Development of deubiquitinase-targeting chimeras (DUBTACs) for stabilisation of PDE4 to treat patients with high risk, androgen resistant prostate cancer.
Supervisors
Professor Will Fuller, School of Cardiovascular & Metabolic Health, University of Glasgow
Professor George Baillie, School of Cardiovascular & Metabolic Health, University of Glasgow
Industry Partner: Katalytic Therapeutics
Summary
Prostate cancer becomes more difficult to treat as the disease progresses so it is important to have diagnostic tools to be able to stratify men into different risk groups. Over the last decade we have shown that a downregulation in the expression of the phosphodiesterase PDE4D7 happens in prostate cancer cells as they transition to an aggressive stage that is unresponsive to androgens. This switch increases cancer cell proliferation renders the cells insensitive to pharmaceuticals and alters the transcriptome to an androgen independent genotype. The prognostic power of PDE4D7 in metastatic PCa positions this enzyme as an attractive drug target where men at risk of deleterious biological outcomes could be given treatments to augment PDE4D7 activity. We have phenocopied aggressive PCa in the laboratory by genetically silencing PDE4D7 with siRNA in the androgen sensitive LNCaP PCa cell line which then adopt the aggressive neoplastic growth phenotype. We propose to use this cellular model to test the hypothesis that the augmentation of PDE4D7 using novel PDE4D7 Deubiquitinase targeting chimeras (DUBTACS) can not only reprogramme the molecular genotype and retard the aggressive growth phenotype but also resensitize the cells to currently used chemotherapies.
If successful we will trial the best treatment in an animal model of prostate cancer that is derived from our reprogrammed cells. Our ultimate goal is to develop a companion therapeutic to use alongside the prognostic power of PDE4D7 in stratifying patients into “at risk” groups
There will be a 30 minute Q&A Zoom call with Will and George about their Project.
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