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.

在美国的VA人群中，黑色素瘤的发病率正在迅速增加，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。护理标准 对于晚期黑色素瘤，包括BRAF和MEK抑制剂的分子靶向疗法，以及 具有检查点抑制剂（例如抗PD1）的免疫疗法。但是，高级的25％至70％ 黑色素瘤患者不能反应或从当前治疗中复发。因此，发现 在VA患者护理任务中，有效的恶性黑色素瘤新疗法仍然是一个紧迫的问题。 BH3 Mimetics是一种有力的新类癌症治疗，抑制依赖Bcl-2的抗凋亡 癌细胞固有的防御能力。标准护理加上针对Bcl-2（venetoclax）的抑制剂给出了 血液系统恶性肿瘤的缓解率高达约80％。但是，用单个BH3模拟治疗 不足以杀死实体瘤，这可能是由于存在不受抑制的Bcl-2家族成员而造成的。 MCL-1 当前正在临床试验中的抑制剂与临床上配对时可能会提高治疗效果 已建立的BH3 Mimetics。此外，大多数使用BH3 Mimetics的研究都集中在杀死肿瘤细胞的能力上 直接，尽管它们增强免疫疗法的潜力仍有待探索。这个目的 项目是测试MCL-1抑制剂与其他BH3 Mimetics的组合处理或与 免疫疗法（抗PD-1）治疗黑色素瘤，尤其是黑色素瘤细胞 对当前治疗无反应。 我们的初步数据表明，与ABT-263结合使用MCL-1抑制剂可以 协同杀死大部分黑色素瘤细胞和黑色素瘤启动细胞（MIC）。这 黑色素瘤包括从当前疗法中复发的。此外，在免疫胜任的模型中 黑色素瘤（C57BL6小鼠的B16），MCL-1抑制剂增加了抗PD1治疗的功效（初步 研究）。我们假设：1）作为组合疗法的一部分，MCL-1抑制剂可以克服抗性 黑色素瘤患者接受当前治疗。 2）消除肿瘤细胞可以通过 直接杀死或通过调节肿瘤微环境的抗肿瘤免疫反应。我们也有 访问大量黑色素瘤的短期培养物和患者衍生的异种移植（PDX）模型 科罗拉多大学黑色素瘤组织库。这些材料中的大多数是从黑色素瘤得出的 从当前治疗中复发的患者，并提供了整个外泌体和RNA-seq数据；他们 将提供独特的机会来检验我们的假设。 AIM 1将确定在发挥作用的机制 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加上其他亲寿世的BCL-2家庭成员的多种BH3 Mimetics将克服 黑色素瘤细胞对当前疗法的抗性，体外和体内的抗性。 AIM 2将确定功效和 MCL-1抑制剂的机制增强免疫疗法。我们将测试MCL-1的假设 抑制剂通过阻止抑制性免疫细胞群体增强免疫疗法并增加 免疫能力小鼠模型中的抗肿瘤免疫。 总而言之，该建议扩展了我们使用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抗性的药物组合。预期 探索这些新的临床准备就绪的BH3 Mimetics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。结果可能会导致积极 对黑色素瘤治疗的影响，确定用于治疗黑色素瘤患者的新疗法 用尽了其他选择。