Modeling New Therapeutic Approaches for Malignant Melanoma

模拟恶性黑色素瘤的新治疗方法

• 批准号: 8966669
• 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/8966669
• 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; Cytotoxic T-Lymphocyte-Associated Protein 4; DNA Damage; Data; Disease regression; Effectiveness; Epidemic; Gene Mutation; Growth; Health; 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; STK6 gene; Severe Adverse Event; Stabilizing Agents; Staging; Sun Exposure; T cell response; TNFRSF10A gene; TNFRSF10B gene; TNFSF10 gene; TP53 gene; Testing; Therapeutic; Time; Toxic effect; Tumor Cell Invasion; Ubiquitination; Unresectable; Veterans; aurora kinase; base; chemotherapy; design; experience; improved; inhibitor/antagonist; kinase inhibitor; macrophage; melanoma; mutant; neoplastic cell; novel therapeutic intervention; older men; pre-clinical; preclinical study; receptor; research study; response; senescence; success; therapeutic effectiveness; treatment response; 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，也是治疗最挑战性的恶性肿瘤之一。虽然最近携带BRAFV600突变的黑色素瘤肿瘤最近取得了一些成功，但反应是短暂的，并且由于耐药性和次要肿瘤的发展而变得复杂。 BRAFWT和BRAFV600黑色素瘤肿瘤均符合CTLA-4或PD1抗体的治疗，以增强T细胞对肿瘤的反应，只有20-30％的肿瘤随着总体生存率的2-4个月而响应。我们的临床前实验集中于通过用极光激酶A（AURKA）抑制剂MLN8237阻止细胞周期来阻止肿瘤生长。大多数植入免疫抑制小鼠的人类黑色素瘤对使用MLN8237的治疗的反应强烈，但是该药物在很大程度上会诱导衰老并减缓肿瘤的生长，但不会导致消退。现在，我们拥有强大的初步数据，表明将Aurka抑制剂与MDM2的抑制剂或死亡受体4或5（DR4，DR5）的激活剂相结合，可将MLN8237通过MLN8237变成凋亡并导致肿瘤回归的肿瘤细胞。 We now want to carryout advanced pre-clinical studies using these combinations of therapy to treat human melanoma tumor imprants 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.有3个具体目的：目的IA：表征与MDM拮抗剂，Nutlin-3A和Aurka抑制剂MLN8237的合并疗法的有效性，用于治疗BRAFWT/P53WT，Nrasmutant/nrasmutant/p53wt，Nraswt/nraswt/p53wwtwwt。目标IB。为了检查Nutlin-3A和MLN8237组合处理对BRAFV600 /p53wt黑色素瘤肿瘤的生长的影响，这些患者对BRAF抑制剂的耐药性产生了抗性。目标IIA。为了表征与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。为了评估增强髓样细胞抗肿瘤反应的潜力，以增强与MLN8237和Nutlin-3A相关的Melano-MA肿瘤细胞死亡。我们将在髓样细胞中表达组成性活性IKK，以将其推入抗肿瘤表型。将用MLN8237和Nutlin-3a治疗，在具有WT或组成型活性IKK小鼠中生长的小鼠的黑色素瘤肿瘤将评估肿瘤的生长以及肿瘤的转移特性。目标IIIA。为了表征将死亡受体DR4和DR5与MLN8237与激动剂相结合的有效性，用于治疗BrafWT，NRAS WT或NRAS突变突变体黑色素瘤肿瘤，该肿瘤是P53WT或P53Mutant。 AIM IIIB。为了评估BRAF抑制剂抗体BRAFV600黑色素瘤的DR4组合的有效性，DR4激动剂具有MLN8237。