Antifungal ‘prodrug’ shows promise in bladder cancer: AACR

brown mouse
A prodrug developed at University of Kansas showed promise in mouse models of bladder cancer and may boost the effectiveness of immunotherapy in people. (Alexandra/München)

The drug ciclopirox, which is contained in many topical antifungal treatments, has long been of interest in the oncology community because of strong preclinical evidence that it has some anticancer properties. But transforming it into a cancer treatment has been challenging: It’s not potent enough in an oral formulation, and it’s not water soluble enough to work as an injectable drug.

So researchers at the University of Kansas Cancer Center developed a “prodrug”—a compound that transforms into ciclopirox as the body metabolizes it. And they presented promising preclinical data in bladder cancer at the annual meeting of the American Association for Cancer Research (AACR) in Chicago.  

The 5-year survival rate for early-stage bladder cancer that hasn’t spread to the organ’s muscles is over 88%, according to the American Cancer Society. But in stage 2, when the cancer has invaded the muscle, survival drops to 63% at best, making the demand for therapies that can prevent the progression to muscle-invasive disease high. During the AACR confab, a KU researcher presented data in mice showing that the prodrug inhibits that progression.

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The prodrug, administered as a once-daily injection, shrank bladder tumors in mice and induced cancer cell death, according to data presented at the AACR confab. Tissues taken from the animals that were treated showed decreases of some tumor-promoting proteins, including Notch 1 and Presenilin 1.

CPX-POM is being developed by CicloMed, a Kansas City startup formed as a public-private partnership between KU’s Institute for Advancing Medical Innovation and BioNOVUS Innovations. The company has moved the prodrug into a phase 1 clinical trial.

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Significant progress has been made in treating bladder cancer in recent years, most notably the FDA approvals of immuno-oncology drugs that inhibit the checkpoints PD-1 and PD-L1. But these drugs don’t work for many people, and even when they do, some patients become resistant to them.

Last December, Roche presented data from a trial of its PD-L1 inhibitor Tecentriq in bladder cancer patients that provided some clues as to why resistance occurs. Researchers from Roche’s Genentech unit discovered that the protein TGF-beta prevents cancer-killing T cells from invading tumors. High expression of TGF-beta was associated with a lack of response to Tecentriq, they discovered.

CicloMed’s strategy for evaluating CPX-POM is to test it in combination with surgery, chemotherapy and immunotherapy, it said in a statement when the phase 1 clinical trial started in February. During the trial, the company will determine the optimal dose for further testing.