The Future of Biomarkers and Genomics

from UroToday.com by  Zachary Klaassen, – Professor Manfred Wirth from Germany provided an update on the future of biomarkers and genomics at this afternoon’s EAU Update in Prostate Cancer in Vienna, Austria. Dr. Wirth divided his presentation into three subsections:

Why are biomarkers needed for prostate cancer?

There are several reasons according to Dr. Wirth why biomarkers are needed for prostate cancer, including (i) for reliable diagnosis of significant prostate cancer and making therapy decisions; (ii) for early prediction of prognosis of the future course of disease, which may lead to adjusted monitoring and optimized therapy; (iii) for prediction of therapy response and thus stratifying potential treatment benefit; (iv) the identification of alternative therapeutic targets based on molecular analyses (eg. target expression and mutational status); (v) developing individualized treatment options and thus improve patient outcomes; (vi) standardization of study/cohort design, permitting standardized reporting. The ideal biomarker would be non-invasive/minimally invasive, have high accuracy and performance, and at low cost. As Dr. Wirth notes, since 2010 there has been an exponential increase in the number of prostate biomarker studies published in the literature. Most important is selecting the right biomarker at the right time, whether a diagnostic or prognostic biomarker. Among some of the more commonly used biomarkers, Dr. Wirth lists Phi, 4Kscore, PCA3, SelectMDx, ConfirmMDx, OncotypeDx, Prolaris and Decipher.

Promising biomarkers for PCa at all molecular levels

Proteomics involves biomarker proteins that are prognostic markers in prostate cancer. According to Dr. Wirth, there are multiple proteomics studies, however only several that are “in translation”. Tissue microarrays have been developed from radical prostatectomy specimens marked for highest and lowest Gleason score, allowing quantitative proteomics to select 12 of 160 promising protein markers for predicting prostate cancer aggressiveness and lethal outcomes. Since then, validation of an 8-biomarker assay (ProMark) has been developed and tested on Gleason 3+3/3+4 biopsy specimens for prediction of pT3 or Gleason pattern 4 after radical prostatectomy, which may help in counseling the need for aggressive therapy [1].

microRNAs are single-stranded, non-coding RNAs with ~22 nucleotides, which act as post-transcriptional regulators (~30% of human mRNAs). One miRNA can regulate numerous genes and one gene can be regulated by many different miRNAs. Indeed, miRNAs are involved in a variety of pathological and oncogenic pathways (proliferation, apoptosis, metastasis, androgen receptor signaling). miRNAs are ideal biomarkers in tissue, blood and urine, considering they are stable molecules and easily measurable. Furthermore, long non-coding RNAs (lncRNAs) are also ideal potential biomarkers, which are ~200 nucleotides in length. These entities have regulatory functions in a multitude of cellular processes and dysregulation of lncRNAs in disease has the potential for diagnostic and prognostic markers, as well as potential therapeutic targets. Early work is ongoing developing a signature of 8 novel lncRNAs through microarray analysis, leading to improved diagnostic performance between prostate cancer and BPH. One such lncRNAs is PCAT-14, which has been shown to be upregulated in prostate cancer compared to normal tissue, however interestingly downregulated in metastatic prostate cancer, OS and CSS [2].

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References:

  1. Blume-Jensen P, Berman DM, Rimm DL, et al. Development and clinical validation of an in situ biopsy-based multimarker assay for risk of stratification in prostate cancer. Clin Cancer Res 2015;21(11):2591-2600. 
  2. White NM, Zhao SG, Zhang J, et al. Multi-institutional analysis shows that low PCAT-14 expression associates with poor outcomes in prostate cancer. Eur Urol 2017;71(2):257-26.
  3. Na R, Zheng SL, Han M, Germline mutations in ATM and BRCA1/2 distinguish risk of lethal and indolent prostate cancer and are associated with early age at death. Eur Urol 2017;71(5):740-747.

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