Computational repositioning and preclinical validation of pentamidine for renal cell cancer.
Although early stages of clear cell renal cell carcinoma (ccRCC) are curable, survival outcome for metastatic ccRCC remains poor. We previously established a highly accurate signature of differentially expressed genes that distinguish ccRCC from normal kidney. The purpose of this study was to apply a new individualized bioinformatics analysis (IBA) strategy to these transcriptome data in conjunction with Gene Set Enrichment Analysis of the Connectivity Map (C-MAP) database to identify and reposition FDA-approved drugs for anticancer therapy. Here, we demonstrate that one of the drugs predicted to revert the RCC gene signature toward normal kidney, pentamidine, is effective against RCC cells in culture and in a RCC xenograft model. ccRCC-specific gene expression signatures of individual patients were used to query the C-MAP software. Eight drugs with negative correlation and P-value <0.05 were analyzed for efficacy against RCC in vitro and in vivo. Our data demonstrate consistency across most patients with ccRCC for the set of high-scoring drugs. Most of the selected high-scoring drugs potently induce apoptosis in RCC cells. Several drugs also demonstrate selectivity for Von Hippel-Lindau negative RCC cells. Most importantly, at least one of these drugs, pentamidine, slows tumor growth in the 786-O human ccRCC xenograft mouse model. Our findings suggest that pentamidine might be a new therapeutic agent to be combined with current standard-of-care regimens for patients with metastatic ccRCC and support our notion that IBA combined with C-MAP analysis enables repurposing of FDA-approved drugs for potential anti-RCC therapy.
International Center for Genetic Engineering and Biotechnology (ICGEB), Cancer Genomics Group and Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa.|BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Luiz Fernando
LF
Zerbini
BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Manoj K
MK
Bhasin
BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Jaira F
JF
de Vasconcellos
International Center for Genetic Engineering and Biotechnology (ICGEB), Cancer Genomics Group and Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa.
Juliano D
JD
Paccez
BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Xuesong
X
Gu
Department of Pediatrics, Columbia University Medical Center, New York, NY.
Andrew L
AL
Kung
BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Towia A
TA
Libermann
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis; D010419:Pentamidine / Q000494:pharmacology*
D000970:Antineoplastic Agents; D000981:Antiprotozoal Agents; D010419:Pentamidine