Impact of IKKB and AurK Inhibitors on Host Immunity and Melanoma

描述(申请人提供)：慢性炎症与许多癌症的发生有因果关系，通常会导致促进肿瘤进展的“细胞因子风暴”。治疗可以被引导到适当的“平息风暴”，虽然有益于肿瘤，但可能导致对宿主的负面影响。核因子-βB家族转录因子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，它为检测肿瘤生长中免疫和内在抵抗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，在黑色素瘤荷瘤小鼠中，抑制IKK2，激活典型的NF-B途径的主要激酶，会导致肿瘤生长减少。此外，靶向删除黑素细胞中的IKK2可以防止突变的RAS介导的黑色素瘤在失去肿瘤抑制基因INK4a/ARF的小鼠中形成肿瘤。目前治疗播散性黑色素瘤的方法大多无效。IKK2的小分子抑制剂通过直接阻断典型的核因子-βB途径，可能在临床上治疗转移性黑色素瘤有效。Aurora Kinase(Aurk)抑制剂很容易阻断肿瘤细胞的细胞周期进程，也间接抑制核因子-kB，而核因子-kB抑制剂则抑制Aurk并靶向多种类型的肿瘤细胞凋亡。目前正在进行临床试验，使用小分子抑制剂IKK2和AurK治疗其他实体肿瘤和血液系统恶性肿瘤。黑色素瘤可能对这两种激酶的抑制剂高度敏感，但在开始这类研究之前，抑制核因子-kB途径对宿主免疫反应的潜在有害影响需要澄清。在这项提案中，我们将测试一种假设，即靶向IKK2或AurkA的好处将超过对侵袭性转移性黑色素瘤患者的风险以及这些通路的结构性激活。我们还假设，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分布从促肿瘤(M2、N2、Th2)转变为抗肿瘤(M1/N1/Th1)来增强对肿瘤的免疫反应。此外，有文献记载的肿瘤对Aurk抑制剂产生耐药性的案例，在这些情况下，我们假设对Aurk或IKK抑制剂治疗的耐药性将与Aurk或IKK通路中的Aurk或激酶的突变有关。有三个具体目标：1)确定IKK2或AurkA抑制剂治疗是否会导致对“沉默”肿瘤的固有免疫力丧失。2)研究系统抑制IKK2和AurkA对肿瘤微环境中白细胞浸润和细胞因子分布的影响；3)研究黑色素瘤对IKK2或Aurk抑制剂敏感的肿瘤生长受阻，然后对这些抑制剂产生耐药性的机制。来自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IKK2和Aurk抑制剂对黑色素瘤治疗的有效性。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以提高生存率而发展洞察力。

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.