Chapter 11 - Overcoming resistance in prostate cancer with targeted and small molecule-based therapies

Abstract

Targeted therapies for cancer treatment utilize a range of small-molecule drugs or monoclonal antibodies to influence cancer cell growth, survival, and spread. For prostate cancer (PCa), there are several major classes of targeted therapies, including androgen-targeted therapies, microtubule (MT) inhibitors, prostate-specific membrane antigen (PSMA) inhibitors, and Poly (ADP-ribose) polymerase (PARP) inhibitors. Androgen-targeted therapies, including flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, and darolutamide, impair androgen-dependent activation pathways essential for PCa growth and survival. MT inhibitors, such as docetaxel, paclitaxel, cabazitaxel, epothilone agents, colchicine-binding agents, and vinca alkaloid agents, influence the dynamic behavior of MTs, which are often altered in PCa cells and associated with tumor progression and spread. PSMA inhibitors, such as conjugates to radium-233, actinium-225, thorium-227, and lutetium-177, involve PSMA-targeting antibodies coupled with small molecules or radioimmunotherapy for selective therapeutic delivery to PCa cells. PARP inhibitors, including rucaparib, olaparib, talazoparib, and niraparib, directly interfere with the normal activity of PARP enzymes, effectively limiting the capacity of DNA repair in cells with additional repair gene mutations, as seen in many PCa tumors. While the mechanisms of therapeutic resistance in PCa provide an ever-present threat, a recent increase in the creation and clinical approval of targeted therapies holds great promise in overcoming each new challenge that may arise.