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-?) showed the potential to provide lasting remission in several phase I/II trials for metastatic RCC. IFN-?, 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-?'s direct tumoricidal effects, and (2) IFN-? 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-?; in the absence of either mechanism, IFN-? triggers a novel form of programmed necrosis (or necroptosis) in RCC cells. One of these mechanisms (NF-?B) 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-? that are easily clinically achievable. Second, we have generated novel IFN-?-antibody fusion antibodies that (1) stabilize IFN-? in serum, and (2) target IFN-? to RCC cells. We expect that the combination of such IFN-? 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-? activates necroptosis, (2) identify additional targets in the pathway inhibited by bortezomib by identifying how IFN-? activates NF-?B, and (3) combine native IFN-? and IFN-?-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.

Public Health Relevance

A class of biotherapeutics called interferons (IFNs) has shown the ability to provide lasting remission in RCC, but IFNs have severe side-effects that limit their use. In this proposal, we have identified resistance mechanisms in RCC which, when disabled, allow IFN-? to kill RCC cells at doses that are clinically achievable. We have also generated novel IFN-? fusion antibodies that target IFN-? to the tumor; together, we expect the twin approaches of disabling resistance mechanisms and targeting IFN-? to the tumor will provide clinical benefit with minimal side-effects in advanced RCC.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Salnikow, Konstantin
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Research Institute of Fox Chase Cancer Center
United States
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Ingram, Justin P; Tursi, Sarah; Zhang, Ting et al. (2018) A Nonpyroptotic IFN-?-Triggered Cell Death Mechanism in Nonphagocytic Cells Promotes Salmonella Clearance In Vivo. J Immunol 200:3626-3634
Ingram, Justin P; Brodsky, Igor E; Balachandran, Siddharth (2017) Interferon-? in Salmonella pathogenesis: New tricks for an old dog. Cytokine 98:27-32
Upton, Jason W; Shubina, Maria; Balachandran, Siddharth (2017) RIPK3-driven cell death during virus infections. Immunol Rev 277:90-101
Nogusa, Shoko; Thapa, Roshan J; Dillon, Christopher P et al. (2016) RIPK3 Activates Parallel Pathways of MLKL-Driven Necroptosis and FADD-Mediated Apoptosis to Protect against Influenza A Virus. Cell Host Microbe 20:13-24
Nogusa, Shoko; Slifker, Michael J; Ingram, Justin P et al. (2016) RIPK3 Is Largely Dispensable for RIG-I-Like Receptor- and Type I Interferon-Driven Transcriptional Responses to Influenza A Virus in Murine Fibroblasts. PLoS One 11:e0158774
Najjar, Malek; Saleh, Danish; Zelic, Matija et al. (2016) RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-like Receptor 4. Immunity 45:46-59
Thapa, Roshan J; Ingram, Justin P; Ragan, Katherine B et al. (2016) DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death. Cell Host Microbe 20:674-681
Najjar, Malek; Suebsuwong, Chalada; Ray, Soumya S et al. (2015) Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1. Cell Rep 10:1850-60
Kaiser, William J; Daley-Bauer, Lisa P; Thapa, Roshan J et al. (2014) RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc Natl Acad Sci U S A 111:7753-8