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Drug discovery in advanced prostate cancer: translating biology into therapy

Nature Reviews Drug Discovery volume 15, pages699–718(2016)Cite this article

Subjects

Key Points

  • Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges.

  • Recent genetic and technological advances have provided insights into prostate cancer biology and enabled the identification of novel drug targets and potent molecularly targeted therapeutics for the disease.

  • Promising targets in CRPC include the androgen receptor and its variants, key signalling pathways such as phosphoinositide 3-kinase (PI3K)–AKT and WNT signalling, and DNA repair defects.

  • The therapeutic landscape of CRPC is evolving, with an increased focus on research into tumour heterogeneity, immuno-oncology, minimally invasive circulating tissue biomarkers, and modern clinical trial designs.

  • The use of state-of-the-art, high-throughput, genomic platforms enabling patient stratification will permit optimization of the development of current and future drugs for CRPC.

Abstract

Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges. Recent genetic and technological advances have provided insights into prostate cancer biology and have enabled the identification of novel drug targets and potent molecularly targeted therapeutics for this disease. In this article, we review recent advances in prostate cancer target identification for drug discovery and discuss their promise and associated challenges. We review the evolving therapeutic landscape of CRPC and discuss issues associated with precision medicine as well as challenges encountered with immunotherapy for this disease. Finally, we envision the future management of CRPC, highlighting the use of circulating biomarkers and modern clinical trial designs.

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Figure 1: The cellular biology of prostate cancer.
Figure 2: CRPC treatment in the present and in the future.

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Acknowledgements

The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a programme grant from Cancer Research UK. Support is also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research).

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  1. The Institute of Cancer Research, 15 Cotswold Road, London, SM2 5NG, UK

    Timothy A. Yap, Alan D. Smith, Roberta Ferraldeschi, Bissan Al-Lazikani, Paul Workman & Johann S. de Bono

  2. Royal Marsden NHS Foundation Trust, Downs Road, London, SM2 5PT, UK

    Timothy A. Yap, Alan D. Smith, Roberta Ferraldeschi & Johann S. de Bono

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All authors are current or former employees of The Institute of Cancer Research, London, UK, which has a commercial interest in the development of abiraterone acetate and phosphoinositide 3-kinase (PI3K) inhibitors, including pictilisib, and operates a rewards-to-discoverers scheme. T.A.Y. has received research funding from AstraZeneca and Vertex Pharmaceuticals; is or was a consultant or advisory board member for Pfizer and Merck Serono; and has received travel support from Bristol-Myers Squibb, Janssen and Merck. R.F. is an employee of Astex Pharmaceuticals. P.W. has received research funding from Astellas Pharma and Piramed Pharma, has ownership interest in Chroma Therapeutics and previously Piramed Pharma, and is or was a consultant or advisory board member for Chroma Therapeutics, Nextech Invest, NuEvolution and Piramed Pharma. J.S.d.B. has received consulting fees from Ortho Biotech Oncology Research and Development; consulting fees and travel support from Amgen, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Medivation, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Supergen and Takeda; and grant support from AstraZeneca and Genentech.

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Glossary

Oncogenome

The collection of cancer-associated genes, epigenetics and transcripts.

Massively parallel sequencing

A method of high-throughput DNA sequencing using multiple sequencing in parallel via spatially separated, clonally amplified DNA templates.

Sequencing depth

The number of times a nucleotide is read during DNA sequencing. Deep sequencing requires a high number of reads.

Base-calling

The identification of a particular base in a strand of nucleic acids.

Sequence coverage

The average number of reads representing a given nucleotide in a reconstructed sequence.

Actionable targets

Specific genomic events that potentially have important diagnostic, prognostic or therapeutic implications in subsets of patients with cancer and for specific therapies.

Comparative genomic hybridization array

(aCGH). An analysis of copy number variation relative to the ploidy level of a set of genes in a test sample.

Fluorescent in situ hybridization

(FISH). A technique using fluorescent nucleic acid probes to highlight only regions of the nucleic acid with a high degree of base sequence complementarity.

DNA methyltransferase

An enzyme that catalyses the transfer of a methyl group to DNA (that is, a type of epigenetic modification).

Microsatellite

Di-, tri- or tetranucleotide tandem repeats in DNA sequences.

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Yap, T., Smith, A., Ferraldeschi, R. et al. Drug discovery in advanced prostate cancer: translating biology into therapy. Nat Rev Drug Discov 15, 699–718 (2016). https://doi.org/10.1038/nrd.2016.120

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