Melanoma Resistance to Apoptosis: Mechanisms and Therapeutic Potential

黑色素瘤对细胞凋亡的抵抗：机制和治疗潜力

• 批准号: 10477193
• 负责人: DAVID A. NORRIS
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477193
• 关键词: Acute Myelocytic Leukemia; Apoptosis; Apoptotic; BCL2 gene; BCL2L1 gene; BRAF gene; CD8-Positive T-Lymphocytes; Cells; Clinical; Clinical Trials; Collection; Colorado; Combined Modality Therapy; Data; Distributional Activity; Drug Combinations; Drug Targeting; Family; Family member; Generations; Hematologic Neoplasms; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunotherapy; In Vitro; Incidence; Link; MCL1 gene; MEKs; Melanoma Cell; Mission; Modeling; Mus; Outcome; Patient Care; Patient-Focused Outcomes; Patients; Play; Population; Proteins; Relapse; Resistance; Role; Solid Neoplasm; Sun Exposure; Testing; Therapeutic; Tissue Banks; Treatment Effectiveness; Tumor Immunity; Tumor-infiltrating immune cells; United States; Universities; Xenograft Model; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; cancer cell; cancer therapy; conventional therapy; design; effective therapy; effectiveness evaluation; efficacy testing; exhaust; exosome; immunogenicity; implantation; improved; improved outcome; in vivo; inhibitor; melanoma; member; military service; mimetics; molecular targeted therapies; mouse model; neoplastic cell; novel; novel therapeutics; patient derived xenograft model; potential biomarker; predictive marker; responders and non-responders; response; small molecule inhibitor; standard care; standard of care; therapy development; therapy resistant; transcriptome sequencing; tumor; tumor microenvironment

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.

在美国退伍军人事务部人群中，黑色素瘤的发病率正在迅速增加，并且阳光 美国服兵役期间的暴露与黑色素瘤发病率增加有关。护理标准 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（例如抗 PD1）进行免疫疗法。然而，25% 到 70% 的高级 黑色素瘤患者对当前的治疗要么没有反应，要么复发。因此，发现 恶性黑色素瘤的有效新疗法仍然是退伍军人管理局患者护理任务中的一个紧迫问题。 BH3 模拟物是一种有效的新型癌症治疗方法，可抑制 BCL-2 依赖性抗细胞凋亡 癌细胞固有的防御能力。标准护理加上 BCL-2 抑制剂（Venetoclax） 血液系统恶性肿瘤的缓解率高达 80%。然而，用单一 BH3 模拟物治疗 不足以杀死实体瘤，可能是由于存在不受抑制的 BCL-2 家族成员。 MCL-1 目前正在进行临床试验的抑制剂与临床药物配合使用可能会提高治疗效果 建立了 BH3 模拟物。此外，大多数 BH3 模拟物的研究都集中在它们杀死肿瘤细胞的能力 直接，而它们增强免疫疗法的潜力仍有待探索。此举的目的 该项目是测试 MCL-1 抑制剂与其他 BH3 模拟物或与 免疫疗法（抗PD-1）治疗黑色素瘤，特别是针对黑色素瘤肿瘤细胞 对当前治疗无反应。 我们的初步数据表明，MCL-1 抑制剂与 ABT-263 联合使用时，可以 协同杀死大量黑色素瘤肿瘤细胞和黑色素瘤起始细胞 (MIC)。这 黑色素瘤包括因当前治疗而复发的黑色素瘤。此外，在免疫能力模型中 黑色素瘤（C57BL6 小鼠中的 B16），一种 MCL-1 抑制剂可提高抗 PD1 治疗的疗效（初步研究） 研究）。我们假设：1）MCL-1抑制剂作为联合疗法的一部分，可以克服耐药性 黑色素瘤患者接受当前治疗。 2) 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物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。这些物质大部分来源于黑色素瘤 从当前治疗中复发的患者，具有可用的完整外泌体和 RNA-seq 数据；他们 将提供独特的机会来检验我们的假设。目标 1 将确定在 MCL-1 抑制剂和 ABT-263 的组合。我们将进一步检验以下假设： 针对 MCL-1 和其他有利于生存的 BCL-2 家族成员的多种 BH3 模拟物将克服 黑色素瘤细胞对当前体外和体内疗法的耐药性。目标 2 将确定功效和 MCL-1抑制剂增强免疫治疗的机制。我们将检验 MCL-1 的假设 抑制剂通过阻断抑制性免疫细胞群并增加免疫治疗的效果 免疫能力强的小鼠模型中的抗肿瘤免疫。 总之，该提案扩展了我们使用 MCL-1 抑制剂作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治疗结果， 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。