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，也是治疗最具挑战性的恶性肿瘤之一。虽然最近对携带BRAFV 600突变的黑色素瘤肿瘤取得了一些成功，但反应是短暂的，并且由于耐药性的发展以及继发性肿瘤的出现，治疗变得复杂。BRAFWT和BRAFV 600黑色素瘤肿瘤都适合用CTLA-4或PD 1抗体治疗，以增强T细胞对肿瘤的应答，只有20- 30%的肿瘤应答，总生存期增加2-4个月。我们的临床前实验集中在通过Aurora激酶A（AURKA）抑制剂MLN 8237阻断细胞周期来阻止肿瘤生长。植入免疫缺陷小鼠的大多数人黑素瘤肿瘤对MLN 8237治疗反应强烈，但该药物在很大程度上诱导衰老并减缓肿瘤生长，但不会导致消退。我们现在有强有力的初步数据显示，AURKA抑制剂与MDM 2抑制剂或死亡受体4或5（DR 4、DR 5）激活剂联合使用可促使MLN 8237衰老的肿瘤细胞凋亡，并导致肿瘤消退。我们现在想要使用这些治疗组合来进行高级临床前研究，以治疗小鼠中的人黑素瘤肿瘤植入物，以测试以下假设：将AURKA抑制剂治疗与通过MDM 2抑制p53的泛素化来稳定p53的药物或激活DR的药物组合将为晚期BRAFWT黑素瘤或对BRAF抑制剂产生耐药性的黑素瘤提供改善的治疗。有三个具体目标：目标IA：表征MDM拮抗剂Nutlin-3a和AURKA抑制剂MLN 8237联合治疗BRAFWT/p53 WT、NRas突变体/p53 WT、NRas WT/p53 WT黑色素瘤的有效性。目标1B。检查Nutlin-3a和MLN 8237联合治疗对BRAF抑制剂耐药患者BRAFV 600/p53 WT黑色素瘤植入物生长的影响。目标IIA。表征MDM 2拮抗剂Nutlin-3a和AURKA抑制剂MLN 8237联合治疗对肿瘤微环境和黑色素瘤转移的影响。Aim IIB.评价MLN 8237和Nutlin-3a联合使用增强骨髓细胞抗肿瘤应答以增强黑素瘤肿瘤细胞死亡的潜力。我们将在髓样细胞中表达组成型活性IKK，将其推向抗肿瘤表型。将用MLN 8237和Nutlin-3a处理骨髓细胞中存在WT或组成型活性IKK？的小鼠中生长的黑色素瘤肿瘤，并评价肿瘤生长和肿瘤转移特性。目标IIIA。表征死亡受体DR 4和DR 5激动剂与MLN 8237联合治疗p53 WT或p53突变型BRAFWT、NRAS WT或NRAS突变型黑色素瘤的有效性。目标三B.评价DR 5、DR 4激动剂与MLN 8237联合治疗BRAF抑制剂耐药BRAFV 600黑色素瘤的有效性。

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.