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Late-stage clear cell renal carcinoma poses a formidable clinical challenge due to the high mortality rate associated with this disease. Molecular and genetic studies have identified functional loss of the von Hippel-Lindau (VHL) gene as a frequent and crucial event in the development of the malignant phenotype of clear cell renal carcinomas. Loss of VHL function thus represents a pathognomonic molecular defect for therapeutic exploitation. The objective of this study was to evaluate the possibility of targeting VHL loss through pharmacologic means. Chromomycin A3 (ChA3) was identified through in silico analysis of existing publicly available drug profiles from the National Cancer Institute as an agent that seemed to selectively target VHL-deficient clear cell renal carcinoma cells. Genotype-selective toxicity was first determined through short-term viability assays and then confirmed with clonogenic studies. Coculture of fluorescently labeled VHL-deficient and VHL-positive cells showed discriminate killing of the VHL-deficient cells with ChA3. Mechanistically, overexpression of hypoxia-inducible factor (HIF)-2alpha in VHL-positive clear cell renal carcinoma cells phenocopied loss of VHL with respect to ChA3 toxicity, establishing ChA3 as a HIF-dependent cytotoxin. This study shows the feasibility of selectively targeting the loss of the VHL tumor suppressor gene in clear cell renal carcinoma for potential clinical benefit and may have greater ramifications in the development of new targeted therapies for the treatment of cancer and other genetic diseases.

Original publication

DOI

10.1158/0008-5472.CAN-07-0604

Type

Journal article

Journal

Cancer Res

Publication Date

15/06/2007

Volume

67

Pages

5896 - 5905

Keywords

Algorithms, Animals, Antibiotics, Antineoplastic, Basic Helix-Loop-Helix Transcription Factors, Blotting, Western, Carcinoma, Renal Cell, Cell Line, Tumor, Chromomycin A3, Drug Delivery Systems, Drug Screening Assays, Antitumor, Humans, Kidney Neoplasms, Von Hippel-Lindau Tumor Suppressor Protein