Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment

Linda K Rushworth,Rachana Patel,Christine Dufès,Anne Straube,Sukrut Somani,Sophie Munnings-Tomes,Daniel James,Kay Hewit,Hing Y Leung,Emma Shanks

doi:10.1038/s41416-019-0681-5

Abstract

BackgroundDocetaxel chemotherapy in prostate cancer has a modest impact on survival. To date, efforts to develop combination therapies have not translated into new treatments. We sought to develop a novel therapeutic strategy to tackle chemoresistant prostate cancer by enhancing the efficacy of docetaxel.MethodsWe performed a drug-repurposing screen by using murine-derived prostate cancer cell lines driven by clinically relevant genotypes. Cells were treated with docetaxel alone, or in combination with drugs (n = 857) from repurposing libraries, with cytotoxicity quantified using High Content Imaging Analysis.ResultsMebendazole (an anthelmintic drug that inhibits microtubule assembly) was selected as the lead drug and shown to potently synergise docetaxel-mediated cell killing in vitro and in vivo. Dual targeting of the microtubule structure was associated with increased G2/M mitotic block and enhanced cell death. Strikingly, following combined docetaxel and mebendazole treatment, no cells divided correctly, forming multipolar spindles that resulted in aneuploid daughter cells. Liposomes entrapping docetaxel and mebendazole suppressed in vivo prostate tumour growth and extended progression-free survival.ConclusionsDocetaxel and mebendazole target distinct aspects of the microtubule dynamics, leading to increased apoptosis and reduced tumour growth. Our data support a new concept of combined mebendazole/docetaxel treatment that warrants further clinical evaluation.

Highlights

Docetaxel chemotherapy in prostate cancer has a modest impact on survival
The drugs were assayed at three different concentrations (0.1, 1 and 10 μM), and the readout was cytotoxicity quantified by nuclear count
The drug window that would support combination therapy was defined as a ≥ 10% increase in growth inhibition when combined with docetaxel

Summary

Introduction

Docetaxel chemotherapy in prostate cancer has a modest impact on survival. To date, efforts to develop combination therapies have not translated into new treatments. CONCLUSIONS: Docetaxel and mebendazole target distinct aspects of the microtubule dynamics, leading to increased apoptosis and reduced tumour growth. Docetaxel is currently the standard cytotoxic regime routinely used to treat metastatic prostate cancer; treatment with this drug leads to only a modest increase in median survival.[2,3] Recent evidence from clinical trials giving hormone-sensitive patients upfront treatment of docetaxel in combination with ADT has demonstrated a robust increase in survival. In contrast to successes observed in other tumours, including breast cancer,[7] efforts to develop combination therapies to incorporate docetaxel have not translated into new treatment regimes in prostate cancer.[8]

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