Researchers at McMaster University in Hamilton, Ontario, have uncovered a promising new avenue in the fight against prostate cancer. Their latest study reveals that canagliflozin, a medication commonly prescribed for type 2 diabetes as a sodium-glucose co-transporter 2 inhibitor (SGLT2i), acts as a novel inhibitor of the androgen receptor pathway. This discovery holds potential for treating both castrate-sensitive prostate cancer, where tumors still respond to hormone deprivation, and castrate-resistant prostate cancer, a more aggressive form that no longer relies on standard androgen deprivation therapy.
The findings, detailed in a recent publication in Cancer Letters, stem from work conducted at McMaster's Centre for Discovery in Cancer Research. Led by PhD candidate Amr Ali and involving collaborators like Professors Sebastien Hotte and Theos Tsakiridis, the research demonstrates how this repurposed drug could address one of the biggest challenges in prostate cancer management: resistance to existing therapies.
Prostate Cancer: A Major Health Concern in Canada
Prostate cancer remains the most common cancer among Canadian men, with projections estimating 29,300 new diagnoses in 2026 alone, accounting for 23% of all male cancer cases. Each day, approximately 80 men receive this diagnosis, and 5,300 are expected to succumb to the disease that year. While early detection through prostate-specific antigen (PSA) screening and treatments like surgery, radiation, and hormone therapy have improved outcomes, advanced stages—particularly metastatic castrate-resistant prostate cancer (mCRPC)—pose significant hurdles. Survival rates drop sharply once the cancer spreads, underscoring the urgent need for innovative approaches.
At McMaster University, a hub for translational oncology research, scientists are bridging this gap. The institution's strong emphasis on metabolism, diabetes, and cancer research uniquely positioned the team to explore SGLT2 inhibitors, drugs that lower blood glucose by promoting its excretion in urine but also disrupt cancer cell energy metabolism.
What is Canagliflozin and How Does It Work?
Canagliflozin, marketed under brand names like Invokana, was approved for diabetes management over a decade ago. It blocks SGLT2 proteins in the kidneys, preventing glucose reabsorption and aiding blood sugar control. Beyond diabetes, preclinical studies have hinted at anti-cancer properties, including growth suppression in prostate and lung cancers.
In the McMaster study, researchers hypothesized direct interaction with the androgen receptor (AR), the primary driver of prostate cancer growth. AR binds androgens like testosterone, fueling tumor proliferation. Standard treatments, known as androgen receptor pathway inhibitors (ARPIs) such as enzalutamide or abiraterone, target this but often fail due to AR mutations or splice variants like AR-V7.
The team confirmed canagliflozin binds the AR ligand-binding domain (LBD) with affinity similar to approved ARPIs, using molecular docking, thermal shift assays, and surface plasmon resonance. This binding disrupts AR signaling comprehensively.
Targeting the Androgen Receptor Pathway: Step-by-Step Mechanism
The mechanism unfolds in several key steps. First, canagliflozin reduces expression of heat shock protein 70 (HSP70), a chaperone stabilizing AR. Without HSP70, full-length AR (AR-FL) and variants destabilize, leading to proteasomal degradation—the cell's protein recycling system.
This lowers cytoplasmic and nuclear AR levels, blocking translocation to the nucleus where it normally activates genes promoting cell survival and division. RNA sequencing revealed broad transcriptional reprogramming: downregulation of AR targets, cell cycle genes, E2F transcription factors, and Myc oncogene pathways.
In experiments, gene signatures from canagliflozin-treated cells mirrored those from AR-FL or AR-V7 knockdown, correlating with better prognosis in patient datasets. This multi-hit approach—energy disruption via SGLT2 inhibition plus AR degradation—makes it potent against resistant tumors.
Preclinical Evidence: From Cells to Animal Models
Using androgen-sensitive LNCaP cells and castrate-resistant PC3, 22Rv1 (AR-V7 positive), and DU145 lines, canagliflozin halted proliferation and colony formation at clinically achievable doses. In mouse xenografts, it shrank tumors significantly, without toxicity.
Building on prior McMaster work showing synergy with radiotherapy—where canagliflozin sensitized tumors by depleting ATP and activating AMPK (AMP-activated protein kinase)—this study positions it as a standalone ARPI candidate. No prior ARPI matched its dual action on full-length and variant ARs.
- Reduced AR protein by 50-70% in sensitive and resistant lines.
- Tumor volume reduction up to 60% in vivo.
- Overlaps with AR silencing signatures, prognostic benefit in TCGA/PRJEB39567 datasets.
Addressing Castrate-Resistant Prostate Cancer
CRPC develops when tumors evade ADT, often via AR amplification, mutations, or variants bypassing ligand dependence. AR-V7, lacking the LBD, drives resistance to ARPIs. Canagliflozin's degradation of AR-V7 via HSP70 reduction offers a fresh strategy, potentially extending treatment windows.
In Canada, where mCRPC affects thousands annually, this could reduce reliance on chemotherapy like docetaxel, with its side effects. Repurposing an approved, safe drug accelerates translation to trials, bypassing lengthy approvals.
Read the full study abstract on PubMed for detailed methods and data.
McMaster University's Role in Cancer Innovation
McMaster's Faculty of Health Sciences, including the Centre for Discovery in Cancer Research and Centre for Metabolism, Obesity and Diabetes Research, fosters interdisciplinary work. Collaborators like Gregory Steinberg (metabolism expert) and Jonathan Bramson (immunology) enabled this breakthrough.
The university's translation focus—evident in prior SGLT2i-radiotherapy synergy—positions Hamilton as a prostate cancer research leader. Partnerships with Juravinski Cancer Centre facilitate patient trials.
Prostate Cancer Landscape in Canadian Higher Education
Canadian universities drive oncology advances amid rising cases. University of Toronto's Princess Margaret Cancer Centre leads PSMA-targeted therapies; BC Cancer advances immunotherapy. McMaster complements with metabolic angles, vital as 1 in 9 Canadian men face lifetime risk.
Funding from CIHR and Ontario Institute for Cancer Research supports such work. Survival has risen to 91% five-year rate overall, but mCRPC lags at under 30%.
Path to Clinical Trials and Future Outlook
Preclinical success warrants phase I/II trials, testing safety with ADT or ARPIs. Low cost, oral administration, and cardiovascular benefits (from diabetes trials) enhance appeal. Challenges include optimal dosing and biomarkers like AR-V7 levels.
Experts anticipate combination strategies, echoing darolutamide's success. McMaster plans investigator-initiated studies, potentially via CCTG.
Stakeholder Perspectives and Broader Implications
Oncologists praise repurposing speed. Patients advocate access, noting diabetes-prostate links. McMaster's model inspires other Canadian institutions like UBC and Dalhousie.
This advances precision medicine, targeting metabolism-AR crosstalk. For higher education, it highlights interdisciplinary training's value.
Photo by Julissa Capdevilla on Unsplash
Actionable Insights for Researchers and Patients
- Monitor SGLT2i trials for prostate applications.
- Discuss repurposing with physicians for high-risk cases.
- Support research via donations to McMaster or Prostate Cancer Canada.
This McMaster discovery exemplifies Canadian higher education's global impact, promising hope for prostate cancer patients.
