Impact of IKKB and AurK Inhibitors on Host Immunity and Melanoma

IKKB 和 AurK 抑制剂对宿主免疫和黑色素瘤的影响

• 批准号: 7992308
• 负责人: Ann Richmond
• 金额: $ 14.95万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-19 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992308
• 关键词: Adult; Affect; Apoptosis; B-Lymphocytes; Benefits and Risks; Biological Assay; Cancer Etiology; Catalytic RNA; Cause of Death; Cell Cycle; Cell Cycle Progression; Childhood Solid Neoplasm; Chronic; Clinic; Clinical Trials; Clinical Trials Design; Curcumin; Data; Development; Disease; Environment; Equilibrium; Family; Gene Expression; Gene Expression Profile; Generations; Genetic Transcription; Goals; Growth; Hematologic Neoplasms; Human; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Inflammation; Kidney; Lesion; Leukocytes; Long-Term Effects; Lymphoma; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metastatic Melanoma; Mitotic; Modeling; Multiple Myeloma; Mus; Mutation; Myeloid Cells; NF-kappa B; Nodule; Oncogenic; Ovarian; Pathway interactions; Patients; Phase; Phase II Clinical Trials; Phosphotransferases; Protein p53; Publishing; Resistance; Resistance development; Risk; Skin Cancer; Solid; Solid Neoplasm; T-Lymphocyte; Testing; Tissues; Tumor Suppressor Proteins; Work; aurora kinase; aurora-A kinase; caspase-3; chemotherapy; cytokine; efficacy testing; improved; inhibitor/antagonist; insight; kinase inhibitor; knock-down; macrophage; melanocyte; melanoma; mouse model; mutant; neoplastic cell; pre-clinical; preclinical study; prevent; response; small molecule; survivin; therapy resistant; thyroid neoplasm; transcription factor; tumor; tumor growth; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Chronic inflammation is causally associated with the development of many cancers, often resulting in a "cytokine storm" that facilitates tumor progression. Therapy could be directed to appropriately "quiet the storm" while beneficial for the tumor, could result in negative effects on the host. The NF-?B family of transcription factors is required for the generation of the 'cytokine storm'. Malignant melanoma, the most deadly type of skin cancer, provides a uniquely valuable model for testing the balance between immunity and intrinsic resistance in tumor growth. We have demonstrated that inhibiting IKK2, the major kinase that activates the canonical NF-?B pathway, in melanoma tumor bearing mice results in reduced tumor growth. Moreover, targeted deletion of IKK2 in melanocytes prevents mutant Ras-mediated melanoma tumor formation in mice that have lost the tumor suppressors INK4a/ARF. Current therapies for disseminated melanoma are largely ineffective. Small molecule inhibitors of IKK2, by directly blocking the canonical NF-?B pathway, may be effective in the clinic for metastatic melanoma. Aurora Kinase (Aurk) inhibitors readily block cell cycle progression in tumor cells and also indirectly inhibit NF-kB, while inhibitors of NF-?B inhibit Aurk and target many types of tumor cells for apoptosis. Clinical trials are currently ongoing using small molecule inhibitors of IKK2 and AurK for other solid tumors and haematological malignancies. Melanoma might be highly responsive to inhibitors to these two kinases, but before initiating such studies, potentially harmful effects of inhibiting the NF-kB pathway on the host immune response require clarification. In this proposal we will test the hypothesis that the benefits of targeting IKK2 or AurkA will outweigh the risks for patients with aggressive metastatic melanoma and constitutive activation of these pathways. We also hypothesize that inhibiting NF-kB with IKK2 or AurKA inhibitors will boost the immune response to the tumor by shifting leukocyte profile in the tumor microenvironment from one that is pro-tumorigenic (M2, N2, Th2) to one that is anti-tumorigenic (M1/N1/Th1). Moreover, there are documented cases of tumors developing resistance to Aurk inhibitors and in these instances we hypothesize that resistance to therapy with Aurk or IKK inhibitors will be associated with mutations in Aurk or kinases in the IKK pathway. There are three specific aims: 1) To determine whether treatment with IKK2 or AurkA inhibitors results in loss of intrinsic immunity to "silent" tumors. 2) To characterize the effects of systemic inhibition of IKK2 versus AurkA on the leukocytes infiltrate and cytokine profile in the tumor microenvironment; 3) To characterize the mechanism by which melanoma tumors sensitive to IKK2 or Aurk inhibitors become growth arrested then later resistant to these inhibitors. Insights from this pre-clinical work should allow appropriate design of clinical trials to test the efficacy of IKK2 and Aurk inhibitors for melanoma therapy. The ultimate goal of this work is to develop insight for improved individualized therapy for malignant melanoma patients to increase survival.

描述（由申请人提供）：慢性炎症与许多癌症的发展有因果关系，通常会导致“细胞因子风暴”，从而促进肿瘤进展。可以指示治疗适当地“平静的风暴”，同时对肿瘤有益，可能会对宿主产生负面影响。生成“细胞因子风暴”需要NF-？B家族。恶性黑色素瘤是最致命的皮肤癌类型，为测试肿瘤生长中免疫力和内在耐药性之间的平衡提供了一个独特的有价值模型。我们已经证明，抑制IKK2是激活规范NF- b途径的主要激酶，在携带小鼠的黑色素瘤肿瘤中会导致肿瘤生长降低。此外，黑素细胞中IKK2的靶向缺失可防止突变的RAS介导的小鼠中的黑色素瘤肿瘤形成，这些小鼠损失了肿瘤抑制剂Ink4a/arf。当前的传播黑色素瘤疗法在很大程度上无效。 IKK2的小分子抑制剂通过直接阻断规范的NF-途径，可能在转移性黑色素瘤的诊所有效。 Aurora激酶（AURK）抑制剂很容易阻止肿瘤细胞中的细胞周期进展，并间接抑制NF-KB，而NF-？B的抑制剂抑制了AURK，并靶向多种类型的肿瘤细胞来凋亡。目前正在使用IKK2的小分子抑制剂和其他实体瘤和血液学恶性肿瘤进行临床试验。黑色素瘤可能对这两种激酶的抑制剂有很高的反应，但是在启动此类研究之前，抑制NF-KB途径对宿主免疫反应的潜在有害作用需要澄清。在此提案中，我们将检验以下假设：靶向IKK2或Aurka的益处将超过侵袭性转移性黑色素瘤和这些途径组成型激活患者的风险。我们还假设，使用IKK2或AURKA抑制剂抑制NF-KB将通过将肿瘤微环境中的白细胞谱转移到抗肿瘤的肿瘤（M2，N2，TH2）中，从而增强对肿瘤的免疫反应，从此外，有记录的肿瘤病例对AURK抑制剂产生抗性，在这些情况下，我们假设对Aurk或IKK抑制剂对治疗的耐药性将与IKK途径中Aurk或激酶的突变有关。有三个特定的目的：1）确定用IKK2或Aurka抑制剂治疗是否导致“沉默”肿瘤的内在免疫力丧失。 2）表征了肿瘤微环境中全身抑制IKK2与Aurka对白细胞浸润和细胞因子谱的影响； 3）表征黑色素瘤对IKK2敏感或Aurk抑制剂敏感的机制，随后对这些抑制剂具有抗药性。这项临床前工作的见解应允许适当设计临床试验，以测试IKK2和AURK抑制剂对黑色素瘤治疗的功效。这项工作的最终目的是为改善恶性黑色素瘤患者的个性化治疗而开发见解，以提高生存率。