Creating a potential diagnostic for prostate cancer risk stratification (InformMDx™) by translating novel scientific discoveries concerning cAMP degrading phosphodiesterase-4D7 (PDE4D7)

Abstract

Increased PSA-based screening for prostate cancer has resulted in a growing number of diagnosed cases. However, around half of these are ‘indolent’, neither metastasizing nor leading to disease specific death. Treating non-progressing tumours with invasive therapies is currently regarded as unnecessary over-treatment with patients being considered for conservative regimens, such as active surveillance (AS). However, this raises both compliance and protocol issues. Great clinical benefit could accrue from a biomarker able to predict long-term patient outcome accurately at the time of biopsy and initial diagnosis. Here we delineate the translation of a laboratory discovery through to the precision development of a clinically validated, novel prognostic biomarker assay (InformMDx™). This centres on determining transcript levels for phosphodiesterase-4D7 (PDE4D7), an enzyme that breaks down cyclic AMP, a signalling molecule intimately connected with proliferation and androgen receptor function. Quantifiable detection of PDE4D7 mRNA transcripts informs on the longitudinal outcome of post-surgical disease progression. The risk of post-surgical progression increases steeply for patients with very low ‘PDE4D7 scores’, while risk decreases markedly for those patients with very high ‘PDE4D7 scores’. Combining clinical risk variables, such as the Gleason or CAPRA (Cancer of the Prostate Risk Assessment) score, with the ‘PDE4D7 score’ further enhances the prognostic power of this personalized, precision assessment. Thus the ‘PDE4D7 score’ has the potential to define, more effectively, appropriate medical intervention/AS strategies for individual prostate cancer patients.

Reduced PDE4D7 expression in prostate cancer correlates with down-regulation of genomic elements within the up-stream PDE4D coding region on chromosome 5

“…This pinpoints not only driver genes but also passenger genes which may be a feature of carcinogenesis. PDE4D7 and PART1 have already been proposed as separate biomarkers for PCa (1,10), however in combination or alongside those identified here with correlative expression, could further enhance the specificity of prognostic approaches, improving diagnostics and therapeutics.…”

“…Given the substantial heterogeneity in prostate cancer (PCa) treatment responses vary, therefore a prognostic biomarker indicating disease progression would influence personalised treatment decisions and identify novel therapeutic targets (1). Dysregulated cyclic AMP (cAMP) signalling is associated with cancer, particularly in the progression from localised androgen-sensitive (AS) PCa to aggressive castration-resistant PCa (CRPC) (2).…”

“…The PDE4D sub-family is germane in PCa, with the isoform PDE4D7 being of unique importance (4). Interestingly, PDE4D7 expression correlates inversely with disease progression, with downregulation conferring an increased risk of disease recurrence (1,4). This highlights the potential of PDE4D7 as a prognostic biomarker to distinguish between insignificant and aggressive tumours, as well as representing potential novel therapeutic avenues.…”

The Important Role of TMPRSS2 Gene in Covid-19 and Prostate Cancer: In Silico Approach

“…The PDE9A gene is phosphodiesterase specific [19], which has a special role in signal transduction, and it regulates the intracellular concentration of cyclic nucleotides. As stated in a study, PDE9A is used as a marker for detecting, determining, diagnosing prostate cancer [35,36]. SLC37A1 is a solute carrier protein that it has pointed out as a potential candidate for the carrying of G3P in the endoplasmic reticulum and/or mitochondria [37].…”

Identification of novel genes in testicular cancer microenvironment based on ESTIMATE algorithm‐derived immune scores

“…Furthermore, Zuo, Shi, and Yan (2016) stated that cAMP could regulate the pro-inflammatory effect of nuclear factor kappa B, revealing that the cAMP may play a vital role in noradrenergic-mediated immune dysfunction. The cAMP signaling pathway was also involved in the development and progression of many kinds of cancer, including colorectal cancer (Xian & Zhao, 2019), prostate cancer (Henderson, Houslay, Bangma, & Hoffmann, 2019), breast cancer (Jiang et al, 2019;Ma, Zhai, Zhu, & Zhang, 2019;Persaud et al, 2018), ovarian cancer (Gong et al, 2018;Yan et al, 2018) and so forth. Nevertheless, to the best of our knowledge, the function of cAMP signaling pathway in the BP of testicular cancer has not been elucidated yet.…”