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  • Martin Laurence

Why are antifungal drugs effective for prostate cancer?

Many studies report that antifungal drugs can be effective in treating advanced prostate cancer (Trachtenberg et al 1984; Mahler et al 1993; Small et al 2004; Antonarakis et al 2013). These drugs cause remission in some patients, while others show little benefit. What’s the mechanism? Here are some of the proposed hypotheses so far:

  • Antifungal drugs reduce sex hormone levels, which cancer cells need to survive.

  • Antifungal drugs kill cancer cells directly.

  • Antifungal drugs limit blood flow to cancer cells.

The evidence supporting each of these hypotheses is weak. Most studies mention a reduction in sex hormones (androgens) as the main mechanism. This is a plausible mechanism for ketoconazole in castration-sensitive prostate cancer. However, itraconazole is effective despite not affecting sex hormones at all (Antonarakis et al 2013), and ketoconazole appears effective in castration-resistant prostate cancer which do not respond to other hormonal therapies (Amery et al 1986; Bok 1999). This suggests efficacy of these antifungal drugs is not due to the suppression of sex hormone levels. The main property that itraconazole and ketoconazole share is antifungal activity.


Recent studies indicate that a fungal infection is commonly present in the prostate, causing chronic inflammation and mutations which eventually lead to prostate cancer (Stott-Miller 2013; Sutcliffe et al 2014; Laurence et al 2018). At first blush, it seems incredibly unlikely that clearing a fungus from the prostate can influence the course of prostate cancer after it has developed, let alone once it has metastasized outside the prostate.


I initially dismissed these studies as a curiosity. Then I read about MALT lymphomas, a type of cancer caused by the bacterium Helicobacter pylori in the stomach. Surprisingly, clearing Helicobacter pylori from the stomach with antibacterial drugs causes MALT lymphomas to enter remission, even after this cancer has developed (Kusters et al 2006)! How is this possible?


Cancer cells typically contain abnormal proteins which can be detected by our immune system, specifically by T cells. When a T cell detects an unusual protein—might this protein originate from a intracellular infection or a mutated human gene—it first activates, and then goes around killing human cells which contain the unusual protein (these cells are deemed either infected or cancerous). This is the basis of newly introduced CAR-T immunotherapies. However, in the presence of chronic infections, regulatory cells of the immune system secrete anti-inflammatory cytokines which prevent T cells from activating (Pushalkar et al 2018).


This is normally a good thing, because it avoids constantly attacking infections which can’t be cleared by our immune system, sparing us from collateral damage caused by activated T cells. But when cancer starts developing in the same organ, this immune tolerance mechanism is a bad thing, because it prevents T cells from detecting and killing cancer cells, allowing cancer to grow and spread.


If a fungus in the prostate is preventing T cells from attacking cancer cells, then:

  1. More effective antifungal treatments (such as combining azoles with terbinafine) might have a better chance of clearing this fungus, and initiate natural immunotherapy.

  2. Antifungal treatments might be more effective at earlier prostate cancer stages.

  3. Antifungal treatments would not be as effective in patients who have had a prostatectomy.

These three elements might partially explain why antifungal drugs are hit-and-miss. Keeping the primary tumor (prostate) in the body and using antifungal drugs to unleash T cells against it might be the natural equivalent of CAR-T therapy, sending T cells all over the body to hunt down prostate cancer cells. MALT lymphomas (Kusters et al 2006) and pancreatic cancer models (Pushalkar et al 2018) suggest this is possible.


Terbinafine and azoles are expected to be synergistic antifungals because they target different ergosterol synthesis steps.

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