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Targeting the adaptive molecular landscape of castration-resistant prostate cancer.

Wyatt AW, Gleave ME - EMBO Mol Med (2015)

Bottom Line: This mechanistic heterogeneity is further complicated by the stress-driven induction of a myriad of overlapping cellular survival pathways.In this review, we describe the heterogeneous and evolvable molecular landscape of CRPC and explore recent successes and failures of therapeutic strategies designed to target AR reactivation and adaptive survival pathways.We also discuss exciting areas of burgeoning anti-tumour research, and their potential to improve the survival and management of patients with CRPC.

View Article: PubMed Central - PubMed

Affiliation: Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada awyatt@prostatecentre.com m.gleave@ubc.ca.

No MeSH data available.


Related in: MedlinePlus

Applicability of the liquid biopsy for CRPCSchematic showing the relative strengths and weaknesses of a tumour tissue biopsy, circulating tumour cell analysis, and cell-free DNA analysis for monitoring patients with CRPC. WGA = whole-genome amplification.
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fig03: Applicability of the liquid biopsy for CRPCSchematic showing the relative strengths and weaknesses of a tumour tissue biopsy, circulating tumour cell analysis, and cell-free DNA analysis for monitoring patients with CRPC. WGA = whole-genome amplification.

Mentions: Since tumour material is continually shed into the bloodstream, liquid biopsy (extensively reviewed in Crowley et al, 2013; Diaz & Bardelli, 2014; Heitzer et al, 2013; Joosse et al, 2014) holds great promise for improving CRPC patient management. From a trial enrichment/biomarker perspective perhaps the most exciting developments have emerged from studies of tumour-derived cell-free DNA (cfDNA) extracted from patient plasma. Compared to circulating tumour cells (CTCs), cfDNA analyses provide a global survey of tumour status, and the recent application of targeted sequencing to cfDNA extracted temporally from 16 advanced prostate cancer patients was able to accurately monitor the dynamics of lethal tumour clones (Carreira et al, 2014). Allowing for the compromising dilution effect of “normal” cfDNA, relatively simple next-generation sequencing approaches are sufficient to robustly detect amplifications and mutations, making cfDNA analyses ideal for monitoring AR status longitudinally in CRPC patients. Indeed, a recent study used combination of copy number profiling and next-generation sequencing to identify AR amplifications and mutations in the cfDNA of mCRPC patients progressing on novel systemic agents (Azad et al, 2015b). Interestingly, AR alterations accompanied enzalutamide resistance, and the presence of pre-treatment AR amplifications or mutations were predictive for adverse outcomes on enzalutamide (Azad et al, 2015b; Gleave & Chi, 2015). CTCs will remain critical for basic and clinical research alike, due to the ability to profile the transcriptome (e.g. for truncated AR variants) and the potential of establishing cultures. However, the broad utility of cfDNA (Fig3) means that it will likely assume a key role alongside CTCs in clinical trial design and CRPC patient management.


Targeting the adaptive molecular landscape of castration-resistant prostate cancer.

Wyatt AW, Gleave ME - EMBO Mol Med (2015)

Applicability of the liquid biopsy for CRPCSchematic showing the relative strengths and weaknesses of a tumour tissue biopsy, circulating tumour cell analysis, and cell-free DNA analysis for monitoring patients with CRPC. WGA = whole-genome amplification.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520654&req=5

fig03: Applicability of the liquid biopsy for CRPCSchematic showing the relative strengths and weaknesses of a tumour tissue biopsy, circulating tumour cell analysis, and cell-free DNA analysis for monitoring patients with CRPC. WGA = whole-genome amplification.
Mentions: Since tumour material is continually shed into the bloodstream, liquid biopsy (extensively reviewed in Crowley et al, 2013; Diaz & Bardelli, 2014; Heitzer et al, 2013; Joosse et al, 2014) holds great promise for improving CRPC patient management. From a trial enrichment/biomarker perspective perhaps the most exciting developments have emerged from studies of tumour-derived cell-free DNA (cfDNA) extracted from patient plasma. Compared to circulating tumour cells (CTCs), cfDNA analyses provide a global survey of tumour status, and the recent application of targeted sequencing to cfDNA extracted temporally from 16 advanced prostate cancer patients was able to accurately monitor the dynamics of lethal tumour clones (Carreira et al, 2014). Allowing for the compromising dilution effect of “normal” cfDNA, relatively simple next-generation sequencing approaches are sufficient to robustly detect amplifications and mutations, making cfDNA analyses ideal for monitoring AR status longitudinally in CRPC patients. Indeed, a recent study used combination of copy number profiling and next-generation sequencing to identify AR amplifications and mutations in the cfDNA of mCRPC patients progressing on novel systemic agents (Azad et al, 2015b). Interestingly, AR alterations accompanied enzalutamide resistance, and the presence of pre-treatment AR amplifications or mutations were predictive for adverse outcomes on enzalutamide (Azad et al, 2015b; Gleave & Chi, 2015). CTCs will remain critical for basic and clinical research alike, due to the ability to profile the transcriptome (e.g. for truncated AR variants) and the potential of establishing cultures. However, the broad utility of cfDNA (Fig3) means that it will likely assume a key role alongside CTCs in clinical trial design and CRPC patient management.

Bottom Line: This mechanistic heterogeneity is further complicated by the stress-driven induction of a myriad of overlapping cellular survival pathways.In this review, we describe the heterogeneous and evolvable molecular landscape of CRPC and explore recent successes and failures of therapeutic strategies designed to target AR reactivation and adaptive survival pathways.We also discuss exciting areas of burgeoning anti-tumour research, and their potential to improve the survival and management of patients with CRPC.

View Article: PubMed Central - PubMed

Affiliation: Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada awyatt@prostatecentre.com m.gleave@ubc.ca.

No MeSH data available.


Related in: MedlinePlus