A New Era of Prostate Cancer Precision Medicine

Abstract

Prostate cancer is the second most common male cancer affecting Western society. Despite substantial advances in the exploration of prostate cancer biomarkers and treatment strategies, men are over diagnosed with inert prostate cancer, while there is also a substantial mortality from the invasive disease. Precision medicine is the management of treatment profiles across different cancers predicting therapies for individual cancer patients. With strategies including individual genomic profiling and targeting specific cancer pathways, precision medicine for prostate cancer has the potential to impose changes in clinical practices. Some of the recent advances in prostate cancer precision medicine comprise targeting gene fusions, genome editing tools, non-coding RNA biomarkers, and the promise of liquid tumor profiling. In this review, we will discuss these recent scientific advances to scale up these approaches and endeavors to overcome clinical barriers for prostate cancer precision medicine.

Keywords: biomarkers; gene fusion; genome editing; liquid biopsy; non-coding genome; precision medicine; prostate cancer; proteomic technologies.

Figure 1

Highlighting the different strategies used for precision medicine. The precision medicine approach could be divided into different strategies and technologies which are being used to target the disease. (A) Diagnosis/prognosis: polygenic risk profiling could help differentiate a population or individual into high/intermediate/low risk patient, whereas molecular markers like gene fusions, protein biomarkers (e.g., 2D gel electrophoresis, MS-based proteomics and immunoassays) and non-coding RNA (short and long) could help detect prostate cancer (PCa) at different stages of the disease including primary tumor stage or treatment response. Gene fusions could help in detecting PCa at different stages and also in reducing overtreatment for patients. (B) Therapy/surveillance: clinical utility of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and cell free DNA (cfDNA), microRNAs (miRNAs), and exosomes represents an evolution in cancer diagnosis, prognosis, and treatment. New viral/nanoparticle-based non-coding RNA (ncRNA) therapeutics have evolved in the twenty-first century with many siRNA and miRNA-based therapies in clinical trials. Antisense oligonucleotides and peptidomimetics offer an out-of-the-box approach to target genes and proteins at transcriptional and translational levels repressing their activities. Gene editing is a fascinating approach being improved on a daily basis, which could target the disease at DNA level to repair mutations or inhibiting fusion genes. Gene editing image credit: Getty images (https://bit.ly/2ql54Gk).

Figure 2

A new age proteomic approach for better validation for biomarker for prostate cancer (PCa) to improve diagnosis and prognosis. A shotgun proteomic approach via data-dependent acquisition (DDA) in combination with sequential window acquisition of all theoretical fragment–ion spectra (SWATH)–MS via data-independent acquisition (DIA), integrative proteomics is a better proposition in identifying biomarkers and protein signatures for improving PCa diagnosis, managing disease, and predicting treatment outcomes. Traditional approaches like immunofluorescence, Western blotting, and ELISA can be replaced by MS-based targeted approaches such as multiple reaction monitoring (MRM) to detect, distinguish, and quantify specific biomarkers obtained from specific samples sets. MRM profile image adapted from Arora et al. (85).

Figure 3

Non-coding genome plays an important role in oncogenesis. The figure highlights the different sets of non-coding RNA which can be used therapeutically as well for diagnosis and prognosis. MicroRNA (miRNA) profiles have been screened in identifying differences in localized and metastatic form of prostate cancer (PCa) with studies also targeting these miRNAs as therapeutics. Long non-coding RNA (lncRNA) including PCA3 and second chromosome locus associated with prostate-1 (SChLAP1) have been screened as potential prognostic markers wherein a PCA3 test has already been FDA recognized as urinary diagnostic biomarker. The crosstalk between these lncRNAs and miRNAs have been studied for identifying novel mechanisms in PCa pathogenesis. The figure highlights the crosstalk between lncRNA PCGEM1 and PCAT1 with miR-145 and miR-3367-3p. ASO and nanoparticle delivered siRNAs based therapeutics have entered the clinical trial stages wherein these non-coding RNAs have been targeted with small antisense oligos to inhibit/restore their activity (⊣ Inhibition).