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Ref Type Journal Article
PMID (18769110)
Authors Turcotte S, Sutphin PD, Giaccia AJ
Title Targeted therapy for the loss of von Hippel-Lindau in renal cell carcinoma: a novel molecule that induces autophagic cell death.
Journal Autophagy
Vol 4
Issue 7
Date 2008 Oct
URL
Abstract Text Radiation and conventional cytotoxic chemotherapies are ineffective in treating renal cancer. Approximately 75 percent of renal cell carcinoma (RCC) is associated with an inactivation of the tumor suppressor gene von Hippel-Lindau (VHL). We exploited the possibility of targeting VHL-deficient RCC through synthetic lethality using a high-throughput screening approach. In this screen, STF-62247 was identified to be selectively toxic and growth inhibitory to renal cells lacking VHL. We recently demonstrated that the cytotoxicity of STF-62247 is due to dysregulated autophagy. Furthermore, the reduction of protein levels of essential autophagy pathway components such as Atg5, Atg7 and Atg9 reduces sensitivity of VHL-deficient cells to killing by STF-62247. Loss of proteins involved in Golgi trafficking sensitized RCC with wild-type VHL to killing by STF-62247, indicating a potential role for these proteins as a target of the compound. Our study supports the concept of using synthetic lethality to selectively kill VHL-deficient cells that represents a new type of targeted therapy for the treatment of RCC.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
STF-62247 STF-62247 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
STF-62247 STF-62247 shows selective toxicity and growth inhibition to VHL-deficient renal carcinoma cells (PMID: 18769110, PMID: 30758995).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
VHL negative renal cell carcinoma sensitive STF-62247 Preclinical Actionable In a preclinical study, STF-62247 induced selective cytotoxicity and inhibited tumor growth of renal cell carcinoma cells lacking VHL (PMID: 18769110, PMID: 18598947). 18769110 18598947