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）是一种不可避免的致命癌症，2013年在美国将夺去超过13,000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该疾病的主要药物干预措施，但这些抑制剂只能延缓肿瘤进展，不能治愈。因此，肾细胞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 (IFN-γ)在几项I/II期试验中显示出提供转移性RCC持久缓解的潜力。然而，IFN-γ有严重的毒副作用，这抑制了它在临床应用的热情。这些副作用来自两个主要的限制，需要高剂量才能获得临床效益：(1)RCC细胞对IFN-γ的直接杀瘤作用有很大的抵抗力，(2)IFN-γ在循环中的半周期非常短，因此肿瘤的生物利用度很差。在本建议中，我们概述了克服这两个缺点的途径。首先，我们确定了两种保护RCC细胞免受IFN-γ侵害的存活机制；在没有这两种机制的情况下，IFN-γ在RCC细胞中触发一种新型的程序性坏死（或坏死性坏死）。其中一种机制（NF-κ b）可以被fda批准的小分子药物硼替佐米（bortezomib）破坏，硼替佐米通过临床上容易达到的IFN-γ剂量使RCC（而非正常细胞）致敏，导致坏死性死亡。其次，我们已经产生了新的IFN-γ-抗体融合抗体，它(1)稳定血清中的IFN-γ，(2)将IFN-γ靶向到RCC细胞。我们期望这种IFN-γ融合物和硼替佐米的结合将发挥强大的杀肿瘤活性，同时极大地减少全身毒性。在三个目标中，我们将(1)确定IFN-γ激活坏死下垂的机制，(2)确定硼替佐米抑制途径中的其他靶点

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.