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Over the past decade, our understanding of the biology and pathophysiology of renal cell carcinoma (RCC) has improved significantly. Insight into the disease process has helped us in developing newer therapeutic approaches toward RCC. In this article, we review the various genetic and immune-related mechanisms involved in the pathogenesis and development of this cancer and how that knowledge is being used to develop therapeutic targeted drugs for the treatment of RCC. The main emphasis of this review article is on the most common genetic alterations found in clear cell RCC and how various drugs are currently targeting such pathways. This article also looks at the role of the immune system in allowing the growth of RCC and how the immune system can be manipulated to reactivate cytotoxic immunity against RCC.

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Purpose The novel fusion protein, DAB389EGF, is comprised of both the catalytic and translocation domains of diphtheria toxin that are fused to the human epidermal growth factor, providing a targeting and a toxicity component. We tested DAB389EGF for anti-tumor activity in both in vitro and in vivo urinary bladder cancer models. Experimental Design Human bladder cancer lines were treated with DAB389EGF and assessed for growth inhibition and clonogenic suppression. Using 6–8 week old female athymic nude mice implanted orthotopically with HTB9 cells, DAB389EGF was administered intravesically twice weekly for two weeks. The response of the luciferase expressing HTB9 cells was monitored via bioluminescence as the primary endpoint.. Results Treatment response with DAB389EGF was specific and robust, with an IC50 ranging from 0.5 to 15ng/ml in 8 tested bladder cancer cell lines, but greater than 50ng/ml in the EGFR-negative H520 control cell line. Simulating short duration intravesical therapy used clinically, a 2 hour treatment exposure of DAB389EGF (10ng/ml) produced clonogenic suppression in three selected bladder cancer cell lines. In vivo, luciferase activity was suppressed in 5 of 6 mice treated with DAB389EGF (70 μl (1ng/μL) per mouse), as compared to only 1 of 6 mice treated with a control DT fusion protein. Histologic assessment of tumor clearance correlated with the bioluminescent changes observed with DAB389EGF treatment. Immunocompetent mice treated with intravesical DAB389EGF did not demonstrate any non-specific systemic toxicity. Conclusions The intravesical delivery of targeted-toxin fusion proteins is a novel treatment approach for non-muscle-invasive urinary bladder cancer. With appropriate targeting, the treatments are effective and well tolerated in vivo.