Validation of Cyclic Adenosine Monophosphate Phosphodiesterase-4D7 for its Independent Contribution to Risk Stratification in a Prostate Cancer Patient Cohort with Longitudinal Biological Outcomes

Inda, Márcia A.; Strijp, Dianne van; Biezen, Eveline den; Brussel, Anne van; Wrobel, Janneke; Zon, Hans van; Vos, Pieter C.; Baillie, George S.; Tennstedt, Pierre; Schlomm, Thorsten; Houslay, Miles D.; Bangma, Chris H.; Hoffmann, Ralf

doi:10.1016/j.euf.2017.05.010

Cited by 12 publications

(41 citation statements)

References 25 publications

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“…In developing PDE4D7 expression as a prognostic biomarker for prostate cancer, we adopted a hybrid development path, taking the initial laboratory observations through to clinical utility using a combination of primary research and re-analysis of existing public gene expression datasets [65,[70][71][72][73]. Firstly we developed an effective bio-assay for PDE4D7 that, in its early form, was sufficient for validation and assessment of clinical utility.…”

Section: Verification Of the Results Generated During The Discovery Pmentioning

confidence: 99%

“…A range of ten candidate reference genes that are commonly used in qPCR studies were used to evaluated PDE4D7 transcript levels in human prostate FFPE samples as well as a number of cell lines. From these studies we chose PUM1, TBP, TUBA1B and HPRT1 as the most stable reference genes for evaluating PDE4 transcripts in prostatic tissue [71]. In order to ensure robust data quality we pre-defined a C q threshold to either accept or refuse a sample for downstream data analysis.…”

Section: Validation Within a Clinical Settingmentioning

confidence: 99%

“…In order to ensure robust data quality we pre-defined a C q threshold to either accept or refuse a sample for downstream data analysis. The selected threshold was based on the analysis of qPCR data on FFPE tissue extracted RNA of known concentrations from which we deduced a C q threshold value as the limit of detection of a single copy of RNA in the sample [71].…”

Section: Validation Within a Clinical Settingmentioning

confidence: 99%

“…Regarding normalization of PDE4D7 C q values, we used a modified C q approach by subtracting the C q mean of the four selected reference genes from the PDE4D7 C q value of each tumour sample. Thus, we generated a normalized PDE4D7 expression value with a normal distribution between −8 and +4 [71]. Subsequently, we translated the normalized expression values by linear transformation into a +1 to +5 distribution.…”

Section: Validation Within a Clinical Settingmentioning

confidence: 99%

“…(2) all PDE4D7 scores between 2 and <3; (3) all PDE4D7 scores 3 and <4; (4) all PDE4D7 scores between 4 and 5 [71].…”

Section: Validation Within a Clinical Settingmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Verification Of the Results Generated During The Discovery Pmentioning

confidence: 99%

Section: Validation Within a Clinical Settingmentioning

confidence: 99%

Section: Validation Within a Clinical Settingmentioning

confidence: 99%

Section: Validation Within a Clinical Settingmentioning

confidence: 99%

“…(2) all PDE4D7 scores between 2 and <3; (3) all PDE4D7 scores 3 and <4; (4) all PDE4D7 scores between 4 and 5 [71].…”

Section: Validation Within a Clinical Settingmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2019

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cAMP‐phosphodiesterase 4D7 (PDE4D7) forms a cAMP signalosome complex with DHX9 and is implicated in prostate cancer progression

Gulliver,

Busiau,

Byrne

et al. 2024

Molecular Oncology

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A robust body of work has demonstrated that a reduction in cAMP‐specific 3',5'‐cyclic phosphodiesterase 4D isoform 7 (PDE4D7) is linked with negative prostate cancer outcomes; however, the exact molecular mechanism that underpins this relationship is unknown. Epigenetic profiling has shown that the PDE4D gene can be hyper‐methylated in transmembrane serine protease 2 (TMPRSS2)–ETS transcriptional regulator ERG (ERG) gene‐fusion‐positive prostate cancer (PCa) tumours, and this inhibits messenger RNA (mRNA) expression, leading to a paucity of cellular PDE4D7 protein. In an attempt to understand how the resulting aberrant cAMP signalling drives PCa growth, we immunopurified PDE4D7 and identified binding proteins by mass spectrometry. We used peptide array technology and proximity ligation assay to confirm binding between PDE4D7 and ATP‐dependent RNA helicase A (DHX9), and in the design of a novel cell‐permeable disruptor peptide that mimics the DHX9‐binding region on PDE4D7. We discovered that PDE4D7 forms a signalling complex with the DExD/H‐box RNA helicase DHX9. Importantly, disruption of the PDE4D7–DHX9 complex reduced proliferation of LNCaP cells, suggesting the complex is pro‐tumorigenic. Additionally, we have identified a novel protein kinase A (PKA) phosphorylation site on DHX9 that is regulated by PDE4D7 association. In summary, we report the existence of a newly identified PDE4D7–DHX9 signalling complex that may be crucial in PCa pathogenesis and could represent a potential therapeutic target.

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Loss of PDE4D7 expression promotes androgen independence, neuroendocrine differentiation and alterations in DNA repair: implications for therapeutic strategies

Gulliver,

Huss,

Semjonow

et al. 2023

Br J Cancer

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Background Androgen signalling remains the seminal therapeutic approach for the management of advanced prostate cancer. However, most tumours eventually shift towards an aggressive phenotype, characterised by androgen independence and treatment resistance. The cyclic adenosine monophosphate (cAMP) pathway plays a crucial role in regulating various cellular processes, with the phosphodiesterase PDE4D7 being a vital modulator of cAMP signalling in prostate cancer cells. Methods Using shRNA-mediated PDE4D7 knockdown in LNCaP cells and downstream analysis via RNA sequencing and phenotypic assays, we replicate clinical observations that diminished PDE4D7 expression promotes an aggressive prostate cancer phenotype. Results Our study provides evidence that loss of PDE4D7 expression represents a pivotal switch driving the transition from an androgen-sensitive state to hormone unresponsiveness and neuroendocrine differentiation. In addition, we demonstrate that PDE4D7 loss affects DNA repair pathways, conferring resistance to poly ADP ribose polymerase (PARP) inhibitors. Conclusion Reinstating PDE4D7 expression sensitises prostate cancer cells to anti-androgens, DNA damage response inhibitors, and cytotoxic therapies. These findings provide significant insight into the regulatory role of PDE4D7 in the development of lethal prostate cancer and the potential of its modulation as a novel therapeutic strategy.

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Validation of Cyclic Adenosine Monophosphate Phosphodiesterase-4D7 for its Independent Contribution to Risk Stratification in a Prostate Cancer Patient Cohort with Longitudinal Biological Outcomes

Cited by 12 publications

References 25 publications

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

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

cAMP‐phosphodiesterase 4D7 (PDE4D7) forms a cAMP signalosome complex with DHX9 and is implicated in prostate cancer progression

Loss of PDE4D7 expression promotes androgen independence, neuroendocrine differentiation and alterations in DNA repair: implications for therapeutic strategies

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