Development of a stress response therapy targeting aggressive prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Cell Biology

Background:

• Oncogenic lesions drive cancer growth by up-regulating demanding cellular processes like protein synthesis.
• These processes induce cell stress, necessitating adaptive responses for cancer cell survival.
• The mechanisms and consequences of these adaptive responses in cancer remain poorly understood.

Purpose of the Study:

• To investigate the adaptive stress response mechanisms in prostate cancer (PCa).
• To determine the functional consequences of these responses on tumor development and patient survival.
• To explore therapeutic implications of targeting these adaptive pathways.

Main Methods:

• Utilized murine and humanized models of prostate cancer (PCa).
• Investigated the role of the unfolded protein response (UPR) pathway.
• Employed patient-derived xenograft models and ISRIB, an inhibitor of P-eIF2α activity.

Main Results:

• Selective activation of a UPR branch, specifically phosphorylation of eukaryotic initiation factor 2-alpha (P-eIF2α), was observed in advanced PCa.
• P-eIF2α resets global protein synthesis, fostering aggressive tumor development and correlating with poor patient survival.
• Targeting P-eIF2α with ISRIB demonstrated selective cytotoxicity against aggressive metastatic PCa.

Conclusions:

• The P-eIF2α-mediated adaptive response is crucial for aggressive prostate cancer progression.
• Inhibition of this adaptive brake represents a promising therapeutic strategy for metastatic PCa.
• Targeting this pathway offers a potential cure for advanced prostate cancer, a disease with limited treatment options.