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Personalization of prostate cancer therapy through phosphoproteomics

Abstract

Castration-resistant prostate cancer (CRPC) remains incurable despite the approval of several new treatments. Identification of new biomarkers and therapeutic targets to enable personalization of CRPC therapy, with the aim of maximizing therapeutic responses and minimizing toxicity in patients, is urgently needed. Prostate cancer progression and therapeutic resistance are frequently driven by aberrantly activated kinase signalling pathways that are amenable to pharmacological inhibition. Personalized phosphoproteomics, which enables the analysis of signalling networks in individual tumours, is a promising approach to advance personalized therapy by discovering biomarkers of pathway activity and clinically actionable targets. Several technologies for global and targeted phosphoproteomic analysis exist, each with its own strengths and shortcomings. Global discovery phosphoproteomics is predominantly conducted using liquid chromatography–tandem mass spectrometry coupled with data-dependent or data-independent acquisition technologies. Multiplexed targeted phosphoproteomics can be divided into platforms based on mass spectrometry or antibodies, including selected or parallel reaction monitoring and triggered by offset, multiplexed, accurate mass, high-resolution, absolute quantification (known as TOMAHAQ) or forward-phase or reverse-phase protein arrays, respectively. Several obstacles still need to be overcome before the full potential of phosphoproteomics can be realized in routine clinical practice, but a future phosphoproteomics-centric trans-omic profiling approach should enable optimized personalized CRPC management through improved biomarkers and targeted treatments.

Key points

  • To improve outcomes of patients with castration-resistant prostate cancer, identification of new biomarkers and therapeutic targets is needed to enable personalized management with maximized therapeutic responses and minimized toxicity.

  • Aberrantly activated kinase signalling frequently drives prostate cancer progression and therapeutic resistance but might be amenable to pharmacological inhibition.

  • Phosphoproteomics approaches that enable the analysis of signalling networks in individual tumours are a promising approach to advance personalized therapy by discovering biomarkers of pathway activity and clinically actionable targets.

  • Phosphoproteomic analysis can be performed on a global discovery or a targeted level, employing methods based on untargeted liquid chromatography–tandem mass spectrometry, or on targeted mass spectrometry or antibody detection, respectively.

  • Current obstacles to the routine clinical use of phosphoproteomics include preanalytical variation, tumour heterogeneity, analysis sensitivity, availability of high-quality phosphosite-specific antibodies, and absolute quantification of kinase pathway activity.

  • A future phosphoproteomics-centric trans-omic profiling approach should enable optimized personalized prostate cancer management through improved biomarkers and targeted treatments.

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Fig. 1: Typical workflow for global phosphoproteomic analysis.
Fig. 2: Multiplexed targeted MS approaches: SRM and PRM.
Fig. 3: Multiplexed targeted MS approaches: TOMAHAQ.
Fig. 4: Common protein microarrays.
Fig. 5: Phosphoproteomic analysis of prostate cancer clinical specimens.
Fig. 6: Phosphoproteomics-centric trans-omics profiling for personalized prostate cancer management.

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Acknowledgements

The authors gratefully acknowledge financial support from the Cedars-Sinai Precision Health Award (W.Y.), the Steven Spielberg Discovery Fund in Prostate Cancer Research (M.R.F.), and the James F. Hardymon Endowment at the University of Kentucky (N.K.).

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N.K. and W.Y. researched data for the article and made substantial contributions to discussion of the article content. All authors wrote and reviewed and/or edited the manuscript before submission.

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Correspondence to Natasha Kyprianou.

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Yang, W., Freeman, M.R. & Kyprianou, N. Personalization of prostate cancer therapy through phosphoproteomics. Nat Rev Urol 15, 483–497 (2018). https://doi.org/10.1038/s41585-018-0014-0

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