Novel signatures of prostate cancer progression and therapeutic resistance

ABSTRACT

Introduction

The extensive heterogeneity of prostate cancer (PCa) and multilayered complexity of progression to castration-resistant prostate cancer (CRPC) have contributed to the challenges of accurately monitoring advanced disease. Profiling of the tumor microenvironment with large-scale transcriptomic studies have identified gene signatures that predict biochemical recurrence, lymph node invasion, metastases, and development of therapeutic resistance through critical determinants driving CRPC.

Areas Covered

This review encompasses understanding of the role of different molecular determinants of PCa progression to lethal disease including the phenotypic dynamic of cell plasticity, EMT-MET interconversion, and signaling-pathways driving PCa cells to advance and metastasize. The value of liquid biopsies encompassing circulating tumor cells and extracellular vesicles to detect disease progression and emergence of therapeutic resistance in patients progressing to lethal disease is discussed. Relevant literature was added from PubMed portal.

Expert Opinion

Despite progress in the tumor-targeted therapeutics and biomarker discovery, distant metastasis and therapeutic resistance remain the major cause of mortality in patients with advanced CRPC. No single signature can encompass the tremendous phenotypic and genomic heterogeneity of PCa, but rather multi-threaded omics-derived and phenotypic markers tailored and validated into a multimodal signature.

KEYWORDS:

• Cell plasticity
• recurrent tumors
• extracellular vesicles
• treatment failure
• metastasis
• lethal disease

Article highlights

• Castration-resistant prostate cancer (CRPC) is a multilayered and complex disease.

• Advance of the field of imaging was achieved by the use of PET PSMA imaging allowing better monitoring of treatment response and disease progression monitoring in patients with prostate cancer.

• Discoveries made regarding EMT-MET interconversion and allows a glimpse into the complex cross talk that exists between cancer cells and the tumor-microenvironment, discovering pathways that play a role in tumor progression and metastasis.

• Novel biomarkers including ctDNA and extracellular vesicles and whole genome sequencing can be harnessed in the future to detect therapeutic resistance patterns at earlier stages, allowing early of non-responders, rendering them to a different beneficial therapy.

This box summarizes key points contained in the article.

Declaration of Interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

J Wang, R Ben-David, and N Kyprianou conceived the idea, and J Wang and R Ben-David performed literature review. N Kyprianou led the manuscript writing. R Mehrazin, W Yang, and A Tewari provided consultation and guidance in manuscript writing. All authors have reviewed and approved this version of the manuscript.

Additional information

Funding

The manuscript was funded by National Institutes of Health grants: [NCI 1R01CA232574-01A1 (NK) and NCI 1R01CA266694-01A1 (WY)].