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: 9446227
• 负责人: Michael Davies
• 金额: $ 64.52万
• 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 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9446227
• 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; 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; experimental study; improved; in vivo; inhibitor/antagonist; kinase inhibitor; melanoma; member; mimetics; mutant; mutational status; new therapeutic target; novel; 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.

项目摘要-项目2 黑色素瘤是皮肤癌中最具侵袭性的一种，其特征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。的 突变形式的蛋白质（BRAFV 600）的活性显著增加，并导致组成型激活 RAS-RAF-MAPK信号通路。这一信息已迅速转化为临床效益，因为5 靶向治疗方案已被批准用于治疗具有以下特征的转移性黑素瘤患者： BrafV 600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BrafV 600突变。因此，仍然存在未满足的临床需求，以确定预防的策略。 具有激活性BrafV 600突变的转移性黑色素瘤患者对获批靶向治疗的耐药性， 以及针对无BRAF V600突变（BRAF野生型）患者的新靶向治疗方法。虽然许多 研究正在进行中，以评估其他激酶抑制剂的治疗潜力，有越来越多的证据表明， 支持测试靶向凋亡机制的试剂的基本原理。与许多其他 在癌症中，皮肤黑色素瘤在Tp 53中具有低突变率（~20%）。另外的研究已经显示 BCL 2蛋白家族的抗凋亡成员可以促进对靶向治疗的抗性， RAS-RAF-MAPK途径和促凋亡蛋白（即，BIM对于其有效性至关重要。 基于在有限数量的临床前模型中的有希望的结果，靶向细胞凋亡的临床试验 与RAS-RAF-MAPK通路抑制剂联合治疗转移性黑色素瘤 患者然而，目前没有生物标志物来优化这些策略的患者选择，也没有生物标志物来优化这些策略的患者选择。 了解它们的抗性机制。这一提议的核心假设是， 分子特征将预测敏感性和抗性的组合策略，利用亲， 凋亡剂和MAPK通路靶向治疗。为了验证这一假设，我们将评估 促凋亡剂联合MAPK通路抑制剂治疗分子特征性黑色素瘤 PDX模型，准确复制这种疾病的分子特征和异质性。在AIM 1中， 将评估navitoclax（一种抑制BCL 2的BH 3模拟物）单独和联合 与达拉非尼（BRAFi）和曲美替尼（MEKi）组合治疗具有BrafV 600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期试验， 该试验的结果将用于临床验证与PDX耐药性相关的标志物。在AIM 2中 我们将评估MDM 2抑制剂AMG 232单独和与曲美替尼组合的功效。测试 将在具有野生型Tp 53的BRAF WT黑色素瘤中进行，包括具有MDM 2扩增的子集。 这些研究将有助于改进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。