Interferon Activated Necroptosis as a New Therapeutic Avenue for Kidney Cancer

干扰素激活的坏死性凋亡作为肾癌的新治疗途径

• 批准号: 8829193
• 负责人: SIDDHARTH BALACHANDRAN
• 金额: $ 37.04万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829193
• 关键词: Adaptor Signaling Protein; Adverse effects; Affect; Agreement; Antibodies; Antibody Affinity; Biological Markers; Biological Response Modifier Therapy; Blood Circulation; Bortezomib; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; Chimera organism; Clinic; Clinical; Clinical Trials; Complex; Data; Disabled Persons; Disease; Disease remission; Dose; FDA approved; Half-Life; Health; Human; Immune; Interferon Type II; Interferons; Interruption; Intervention; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metastatic Renal Cell Cancer; Modeling; Modification; Molecular; Mus; Necrosis; Normal Cell; Pathway interactions; Patients; Phase; Phase I/II Trial; Phosphotransferases; Production; Property; RIPK3 gene; Reactive Oxygen Species; Relapse; Renal Cell Carcinoma; Renal carcinoma; Resistance; Serum; Signal Transduction; Technology; Testing; Therapeutic; Time; Toxic effect; Twin Multiple Birth; Velcade; angiogenesis; antitumor agent; chemotherapy; combinatorial; cytokine; cytokine therapy; cytotoxicity; detection of nutrient; improved; in vivo; inhibitor/antagonist; killings; mouse model; next generation; novel; novel therapeutics; prevent; programs; resistance mechanism; response; small molecule; tumor; tumor progression

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.

描述（由适用提供）：晚期肾细胞癌（RCC）是一种致命的致命癌症，将在2013年在美国夺取13,000多次生命。目前，针对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原发性药物干预，但这些抑制剂仅抑制了这些抑制剂，但仅延迟了肿瘤的进度，并不是现代的。因此，RCC代表了一个重大的热挑战。与当前的小分子疗法不同，细胞因子干扰素 - γ（IFN-γ）显示出在多个I/II期试验中为转移性RCC提供持久缓解的潜力。然而，IFN-γ具有严重的毒性副作用，对其在诊所中的使用而受到谴责。这些副作用来自两个主要局限性，需要高剂量才能获得临床益处：（1）RCC细胞在很大程度上对IFN-γ的直接结核效应具有抗性，（2）IFN-γ的循环中很短，因此肿瘤的生物利用度较差。在此提案中，我们概述了克服这两个缺点的途径。首先，我们已经确定了保护RCC细胞免受IFN-γ的两种生存机制。在没有任何机制的情况下，IFN-γ会触发RCC细胞中一种新型的编程坏死（或坏死）。这些机制之一（NF-κB）可以通过小分子FDA批准的硼替佐米和bortezomib感受到RCC的感觉 - 但不能正常细胞对坏死死亡，而bortezomib易于临床成功。其次，我们生成了（1）在血清中稳定IFN-γ的新型IFN-γ-抗体融合抗体，（2）靶向IFN-γ对RCC细胞。我们预计，这种IFN-γ融合和硼替佐米的结合将发挥潜在的结核性活性，同时极大地最大程度地减少了全身毒性。在三个目标中，我们将（1）确定IFN-γ激活坏死的机制，（2）确定硼替佐米抑制的途径中的其他靶标 通过识别IFN-γ如何激活NF-κB，以及（3）在RCC的鼠模型中，与硼替佐米合并了天然的IFN-γ和IFN-γ-抗体融合。这项研究的发现直接适用于IFN先前显示的治疗潜力的几种人类癌症。