Terbinafine

[pjoshea13]

New German study below [1].

"... squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival ..."

"Inhibition of SQLE with the FDA approved antifungal drug terbinafine ... efficiently blocked orthotopic tumour growth in mice."

"... terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients."

Terbinafine [2] is an antifungal. "In the United States the price in 1999 was $547 for a 12-week course; this fell to $10 by 2015, after the patent had expired."

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/344...

Nat Commun

. 2021 Aug 20;12(1):5066. doi: 10.1038/s41467-021-25325-9.

MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer

C Kalogirou 1 2 , J Linxweiler 3 , P Schmucker 2 , M T Snaebjornsson 4 , W Schmitz 1 , S Wach 5 , M Krebs 2 , E Hartmann 6 , M Puhr 7 , A Müller 8 , M Spahn 9 , A K Seitz 2 , T Frank 2 , H Marouf 1 , G Büchel 1 10 , M Eckstein 11 , H Kübler 2 , M Eilers 1 , M Saar 3 , K Junker 3 , F Röhrig 1 , B Kneitz 2 , M T Rosenfeldt 6 , A Schulze 12 13

Affiliations collapse

Affiliations

1 Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocenter, Würzburg, Germany.

2 Department of Urology and Paediatric Urology, University Hospital Würzburg, Würzburg, Germany.

3 Department of Urology, Saarland University, Homburg/Saar, Germany.

4 German Cancer Research Center, Division of Tumor Metabolism and Microenvironment, Heidelberg, Germany.

5 Department of Urology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.

6 Institute of Pathology, Julius Maximilians University and Comprehensive Cancer Center (CCC) Mainfranken, Würzburg, Germany.

7 Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.

8 Clinic for Diagnostic and Interventional Radiology, Saarland University, Homburg/Saar, Germany.

9 Center for Urology, Hirslanden Private Hospital Group, Zurich, Switzerland.

10 Mildred Scheel Early Career Center, University Hospital Würzburg, Würzburg, Germany.

11 Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.

12 Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocenter, Würzburg, Germany. [e-mail].

13 German Cancer Research Center, Division of Tumor Metabolism and Microenvironment, Heidelberg, Germany. [e-mail].

PMID: 34417456 DOI: 10.1038/s41467-021-25325-9

Abstract

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.

[2] en.wikipedia.org/wiki/Terbi...

[Hidden]

Thanks. I save lots of these things to a "future" folder. If and when my cancer grows I'll at least have a starting point for research.

Interesting that it is in the same class as several other antifungals and some speculate that they are also protective against APC "Oral antifungal drugs currently in use include itraconazole, fluconazole, ketoconazole and terbinafine".

[Shooter1]

Put on list with fenbendazole goat dewormer and other way off label meds that may work.

[Garp41]

academic.oup.com/biolreprod...

Luteolin may work.

Doug

[GP24]

The abstract Patrick posted mentions: „Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients.„

There is a graphic below how much the PSA levels were reduced by terbinafine (Lamisil) and a table with the data of these patients. This is the link to the complete study:

nature.com/articles/s41467-...

static-content.springer.com...

This were very late-stage patients. For a test they got terbinafine for two weeks, one patient for six weeks. Although the patients had a PSA doubling time below three months, their PSA value stopped rising and even got reduced just by two weeks of terbinafine. In this trial the patients got 500 mg terbinafine per day, the usual dose against fungus infections is 250 mg. Patient #2 shows that 250 mg apparently works just as well as the higher dose.

All patients died a few months after terminating the terbinafine therapy. Patient #1 died from pulmonary embolism, an unrelated cause, patient #2 died of accelerating disease and patient #3 died due to progressive bone marrow infiltration of the tumour. For patient #4 no cause of death is specified.

Data of the patients in the terbinafine study.

[MateoBeach in reply to GP24]

Very good science in that article. Thank you. Would be interesting to see how a terbinafine trial in less advanced patients might work. It is available, inexpensive and of low toxicity.

[MateoBeach]

Interesting indeed. As RSH1 points out there are a few antifungals with similarities in structure but surprisingly different mechanisms of action: itraconazole is a sonic-Hedgehog signaling pathway inhibitor; ketaconazole is a CYP17A inhibitor of androgen synthesis (like abiraterone); And now this role for terbinafine via SQLE pathway. Hmm.. (And they couldn't even cure my toenails.) 🤔😆

[Ralph1966]

Why they stopped taking the antifungal, if it helped? Is there a possible resistance with time?

[GP24]

The second link I provided reports detailed case descriptions of the four patients:

static-content.springer.com...

The therapy was stopped at the patient’s request. I assume these very late-stage patients were suffering from the side effects of their many previous therapies and did not want to continue with this experiment. In the study the authors report that terbinafine did not induce any adverse side effects. But patients may see it differently.

There is also a Swedish population-based study where they determined that patients that received oral treatment of terbinafine had a decreased risk of death from prostate cancer.

onlinelibrary.wiley.com/doi...

[seansand]

In England you can get get Terbinafine on prescription for fungal toe nails.

[Fatjoe97]

my dad took terbafinine and his psa dropped from 2.5 to 1.9 in two months