Modeling New Therapeutic Approaches for Malignant 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，治疗因耐药性的发展以及继发性肿瘤而变得复杂。BRAFWT和BRAFV600黑色素瘤均可接受CTLA-4或PD1抗体的治疗，以增强T细胞对肿瘤的应答，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使用极光激酶A(AURKA)抑制剂MLN8237阻断细胞周期来阻止肿瘤生长。大多数移植到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，但该药物在很大程度上会诱导衰老和减缓肿瘤生长，但不会导致消退。我们现在有强有力的初步数据表明，AURKA抑制剂与MDM2抑制剂或死亡受体激活剂4或5(DR4，DR5)联合使用可推动MLN8237导致衰老的肿瘤细胞进入凋亡状态，并导致肿瘤消退。我们现在想进行高级临床前研究，使用这些治疗方法的组合来治疗人类黑色素瘤植入小鼠体内，以测试这样一个假设，即将AURKA抑制剂治疗与通过抑制MDM2泛素化来稳定P53的药物或激活DRS的药物相结合，将为对BRAF抑制剂产生耐药性的晚期BRAFWT黑色素瘤或黑色素瘤提供改进的治疗方法。目的IA：研究MDM拮抗剂Nutlin-3a和AURKA抑制剂MLN8237联合治疗BRAFWT/p53WT、NRasmutic/p53WT、NRasWT/p53WT黑色素瘤的疗效。瞄准IB。研究Nutlin-3a和MLN8237联合治疗对对BRAF抑制剂产生耐药性的患者的BRAFV600/p53WT黑色素瘤移植瘤生长的影响。瞄准IIA。探讨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。AIM IIB。目的：探讨MLN8237和Nutlin-3a在促进髓系细胞抗肿瘤反应中增强黑色素瘤细胞死亡的可能性。我们将在髓系细胞中表达具有结构性活性的IKK，以推动它们进入抗肿瘤表型。MLN8237和Nutlin-3a将用MLN8237和Nutlin-3a治疗在具有WT或髓系细胞IKK活性的小鼠中生长的黑色素瘤，并将评估肿瘤的生长和肿瘤的转移特性。目标IIIA。目的探讨死亡受体DR4和DR5激动剂与MLN8237联合治疗p53WT或p53突变的BRAFWT、NRAS WT或NRAS突变型黑色素瘤的疗效。瞄准IIIB。目的：评价DR5、DR4激动剂联合MLN8237治疗耐BRAF抑制剂的BRAFV600黑色素瘤的疗效。

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.