Melanoma Resistance to Apoptosis: Mechanisms and Therapeutic Potential

在美国退伍军人中，黑色素瘤的发病率正在迅速增加，而太阳 美国服兵役期间的暴露与黑色素瘤发病率的增加有关。护理的标准 针对晚期黑色素瘤的治疗包括BRAF和MEK抑制剂的分子靶向治疗，以及 使用检查点抑制剂(如抗PD1)的免疫疗法。然而，25%至70%的高级 黑色素瘤患者要么对目前的治疗没有反应，要么复发。因此，发现 有效的恶性黑色素瘤新疗法仍然是退伍军人事务部患者护理任务中的一个紧迫问题。 BH3模拟物是一类有效的新型癌症治疗方法，可抑制bcl2依赖的抗细胞凋亡 癌细胞固有的防御系统。标准护理加bcl-2的抑制剂(Venetclax)给出了 血液系统恶性肿瘤的有效率高达80%。然而，用单一的BH3模拟物治疗 不足以杀死实体瘤，可能是因为存在不受抑制的bcl2家族成员。MCL-1 目前正在进行临床试验的抑制剂，如果与临床配对，可能会提高治疗效果。 建立了BH3模拟物。此外，大多数关于BH3模拟物的研究都集中在它们杀死肿瘤细胞的能力上 虽然它们在加强免疫疗法方面的潜力仍有待探索。这样做的目的是 该项目是测试MCL-1抑制剂与其他BH3模拟物或与 免疫治疗(抗PD-1)治疗黑色素瘤，特别是黑色素瘤细胞 对目前的治疗没有反应。 我们的初步数据表明，当MCL-1抑制剂与ABT-263联合使用时，可以 协同杀灭大部分黑色素瘤细胞和黑色素瘤起始细胞(MICs)。这个 黑色素瘤包括那些从目前的治疗中复发的人。此外，在一种免疫能力模型中 黑色素瘤(C57BL6小鼠中的B16)，一种MCL-1抑制剂，增加了抗PD1治疗的疗效(初步 研究)。我们假设：1)MCL-1抑制剂，作为联合治疗的一部分，可以克服耐药性 黑色素瘤患者对目前的治疗方法。2)这种对肿瘤细胞的消除可以通过以下方式实现 直接杀伤或通过调节肿瘤微环境的抗肿瘤免疫反应。我们还有 获取大量黑色素瘤短期培养和患者来源的异种移植(PDX)模型 科罗拉多大学黑色素瘤组织库。这些材料大多来自黑色素瘤 从目前的治疗中复发的患者，拥有完整的exosome和rna-seq数据；他们 将提供一个独特的机会来检验我们的假设。目标1将确定在比赛中发挥作用的机制(S) MCL-1抑制剂与ABT-263的联合应用。我们将进一步检验这一假设 多个BH3模拟物，针对MCL-1和其他支持生存的BCL-2家族成员，将克服 黑色素瘤细胞对当前治疗方法的抵抗力，体外和体内。目标2将确定疗效和 MCL-1抑制剂加强免疫治疗的机制。我们将检验假设MCL-1 抑制剂通过阻断受抑制的免疫细胞群和增加 免疫功能正常的小鼠模型的抗肿瘤免疫。 总之，这项建议扩展了我们以mcl1抑制剂为合作伙伴的有希望的初步研究。 旨在克服黑色素瘤对标准疗法的耐药性的药物组合。预期中的 探索这些新的临床试验就绪的BH3模拟物的结果可能会改善患者的预后， 特别是对于迫切需要替代策略的患者群体。结果可能会带来积极的结果 对黑色素瘤治疗的影响，确定治疗黑色素瘤患者的新疗法 用尽了他们的其他选择。

The incidence of melanoma is increasing rapidly in the VA population in the United States, and sun exposure during US military service has been linked to increased melanoma incidence. The standard of care for advanced melanomas includes molecular-targeted therapies of BRAF and MEK inhibitors, as well as immunotherapies with checkpoint inhibitors such as anti-PD1. However, between 25% to 70% of advanced melanoma patients either do not respond or relapse from the current treatments. Therefore, discovering effective new therapies for malignant melanoma is still a pressing issue in the VA patient care mission. BH3 mimetics are a potent new class of cancer treatments that inhibit the BCL-2 dependent anti-apoptotic defenses inherent in cancer cells. Standard care plus an inhibitor against BCL-2 (Venetoclax) gave a response rates as high as ~80% in hematological malignancies. However, treatment with a single BH3 mimetic is insufficient to kill solid tumors, likely due to the presence of uninhibited BCL-2 family members. MCL-1 inhibitors, currently in clinical trials, can potentially boost treatment effectiveness when paired with clinically established BH3 mimetics. Further, most studies with BH3 mimetics focus on their ability to kill tumor cells directly, while their potential to enhance immunotherapies remains to be explored. The objective of this project is to test the combination treatment of MCL-1 inhibitors with other BH3 mimetics or with immunotherapy (anti-PD-1) in the treatment of melanoma, especially for melanoma tumor cells unresponsive to current treatments. Our preliminary data have indicated that MCL-1 inhibitors, when combined with ABT-263, can synergistically kill both the bulk of melanoma tumor cells and the melanoma initiating cells (MICs). The melanomas included those relapsed from current therapies. Further, in an immune competent model for melanoma (B16 in C57BL6 mice), a MCL-1 inhibitor increased the efficacy of anti-PD1 therapy (Preliminary Studies). We hypothesize: 1) MCL-1 inhibitors, as part of combination therapies, can overcome the resistance of melanoma patients to current treatments. 2) This elimination of tumor cells can be achieved either through direct killing or through modulating the antitumor immune response of tumor microenvironment. We also have access to a large collection of melanoma short-term cultures and patient-derived xenograft (PDX) models from the University of Colorado Melanoma Tissue Bank. Most of these materials were derived from melanomas of patients who had relapsed from the current treatments, with whole exosome and RNA-seq data available; they will provide the unique opportunity to test our hypotheses. Aim 1 will determine the mechanism(s) at play in the combination of MCL-1 inhibitors and ABT-263. We will further test the hypothesis that the combination of multiple BH3 mimetics, targeting MCL-1 plus other pro-survival BCL-2 family members, will overcome the resistance of melanoma cells to current therapies, in vitro and in vivo. Aim 2 will determine the efficacy and mechanisms of MCL-1 inhibitors to potentiate immunotherapies. We will test the hypothesis that MCL-1 inhibitors potentiate immunotherapies through blocking suppressive immune cell populations and increasing antitumor immunity in immune-competent mouse models. In summary, this proposal extends our promising preliminary studies using MCL-1 inhibitors as partners in drug combinations designed to overcome melanoma resistance to standard therapies. The expected outcome of exploring these new clinical-trial-ready BH3 mimetics will likely improve patient outcomes, especially for patient groups in dire need for alternative strategies. Results will likely lead to a positive impact on melanoma treatments, identifying new therapies for treating melanoma patients who have exhausted their other options.