PDE4 as a Therapeutic Target in Cancer

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With over 20 families identified, phosphodiesterases are involved in the modulation of numerous pathologies. Specific for the hydrolysis of cAMP, the PDE4 family plays a large role in many inflammatory processes. There is a growing body of literature examining the role of PDE4 in cancer, so we set out to consolidate and describe the current literature for investigators interested in pursuing this as a potential pharmacologic target in cancer treatment. In our recent article in Oncogene, PDE4 Subtypes in Cancer, we described the specific roles of PDE4A, PDE4B, PDE4C, and PDE4D in malignancy (1).  

PDE4A was overexpressed in medulloblastoma, glioblastoma, and glioma cells, among others. PDE4A overexpression was also linked to significantly shortened doubling times suggesting a role for increased PDE4A in CNS tumor proliferation. Studies examining PDE4A expression in hematologic malignancies showed a distinct upregulation in chronic lymphocytic leukemia, myelodysplastic syndrome, and T-leukemic cell lines. Other studies found a potential link between PDE4A expression and resistance to cytotoxic agents in leukemic and myelodysplastic cell lines. Additionally, PDE4A was linked to tumorigenesis and metastasis in lung and liver cancer. One study showed that under-expression of PDE4A decreased survival in breast cancer, but, overall, the common theme is that PDE4A upregulation is a response to mitogenic stimulation in tumors and hematologic malignancies.  

PDE4B expression was elevated in many hematologic malignancies. PDE4B was also over- expressed in colorectal cancer, non-small cell lung cancer, and human glioblastoma. PDE4B was found to inhibit the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway, decrease cAMP-mediated apoptosis, and increase microvessel density. Of note, PDE4B was found to be down-regulated in castration-resistant and advanced prostate cancer suggesting a variable role in hormonally-regulated cancer.  

The literature supporting a role for PDE4C in cancer is both scant and contradictory. As a novel target gene of mutated transcription factor p53, PDE4C could be potentially linked to a range of p53-associated malignancies. Given the lack of clinically available tools for targeting PDE4C, and the paucity of data supporting a role for PDE4C-mediated oncogenesis, PDE4C seems to be the least worth pursing for future studies. 

PDE4D is the most heavily studied of all the PDE4 subtypes in cancer. With conflicting data concerning the role of PDE4D in hematologic malignancies, the data is more clear on a role for PDE4D in solid tumors. There is strong evidence that PDE4D contributes to tumor progression in lung, CNS, and skin cancers. However, PDE4D appears to play opposing roles in prostate cancer, depending on the specific isotype. The large majority of studies showed an overall increase in PDE4D expression in cancer. In breast and bladder cancer, however, PDE4D under-expression was associated with poor prognoses. 

Cumulatively, these findings suggest that PDE4 subtypes may be viable targets for cancer therapy, and pathways of potential interest for future research include the AKT, PI3K, VEGF, and KRAS pathways. Given the recent success of adoptive cell transfer therapies, the anti-inflammatory nature of this targeting should be closely evaluated.  

You can read more about this work here: https://rdcu.be/b271k  

1. Lai S#, Zervoudakis G#, Chou J, Gurney ME, Quesnelle KM. PDE4 Subtypes in Cancer. Oncogene. Epub ahead of print. 20 March 2020. #these authors contributed equally

Gus Zervoudakis

Resident, WMU Homer Stryker MD School of Medicine

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