Impact of IKKB and AurK Inhibitors on Host Immunity and Melanoma

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，通常导致促进肿瘤进展的“细胞因子风暴”。治疗可以适当地“平息风暴”，同时对肿瘤有益，可能会对宿主产生负面影响。NF-？转录因子的B家族是产生“细胞因子风暴”所必需的。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抵抗力之间的平衡提供了一个独特的有价值的模型。我们已经证明，抑制IKK 2，激活典型的NF-？B途径，在黑色素瘤荷瘤小鼠中导致肿瘤生长减少。此外，黑素细胞中IKK 2的靶向缺失可防止缺失肿瘤抑制因子INK 4a/ARF的小鼠中突变Ras介导的黑色素瘤肿瘤形成。目前对播散性黑色素瘤的治疗在很大程度上无效。IKK 2的小分子抑制剂，通过直接阻断典型的NF-？B通路的特异性，可能在临床上对转移性黑色素瘤有效。极光激酶（Aurk）抑制剂很容易阻断肿瘤细胞的细胞周期进程，也间接抑制NF-κ B，而NF-κ B抑制剂？B抑制Aurk并靶向多种类型的肿瘤细胞进行凋亡。目前正在进行使用IKK 2和AurK的小分子抑制剂治疗其他实体瘤和血液恶性肿瘤的临床试验。黑色素瘤可能对这两种激酶的抑制剂有高度反应，但在开始此类研究之前，抑制NF-κ B通路对宿主免疫反应的潜在有害影响需要澄清。在本提案中，我们将检验以下假设：靶向IKK 2或AurkA的获益将超过侵袭性转移性黑色素瘤和这些通路组成性激活患者的风险。我们还假设用IKK 2或AurKA抑制剂抑制NF-kB将通过将肿瘤微环境中的白细胞谱从促肿瘤发生（M2、N2、Th 2）转变为抗肿瘤发生（M1/N1/Th 1）来增强对肿瘤的免疫应答。此外，有文献记载的肿瘤对Aurk抑制剂产生耐药性的病例，在这些情况下，我们假设对Aurk或IKK抑制剂治疗的耐药性与Aurk或IKK通路中的激酶突变相关。有三个具体目标：1）确定用IKK 2或AurkA抑制剂治疗是否导致对“沉默”肿瘤的固有免疫力丧失。2)表征IKK 2与AurkA的全身抑制对肿瘤微环境中白细胞浸润和细胞因子谱的影响; 3）表征对IKK 2或Aurk抑制剂敏感的黑素瘤肿瘤变得生长停滞然后随后对这些抑制剂耐药的机制。这项临床前工作的见解应该允许适当设计临床试验，以测试IKK 2和Aurk抑制剂对黑色素瘤治疗的疗效。这项工作的最终目标是为改善恶性黑色素瘤患者的个体化治疗提供见解，以提高生存率。

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.