targeted therapies for BRAFWT melanoma patients. Further, only ~40% of metastatic melanomas achieve durable responses to immune checkpoint inhibitors. Thus, there is a significant unmet clinical need to identify novel strategies to prevent/counteract resistance to clinically approved targeted therapies in BRAFV600-mutant melanoma patients, and to develop effective therapeutic approaches for BRAFWT cutaneous and non-cutaneous melanomas like acral melanomas which are under- represented in clinical studies. Therapeutic resistance in melanoma is mostly mediated by proteins that prevent apoptosis of the tumor cells and promote their survival. Therefore, to address the unmet needs for melanoma therapy, we will develop personalized therapeutic approaches targeting aberrant anti-apoptotic pathways driving drug resistance. We hypothesize that inhibiting survival mechanisms in targeted therapy-resistant melanoma will sensitize them to undergo apoptosis, leading to tumor regression. We will test this hypothesis with two aims. Aim 1, is based on our preliminary results showing that BRAFV600-mutant melanoma PDXs with high MCL1 are resistant to BRAFi+MEKi. Our preliminary studies also show that MCL1Hi tumors are sensitive to MCL1 inhibition. We will optimize MCL1 inhibition in combination with MAPKi to overcome drug resistance. In Aim 2, we will exploit the presence of somatic mutations in DNA damage repair (DDR) genes in BRAFWT melanomas and will determine the efficacy of DDR inhibitors in PDXs selected based on alterations in DDR genes. Importantly, as a large percentage of acral melanomas are BRAFWT and are resistant to current therapies, we will include acral melanoma PDXs in this study and determine the therapeutic value of DDR inhibitors. For both aims, we will use a novel in vitro MicroOrganoSphere platform (Xilis Inc.) and in vivo tumor growth inhibition studies in our large collection of molecularly characterized PDXs, to identify the most effective treatments that can be translated into future clinical trials. We will then perform whole tumor/spatial/single cell molecular analyses on responders and non-responders to identify biomarkers of response and resistance. To achieve these goals, we have assembled an outstanding team of investigators with diverse and complementary expertise. Together, our expertise and resources will facilitate optimization and prioritization of the best combination treatments to effectively address the two urgent unmet needs for melanoma patients.