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New Use for Older Antifungal Agent: Adjunct to Therapy for Kidney Cancer?

By: Jenna Carter, PhD
Posted: Friday, July 2, 2021

Metastatic clear cell renal cell carcinoma is resistant to conventional targeted pharmacotherapy, so the search for novel treatment options continues. A recent article published in Scientific Reports highlighted the efficacy of repurposing the approved antifungal agent ketoconazole as a possible addition to sunitinib in this patient population. Previous research has shown that in addition to its antifungal properties, ketoconazole also suppresses exosome genesis, which is a key mechanism involved in tumor signaling and known to perpetuate drug resistance in patients with cancer. Louis S. Krane, MD, of Tulane University School of Medicine, New Orleans, and colleagues found that the drug selectively reduced exosome secretion and decreased exosome biogenesis in patients with metastatic clear cell renal cell carcinoma.

“Currently, exosomes in the cancer cell environment provide extracellular information transmission and drug resistance. Identifying novel mechanisms for inhibition of exosomal transfer could be paramount to the success of cancer therapies,” stated Dr. Krane and colleagues.

A total of 25 patients were included in this study. Plasma samples from these patients were procured from the Louisiana Cancer Research Center lab, and exosomes were isolated and analyzed. Renal cancer cell lines and embryonic kidney cell lines were cultured and used for ketoconazole efficacy studies, where exosome diameter, size distribution, and quantity were examined. Additionally, molecular imaging assays were used to examine signaling pathways linked to ketoconazole-induced reductions in exosome activity.

Overall findings revealed that patients had significantly higher levels of exosomes compared with their control counterparts (P < .01). Additionally, a dose-dependent time course revealed inhibited exosome biogenesis and reduced exosome secretion in renal cells treated with ketoconazole (P < .05, respectively). Further testing on cell proliferation following sunitinib and ketoconazole treatment revealed that pretreatment with ketoconazole may potentiate the efficacy of sunitinib in reducing cell proliferation. They also noted this increased efficacy was evident in sunitinib-resistant cells.

Disclosure: The study authors reported no conflicts of interest.



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