Modeling New Therapeutic Approaches for Malignant Melanoma

模拟恶性黑色素瘤的新治疗方法

• 批准号: 8633274
• 负责人: Ann Richmond
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633274
• 关键词: Address; Adverse effects; Affect; Age; Agonist; American; Antibodies; Antitumor Response; Apoptosis; BRAF gene; Cell Aging; Cell Cycle; Cell Death; Cells; Cessation of life; Chemical Exposure; Chemotherapy-Oncologic Procedure; Clinical Trials; Combined Modality Therapy; DNA Damage; Data; Disease regression; Effectiveness; Epidemic; Gene Mutation; Growth; Human; Immune; Immunologic Surveillance; Immunotherapy; Implant; Induction of Apoptosis; Leukocytes; Link; MDM2 gene; MEKs; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Mitosis; Modeling; Mus; Mutate; Mutation; Myeloid Cells; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Placebos; Population; Production; Progression-Free Survivals; Property; Proteins; Recruitment Activity; Relapse; Resistance; Resistance development; Severe Adverse Event; Stabilizing Agents; Staging; Sun Exposure; T cell response; TNFRSF10A gene; TNFRSF10B gene; TNFSF10 gene; Testing; Therapeutic; Time; Toxic effect; Tumor Cell Invasion; Ubiquitination; Unresectable; Veterans; aurora kinase; aurora-A kinase; base; chemotherapy; death receptor-4; design; experience; human TNFRSF10A protein; improved; inhibitor/antagonist; kinase inhibitor; macrophage; melanoma; mutant; neoplastic cell; novel therapeutic intervention; older men; pre-clinical; preclinical study; public health relevance; receptor; research study; response; senescence; success; therapeutic effectiveness; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): Metastatic melanoma is one of the fastest growing tumor types in the US, especially in Veterans, and also is one of the most challenging malignancies to treat. While there has been some recent success for melanoma tumors that carry the BRAFV600 mutation, the response is transient and treatment is complicated by development of resistance as well as secondary tumors. Both BRAFWT and BRAFV600 melanoma tumors are eligible for treatment with CTLA-4 or PD1 antibody to boost the T cell response to tumor, only 20-30 percent of the tumors respond with the 2-4 month increase in overall survival. Our preclinical experiments have focused on stopping tumor growth by blocking cell cycle with the Aurora kinase A (AURKA) inhibitor, MLN8237. Most human melanoma tumors implanted into immune deficient mice respond strongly to therapy with MLN8237, but the drug largely induces senescence and slows tumor growth, but does not cause regression. We now have strong preliminary data showing that combining the AURKA inhibitor with inhibitors of MDM2 or activators of death receptors 4 or 5 (DR4, DR5) pushes the tumor cells rendered senescent by MLN8237 into apoptosis and causes tumor regression. We now want to carryout advanced pre-clinical studies using these combinations of therapy to treat human melanoma tumor implants into mice to test the hypothesis that combining AURKA inhibitor therapy with agents that stabilize p53 by inhibition its ubiquitination by MDM2 or agents that activate DRs will provide improved therapy for late BRAFWT melanoma or melanomas that develop resistance to BRAF inhibitors. There are 3 specific aims: Aim IA: To characterize the effectiveness of combined therapy with the MDM antagonist, Nutlin-3a, and the AURKA inhibitor, MLN8237, for treatment of BRAFWT/p53WT, NRasmutant/p53WT, NRasWT/p53WT melanoma. Aim IB. To examine the effect of the Nutlin-3a and MLN8237 combination treatment on the growth of BRAFV600 /p53WT melanoma tumor implants from patients that have developed resistance to BRAF inhibitors. Aim IIA. To characterize the effects of combined treatment with MDM2 antagonist Nutlin-3a and AURKA inhibitor MLN8237 on tumor microenvironment an on melanoma metastasis. Aim IIB. To evaluate the potential for boosting the antitumor response of myeloid cells to enhance melano-ma tumor cell death in association with MLN8237 and Nutlin-3a. We will express constitutively active IKK¿ in myeloid cells to push them into an antitumor phenotype. Melanoma tumors growing in mice with WT or constitutively active IKK¿ in myeloid cells will be treated with MLN8237 and Nutlin-3a and growth of tumor and metastatic properties of tumor will be evaluated. Aim IIIA. To characterize the effectiveness of combining treatment with agonist for the death receptors DR4 and DR5 with MLN8237 for treatment of BRAFWT, NRAS WT or NRAS mutant melanoma tumors that are either p53WT or p53mutant. Aim IIIB. To evaluate the effectiveness of combined DR5, DR4 agonists with MLN8237 for BRAF inhibitor resistant BRAFV600 melanoma.

描述（由申请人提供）： 转移性黑色素瘤是美国增长最快的肿瘤类型之一，尤其是在退伍军人中，也是最具挑战性的恶性肿瘤之一。虽然最近在携带 BRAFV600 突变的黑色素瘤肿瘤方面取得了一些成功，但这种反应是短暂的，并且由于耐药性和继发性肿瘤的发展，治疗变得复杂。 BRAFWT 和 BRAFV600 黑色素瘤肿瘤都适合用 CTLA-4 或 PD1 抗体治疗，以增强 T 细胞对肿瘤的反应，只有 20-30% 的肿瘤有反应，总生存期增加 2-4 个月。我们的临床前实验重点是通过极光激酶 A (AURKA) 抑制剂 MLN8237 阻断细胞周期来阻止肿瘤生长。大多数植入免疫缺陷小鼠体内的人类黑色素瘤肿瘤对 MLN8237 治疗反应强烈，但该药物很大程度上会诱导衰老并减缓肿瘤生长，但不会引起消退。我们现在拥有强有力的初步数据表明，将 AURKA 抑制剂与 MDM2 抑制剂或死亡受体 4 或 5（DR4、DR5）激活剂相结合，可推动 MLN8237 导致衰老的肿瘤细胞凋亡并导致肿瘤消退。我们现在希望使用这些组合疗法来治疗植入小鼠体内的人类黑色素瘤肿瘤，以进行高级临床前研究，以测试以下假设：将 AURKA 抑制剂疗法与通过抑制 MDM2 泛素化来稳定 p53 的药物或激活 DR 的药物相结合，将为晚期 BRAFWT 黑色素瘤或对 BRAF 抑制剂产生耐药性的黑色素瘤提供改进的治疗。有 3 个具体目标： 目标 IA：表征 MDM 拮抗剂 Nutlin-3a 和 AURKA 抑制剂 MLN8237 联合疗法治疗 BRAFWT/p53WT、NRasmutant/p53WT、NRasWT/p53WT 黑色素瘤的有效性。目标IB。旨在检查 Nutlin-3a 和 MLN8237 联合治疗对来自对 BRAF 抑制剂产生耐药性的患者的 BRAFV600 /p53WT 黑色素瘤肿瘤植入物生长的影响。目标IIA。旨在表征 MDM2 拮抗剂 Nutlin-3a 和 AURKA 抑制剂 MLN8237 联合治疗对肿瘤微环境和黑色素瘤转移的影响。目标IIB。评估与 MLN8237 和 Nutlin-3a 相关的增强骨髓细胞抗肿瘤反应以增强黑色素瘤细胞死亡的潜力。我们将在骨髓细胞中表达组成型活性 IKK，以将它们推向抗肿瘤表型。将用 MLN8237 和 Nutlin-3a 治疗在骨髓细胞中具有 WT 或组成型活性 IKK 的小鼠中生长的黑色素瘤肿瘤，并评估肿瘤的生长和肿瘤的转移特性。目标IIIA。旨在表征死亡受体 DR4 和 DR5 激动剂与 MLN8237 联合治疗 p53WT 或 p53 突变的 BRAFWT、NRAS WT 或 NRAS 突变黑色素瘤的有效性。目标 IIIB。评估 DR5、DR4 激动剂与 MLN8237 联合治疗 BRAF 抑制剂耐药性 BRAFV600 黑色素瘤的有效性。