Interferon Activated Necroptosis as a New Therapeutic Avenue for Kidney Cancer

描述(申请人提供)：晚期肾细胞癌(RCC)是一种致命的癌症，2013年将在美国夺走超过13,000人的生命。目前，针对血管生成或营养感知途径的小分子抑制剂是治疗这种疾病的主要药物干预措施，但这些抑制剂只能延缓肿瘤的进展，并不能治愈。因此，肾癌是一个重大的治疗挑战。与目前的小分子疗法不同，细胞因子干扰素-γ在几个转移性肾癌的I/II期试验中显示出提供持久缓解的潜力。然而，干扰素-γ具有严重的毒副作用，这抑制了人们对其在临床上使用的热情。这些副作用源于两个需要高剂量才能临床受益的主要局限性：(1)肾癌细胞对干扰素-γ的S直接杀瘤作用具有很大的抗药性，(2)干扰素-γ在循环中的半衰期非常短，因此在肿瘤中的生物利用度很低。在这项提案中，我们概述了克服这两个缺点的途径。首先，我们已经确定了两种保护肾癌细胞免受干扰素-γ影响的生存机制；在缺乏这两种机制的情况下，干扰素-γ会在肾癌细胞中触发一种新型的程序性坏死(或坏死性下垂)。其中一个机制(NF-κB)可以被FDA批准的小分子药物Bortezomib禁用，Bortezomib通过临床上容易实现的剂量的干扰素-γ使肾癌-但不是正常-细胞对坏死性死亡敏感。第二，我们制备了新型的干扰素-γ-抗体融合抗体，它(1)稳定血清中的干扰素-γ，(2)靶向肾癌细胞的干扰素-γ。我们预计，这种干扰素-γ融合与硼替佐米的组合将在极大地降低全身毒性的同时发挥强大的杀瘤活性。在三个目标中，我们将(1)确定干扰素-γ激活坏死性下垂的机制，(2)在被硼替佐米抑制的途径中确定更多的靶点。 通过确定干扰素-γ如何激活核因子-κB，以及(3)将天然干扰素-γ和干扰素-γ-抗体与Bortezomib在小鼠肾癌模型中融合。这项研究的发现直接适用于几种人类癌症，在这些癌症中，IFN以前显示出治疗潜力。

DESCRIPTION (provided by applicant): Advanced renal cell carcinoma (RCC) is an invariably fatal cancer that will claim over 13,000 lives in the US in 2013. Currently, small-molecule inhibitors that target angiogenesis or nutrient-sensing pathways represent the primary pharmacological interventions for this disease, but these inhibitors only delay tumor progression and are not curative. RCC therefore represents a significant therapeutic challenge. Unlike current small-molecule therapies, the cytokine interferon-gamma (IFN-γ) showed the potential to provide lasting remission in several phase I/II trials for metastatic RCC. IFN-γ, however, has severe toxic side-effects that have dampened enthusiasm for its use in the clinic. These side-effects arise from two major limitations that require high doses for clinical benefit: (1) RCC cell are largely resistant to IFN-γ's direct tumoricidal effects, and (2) IFN-γ has a very short half-lie in circulation, with consequently poor bioavailabity at the tumor. In this proposal, we outline avenues to overcome both these shortcomings. First, we have identified two survival mechanisms that protect RCC cells from IFN-γ; in the absence of either mechanism, IFN-γ triggers a novel form of programmed necrosis (or necroptosis) in RCC cells. One of these mechanisms (NF-κB) can be disabled by the small molecule FDA-approved agent bortezomib, and bortezomib sensitizes RCC - but not normal - cells to necroptotic death by doses of IFN-γ that are easily clinically achievable. Second, we have generated novel IFN-γ-antibody fusion antibodies that (1) stabilize IFN-γ in serum, and (2) target IFN-γ to RCC cells. We expect that the combination of such IFN-γ fusions and bortezomib will exert potent tumoricidal activity while greatly minimizing systemic toxicity. In three aims, we will (1) identify the mechanism by which IFN-γ activates necroptosis, (2) identify additional targets in the pathway inhibited by bortezomib by identifying how IFN-γ activates NF-κB, and (3) combine native IFN-γ and IFN-γ-antibody fusions with bortezomib in murine models of RCC. The findings from this study are directly applicable to several human cancers in which IFNs have previously shown therapeutic potential.