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Publications of the Week

Androgen Receptor (AR) Antagonism Triggers Acute Succinate‐Mediated Adaptive Responses to Reactivate AR Signaling

By March 30, 2021April 1st, 2021No Comments

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This week we profile a recent publication in EMBO Molecular Medicine
from the laboratory of Dr. Martin Gleave (pictured, left) at UBC.

Can you provide a brief overview of your lab’s current research focus?

Androgen receptor (AR) is a major driver of prostate cancer and AR pathway inhibition (ARPI) is a standard first-line therapy for advanced prostate cancer, however, cancer cells inevitably develop resistance to this therapy. The major focus of our research has been on exploring the adaptive survival mechanisms in response to acute treatment stress which assist in the development of treatment-resistant prostate cancer and then further develop co-targeting strategies to re-sensitize them. OGX-011 and OGX-427 inhibitors have been developed against stress chaperones clusterin and Hsp27, respectively which have been shown to play a crucial role in various adaptive processes. These inhibitors have completed phase III and II trials, respectively. Currently, our lab is expanding investigation in the lesser explored area of cell metabolism and RNA biology aiding in treatment resistance. Cancer cells need to rewire their metabolism to maintain their viability and growth under constant cellular insults. Therefore, based on her prior training in the cancer metabolism field at the National Institutes of Health, Dr. Neetu Saxena, a research associate, initiated an exciting project to address the fundamental question of how prostate cancer cells remodel their metabolism in response to acute treatment stress and help them adapt.

What is the significance of the findings in this publication?

The study recently published by Saxena et al in EMBO Mol Med elucidates for the first time that AR has the potential to directly regulate the expression and activity of succinate dehydrogenase, one of the key enzymes involved in energy metabolism. Succinate dehydrogenase is the only enzyme, which links the citric acid cycle to the electron transport chain and possesses a tumor suppressor activity; loss of which as a result of AR pathway inhibition leads to accumulation of oncometabolite succinate. Succinate further leads to reactivation of AR signaling through the Ca2+/p-CAMKK2/p-AMPK/p-p38/p-Hsp27 axis and co-targeting ARPI with ivermectin, the p-Hsp27 inhibitor, truncates this adaptive loop and re-sensitize the prostate cancer cells to ARPI. This study was validated in prostatectomy and patient-derived xenografts. Succinate signaling is a well-documented phenomenon supporting tumor progression in cancers with mutations in SDH subunits. However, this is the first study where we have reported the role of succinate in treatment resistance. Additionally, this study not only uncovers novel crosstalk between AR and energy metabolism but also introduces a potential co-targeting approach to overcome treatment resistance.

What are the next steps for this research?

We will continue to explore how succinate or SDH enzyme promote treatment resistance and plasticity in prostate cancers and identify new combination therapies. Screening of SDH mutations and succinate levels in prostate cancers at different stages of the disease could help in developing precision medicine. 

Additionally, clinical trial in prostate cancer patients with ivermectin analogs in combination with ARPI is one of the objectives in the future. A Patent application (62/756,707) on ivermectin analogues has been submitted to University of British Columbia. 

This project was supported by the “Terry Fox New Frontiers Program Project Grant # 1062”.

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