Interferon Activated Necroptosis as a New Therapeutic Avenue for Kidney Cancer

描述（由申请人提供）：晚期肾细胞癌（RCC）是一种始终致命的癌症，2013年在美国将夺去13，000多人的生命。目前，靶向血管生成或营养感应途径的小分子抑制剂代表了这种疾病的主要药理学干预措施，但这些抑制剂只能延迟肿瘤进展，不能治愈。因此，RCC代表了重大的治疗挑战。与目前的小分子疗法不同，细胞因子干扰素-γ（IFN-γ）在转移性RCC的几项I/II期试验中显示出提供持久缓解的潜力。然而，IFN-γ具有严重的毒副作用，这抑制了其在临床中使用的热情。这些副作用由两个主要限制引起，其需要高剂量以获得临床益处：（1）RCC细胞在很大程度上对IFN-γ的直接杀肿瘤作用具有抗性，以及（2）IFN-γ在循环中具有非常短的半衰期，因此在肿瘤处具有差的生物利用度。在本建议中，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RCC细胞免受IFN-γ影响的生存机制;在缺乏任何一种机制的情况下，IFN-γ都会触发RCC细胞中一种新形式的程序性坏死（或坏死性凋亡）。这些机制之一（NF-κB）可以被小分子FDA批准的药物硼替佐米禁用，并且硼替佐米通过临床上容易实现的IFN-γ剂量使RCC细胞（但不是正常细胞）对坏死性死亡敏感。第二，我们已经产生了新的IFN-γ-抗体融合抗体，其（1）稳定血清中的IFN-γ，和（2）将IFN-γ靶向RCC细胞。我们预期，这种IFN-γ融合物和硼替佐米的组合将发挥有效的杀肿瘤活性，同时大大降低全身毒性。在三个目标中，我们将（1）确定IFN-γ激活坏死性凋亡的机制，（2）确定硼替佐米抑制的途径中的其他靶点， 通过鉴定IFN-γ如何激活NF-κB，以及（3）在RCC小鼠模型中将天然IFN-γ和IFN-γ抗体融合物与硼替佐米组合。这项研究的结果直接适用于IFN先前显示出治疗潜力的几种人类癌症。

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.