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，在每种癌症损失的生命年数中仅居第二位- 在美国相关死亡。尽管BRAF和MEK抑制剂的联合靶向治疗 （BRAFi+MEKi）在BRAFV 600突变型黑色素瘤中实现了非常高的临床应答率，最终约80%的患者在BRAFV 600突变型黑色素瘤中获得了非常高的临床应答率。 患者产生耐药性。值得注意的是，没有批准用于BRAFWT黑色素瘤患者的靶向疗法。 此外，只有约40%的转移性黑色素瘤对免疫检查点抑制剂实现持久应答。因此，在本发明中， 存在显著的未满足的临床需要，以确定新的策略来预防/抵消对临床上已知的抗肿瘤药物的抗性， 在BRAFV 600突变型黑色素瘤患者中批准的靶向治疗，并开发有效的治疗方法， BRAFWT皮肤和非皮肤黑色素瘤（例如肢端黑色素瘤）的治疗方法 在临床研究中。黑色素瘤的治疗抗性主要是由阻止黑色素瘤生长的蛋白质介导的。 促进肿瘤细胞凋亡，促进其存活。因此，为了解决黑色素瘤未满足的需求， 治疗，我们将开发针对异常抗凋亡途径驱动的个性化治疗方法， 耐药性我们假设，抑制靶向治疗耐药的肿瘤细胞的生存机制， 黑色素瘤将使它们敏感，从而经历细胞凋亡，导致肿瘤消退。我们将测试这个 假设有两个目的。目的1是基于我们的初步结果，显示BRAFV 600突变型黑色素瘤 具有高MCLl的PDX对BRAFi+MEKi具有抗性。我们的初步研究还表明，MCL 1Hi肿瘤是 对MCL 1抑制敏感。我们将优化MCL 1抑制与MAPKi的组合，以克服药物 阻力在目标2中，我们将利用DNA损伤修复（DDR）基因体细胞突变的存在， BRAFWT黑色素瘤，并将确定DDR抑制剂在PDX中的疗效， DDR基因。重要的是，由于很大比例的肢端黑色素瘤是BRAFWT，并且对电流有抵抗力， 治疗，我们将包括肢端黑色素瘤PDX在这项研究中，并确定DDR的治疗价值 抑制剂的对于这两个目标，我们将使用一种新的体外MicroOrganoSphere平台（Xilis Inc.）和体内肿瘤 在我们大量的分子特征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。然后我们将进行全肿瘤/空间/单细胞 对应答者和非应答者进行分子分析，以鉴定应答和抗性的生物标志物。到 为了实现这些目标，我们组建了一支优秀的调查团队， 专业知识我们的专业知识和资源将共同促进优化和优先考虑最好的 联合治疗，以有效地解决黑色素瘤患者的两个迫切的未满足的需求。

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.