Project 3 - Deciphering the Role of the Translational Oncogenic Program in Prostate Cance

PROJECT SUMMARY/ABSTRACT – PROJECT 3 (RUGGERO): DECIPHERING THE ROLE OF THE TRANSLATIONAL ONCOGENIC PROGRAM IN PROSTATE CANCER While the approved treatments for castrate-resistant prostate cancer (CRPC), such as chemotherapy and androgen signaling inhibition (ASI), confer significant survival benefits, up to 30% of patients have primary

refractory disease and, inevitably over time, all patients experience disease progression. There is an urgent need for the development of novel alternative therapies that may be combined with, or used in place of, conventional androgen receptor (AR)-targeted approaches. Recently we have discovered that phosphorylation

of eIF4E at serine 209 (P-eIF4E) by the MAP-kinase interacting serine/threonine kinase 1 and 2 (Mnk1/2) is essential for prostate cancer (PCa) development. However, the role of eIF4E phosphorylation in PCa development and the mechanisms by which P-eIF4E contributes to oncogenesis remain poorly understood. In

this proposal, we seek to address the outstanding question of how human metastatic PCa cells tailor their proteome via regulation of eIF4E activity, and to unveil the therapeutic benefits of targeting eIF4E in the lethal state of castration resistance. We propose to explore this question with the following aims: (1) Targeting the

eIF4E-dependent translational oncogenic program in a pre-clinical metastatic CRPC model; (2) To undertake a clinical trial to examine the effects of tomivosertib in combination with enzalutamide in patients with metastatic CRPC; (3) To characterize novel eIF4E interacting partners in PCa that may modulate eIF4E-dependent

therapies. Important to the completion of these aims, several interaction hits that confer sensitization to tomivosertib therapies already have been identified in our laboratories. With this knowledge, we believe that we are in a unique position to implement rational and highly specific compounds for translation control as novel

therapies for metastatic PCa.