Abstract 4858: Effect of mTOR activity in peripheral blood mononuclear cells with metformin in high-risk prostate cancer patients receiving external beam radiotherapy and androgen deprivation therapy
Authors: Antony Febin , Shrivastav Anuraag , Dubey Arbind , Usmani Nawaid , Ong Aldrich , Koul Rashmi , Quon Harvey , Sivananthan Gokulan , Hunter William , Yee Don , Rowe Lindsay , Danielson Brita , Plesniarski Andrew , Su Ruey-Chyi , Kim Julian O. 
Published: April 2023

Abstract
Introduction: There is considerable interest in the antineoplastic properties of metformin for prostate cancer treatment, however, the underlying mechanism of action of metformin in this setting is poorly understood. It is suspected that metformin’s antineoplastic activity is related to inhibition of mTOR (mammalian target of rapamycin), which ultimately inhibits cell proliferation. In this pilot study, we assessed the mTOR activity of peripheral blood mononuclear cells (PBMCs) from high-risk Prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) and external beam radiotherapy (EBRT) plus metformin versus placebo. We hypothesized decreased mTOR expression in PBMCs from patients receiving metformin versus placebo.
Methods: Normoglycemic adult males with high-risk PCa receiving ADT & EBRT were randomized to metformin 500 mg 3 times daily or placebo. Peripheral blood samples were collected from participants
≥ 6 months after starting study drug, buffy coats were extracted, and PBMCs were isolated ≤2 hours after specimen collection using ficoll-hypaque density gradient method. The mTOR expression was assessed by phosphorylation of serine 2448 (pmTOR; S2448). Activity of mTOR was measured in both unstimulated or stimulated (using CD3/CD28 antibodies) CD4+ and CD8+ T cells.
Results: Samples from 15 patients were analyzed (11 placebo & 4 metformin). We observed lower expression of pmTOR in PBMCs in patients receiving metformin compared to placebo indicating metformin demonstrated inhibition of mTOR activity in PBMCs. A general trend of mTOR inhibition was observed in the metformin group across the cell population and conditions (unstimulated vs. stimulated T cell populations). However, the most pronounced difference was observed in unstimulated CD4+ cells, which is of interest since they represent the closest physiological state to the study participants.
Conclusion: In this pilot study, we observed mTOR inhibition in the PBMCs of PCa patients treated with metformin. Further assessment of mTOR activity amongst PCa patients receiving metformin is warranted in order to confirm these findings.
Citation Format: Febin Antony, Anuraag Shrivastav, Arbind Dubey, Nawaid Usmani, Aldrich Ong, Rashmi Koul, Harvey Quon, Gokulan Sivananthan, William Hunter, Don Yee, Lindsay Rowe, Brita Danielson, Andrew Plesniarski, Ruey-Chyi Su, Julian O. Kim. Effect of mTOR activity in peripheral blood mononuclear cells with metformin in high-risk prostate cancer patients receiving external beam radiotherapy and androgen deprivation therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4858.