Targeting P21-Activated Kinase-1 for Metastatic Prostate Cancer.
Payaningal R SomanathJonathan ChernoffBrian S CummingsSandip M PrasadHarvey D HomanPublished in: Cancers (2023)
Metastatic prostate cancer (mPCa) has limited therapeutic options and a high mortality rate. The p21-activated kinase (PAK) family of proteins is important in cell survival, proliferation, and motility in physiology, and pathologies such as infectious, inflammatory, vascular, and neurological diseases as well as cancers. Group-I PAKs (PAK1, PAK2, and PAK3) are involved in the regulation of actin dynamics and thus are integral for cell morphology, adhesion to the extracellular matrix, and cell motility. They also play prominent roles in cell survival and proliferation. These properties make group-I PAKs a potentially important target for cancer therapy. In contrast to normal prostate and prostatic epithelial cells, group-I PAKs are highly expressed in mPCA and PCa tissue. Importantly, the expression of group-I PAKs is proportional to the Gleason score of the patients. While several compounds have been identified that target group-I PAKs and these are active in cells and mice, and while some inhibitors have entered human trials, as of yet, none have been FDA-approved. Probable reasons for this lack of translation include issues related to selectivity, specificity, stability, and efficacy resulting in side effects and/or lack of efficacy. In the current review, we describe the pathophysiology and current treatment guidelines of PCa, present group-I PAKs as a potential druggable target to treat mPCa patients, and discuss the various ATP-competitive and allosteric inhibitors of PAKs. We also discuss the development and testing of a nanotechnology-based therapeutic formulation of group-I PAK inhibitors and its significant potential advantages as a novel, selective, stable, and efficacious mPCa therapeutic over other PCa therapeutics in the pipeline.
Keyphrases
- prostate cancer
- radical prostatectomy
- cancer therapy
- end stage renal disease
- extracellular matrix
- chronic kidney disease
- single cell
- ejection fraction
- squamous cell carcinoma
- newly diagnosed
- drug delivery
- biofilm formation
- type diabetes
- signaling pathway
- cell therapy
- small cell lung cancer
- stem cells
- prognostic factors
- magnetic resonance imaging
- induced apoptosis
- pseudomonas aeruginosa
- patient reported outcomes
- bone marrow
- metabolic syndrome
- endothelial cells
- protein kinase
- subarachnoid hemorrhage
- cardiovascular disease
- clinical practice
- structural basis
- endoplasmic reticulum stress
- childhood cancer