Research Project 2 - Targeting Melanoma Tumor Survival and Apoptotic Machinery

研究项目 2 - 靶向黑色素瘤肿瘤存活和凋亡机制

• 批准号: 10681845
• 负责人: Michael Davies
• 金额: $ 12.97万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10681845
• 关键词: Affect; Apoptosis Regulation Gene; Apoptotic; BCL-2 Protein; BCL2 gene; BCL2L11 gene; BRAF gene; Biological Markers; Cell Line; Clinical; Clinical Trials; Combined Modality Therapy; Cutaneous Melanoma; Data; Effectiveness; Genotype; Growth; Heterogeneity; High Prevalence; Human; In Vitro; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MDM2 gene; MEK inhibition; MEKs; Malignant Neoplasms; Maximum Tolerated Dose; Melanoma Cell; Metastatic Melanoma; Modeling; Molecular; Mutation; Outcome; Pathway interactions; Patient Selection; Patients; Phase; Phase I Clinical Trials; Pre-Clinical Model; Protein Family; Protein-Serine-Threonine Kinases; Proteins; Randomized; Ras/Raf; Regimen; Research Project Grants; Resistance; Resistance development; Safety; Skin Cancer; Solid; Solid Neoplasm; Somatic Mutation; TP53 gene; Testing; Therapeutic; Translating; Tumor Suppressor Genes; base; chemotherapy; combinatorial; disease heterogeneity; efficacy evaluation; experimental study; improved; in vivo; inhibitor; inhibitor therapy; kinase inhibitor; melanoma; member; mimetics; mutant; mutational status; new therapeutic target; novel; patient derived xenograft model; personalized medicine; personalized strategies; phase II trial; preclinical study; prevent; pro-apoptotic protein; research clinical testing; resistance mechanism; response; targeted agent; targeted treatment; therapy resistant; tumor

Project Summary – Project 2 Melanoma, the most aggressive form of skin cancer, is characterized by a very high rate of somatic mutations. Approximately 50% of cutaneous melanomas have a mutation that affects the V600 residue in Braf. The activity of the mutant form of the protein (BRAFV600) is markedly increased and results in constitutive activation of the RAS-RAF-MAPK signaling pathway. This information has rapidly translated into clinical benefit, as five targeted therapy regimens have been approved for the treatment of metastatic melanoma patients with a BrafV600 mutation. While these agents have very high clinical response rates, unfortunately the majority of patients develop resistance within 2 years. Further, these targeted therapies cannot be used in patients who do not have a BrafV600 mutation. Thus, there remain unmet clinical needs to identify strategies to prevent resistance to approved targeted therapies in metastatic melanoma patients with an activating BrafV600 mutation, and new targeted therapy approaches for patients without a BrafV600 mutation (BRAF Wild-Type). While many studies are ongoing to evaluate the therapeutic potential of other kinase inhibitors, there is growing evidence to support the rationale for the testing of agents that target the apoptotic machinery. In contrast to many other cancers, cutaneous melanomas have a low rate (~20%) of mutations in Tp53. Additional studies have shown anti-apoptotic members of the BCL2 family of proteins can promote resistance to targeted therapies against the RAS-RAF-MAPK pathway, and that pro-apoptotic proteins (i.e., BIM) are critical to their effectiveness. Based on promising results in a limited number of preclinical models, clinical trials targeting the apoptotic machinery in combination with RAS-RAF-MAPK pathway inhibitors are ongoing in metastatic melanoma patients. However, currently there are no biomarkers to optimize patient selection for these strategies, nor understanding of resistance mechanisms to them. The central hypothesis of this proposal is that specific molecular features will predict sensitivity and resistance to combinatorial strategies utilizing pro- apoptotic agents and MAPK pathway targeted therapies. In order to test this hypothesis we will evaluate pro-apoptotic agents in combination with MAPK pathway inhibitors in molecularly characterized melanoma PDX models, which accurately replicate the molecular features and heterogeneity of this disease. In AIM 1 we will evaluate the efficacy and molecular effects of navitoclax, a BH3 mimetic that inhibits BCL2, alone and in combination with dabrafenib (BRAFi) and trametinib (MEKi) in melanoma PDX with a BrafV600 mutation. These experiments mirror an ongoing randomized phase II of these agents in metastatic melanoma patients, and the results of that trial will be used to clinically validate markers associated with resistance in the PDX. In AIM 2 we will evaluate the efficacy of the MDM2 inhibitor AMG232, alone and in combination with trametinib. Testing will be performed in BRAF WT melanomas with wild-type Tp53, including a subset with MDM2 amplification. These studies will help to refine and prioritize strategies using these agents in metastatic melanoma patients.

项目总结 – 项目 2 黑色素瘤是最具侵袭性的皮肤癌，其特点是体细胞突变率非常高。 大约 50% 的皮肤黑色素瘤具有影响 Braf 中 V600 残基的突变。这 蛋白质突变体 (BRAFV600) 的活性显着增加并导致组成型激活 RAS-RAF-MAPK 信号通路。这些信息已迅速转化为临床效益，因为五个 靶向治疗方案已被批准用于治疗转移性黑色素瘤患者 BrafV600 突变。虽然这些药物具有非常高的临床反应率，但不幸的是大多数 患者在2年内产生耐药性。此外，这些靶向治疗不能用于以下患者： 没有 BrafV600 突变。因此，仍然存在未满足的临床需求，以确定预防策略 具有激活 BrafV600 突变的转移性黑色素瘤患者对已批准的靶向治疗产生耐药性， 以及针对没有 BrafV600 突变（BRAF 野生型）的患者的新靶向治疗方法。虽然很多 评估其他激酶抑制剂治疗潜力的研究正在进行中，越来越多的证据表明 支持测试针对细胞凋亡机制的药物的基本原理。与许多其他 癌症、皮肤黑色素瘤的 Tp53 突变率较低（约 20%）。其他研究表明 BCL2蛋白家族的抗凋亡成员可以促进针对靶向治疗的耐药性 RAS-RAF-MAPK 通路，促凋亡蛋白（即 BIM）对其有效性至关重要。 基于有限数量的临床前模型的有希望的结果，针对细胞凋亡的临床试验 机器与 RAS-RAF-MAPK 通路抑制剂相结合正在治疗转移性黑色素瘤 患者。然而，目前没有生物标志物可以优化这些策略的患者选择，也没有 了解它们的抵抗机制。该提案的中心假设是具体 分子特征将预测利用亲组合策略的敏感性和耐药性 细胞凋亡剂和 MAPK 通路靶向治疗。为了检验这个假设，我们将评估 促凋亡药物与 MAPK 通路抑制剂联合治疗分子特征黑色素瘤 PDX 模型，准确复制该疾病的分子特征和异质性。在 AIM 1 中，我们 将评估 navitoclax 的功效和分子效应，navitoclax 是一种抑制 BCL2 的 BH3 模拟物，单独使用和在 与达拉非尼 (BRAFi) 和曲美替尼 (MEKi) 联合治疗具有 BrafV600 突变的黑色素瘤 PDX。这些 实验反映了这些药物在转移性黑色素瘤患者中正在进行的随机 II 期临床试验， 该试验的结果将用于临床验证与 PDX 耐药性相关的标记物。在目标 2 中 我们将评估 MDM2 抑制剂 AMG232 单独使用以及与曲美替尼联合使用的疗效。测试 将在具有野生型 Tp53 的 BRAF WT 黑色素瘤中进行，包括具有 MDM2 扩增的子集。 这些研究将有助于完善和优先考虑在转移性黑色素瘤患者中使用这些药物的策略。