Optimising Cancer Therapy: Understanding how SGLT2 Inhibitors Enhance Neoplastic Efficacy and offer Cardioprotection against immunotherapies.

About the Project

This project aspires to make immunotherapy safer and more effective by discovering how SGLT2 inhibitors can simultaneously guard the heart and strengthen antitumour immunity. In revealing these mechanisms, we aim to spark a new era of treatment that delivers deeper impact with fewer risks.

About this opportunity

Immune checkpoint inhibitors (ICIs) have significantly improved the survival of patients with solid cancers by enhancing the immune system’s ability to target and destroy tumour cells. However, ICIs are associated with immune-related adverse events, including cardiotoxicity, which affects 1-3% of patients and is fatal in up to 50% of cases.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i), originally developed to treat diabetes, have been shown clinically to be cardioprotective whilst enhancing antitumour activity. However, the mechanisms that remain largely unknown limit the adoption of these drugs in routine clinical practice.

Our previous work has led to the hypothesis that the addition of Empagliflozin (SGLT2i), differentially modulates the expression of PD-L1 protein at the membrane of cardiac and cancer cells, engaging the immune cells in both cardioprotection and increased immunosurveillance-mediated cell death.

Objectives

1. Elucidate the molecular pathways involved in SGLT2i-mediated cancer damage and cardioprotection during ICI therapy.
2. Assess the impact of SGLT2i on immune cell modulation.

Experimental Approach

We have developed in vitro breast cancer and cardiac models, which encompass volunteer and patient-derived immune cells, and have shown that the post-translational modification (PTM) of the PD-L1 protein occurs in the presence of the SGLT2i Empagliflozin. We hypothesise that these changes are cell-type specific; as such, this project will:

1. Fully characterise PTM of PD-L1 in the presence of Empagliflozin using mass spectrometry in both MCF7 breast cancer cells and iPSC-CM.
2. Use Crisper/Cas 9 to knock out PD-L1 and SGLT2 protein in MCF7 cells and iPSC-CM to understand their functional impact on a) cancer cell survival and proliferation using live cell imaging and b) cardiac cell function and electrophysiology using our state-of-the-art MEA system.
3. Profile a) which subsets of T-cells are stimulated using flow cytometry-based T-cell proliferation assay, b) which cytokines are released by T-cells and thereby responsible for cancer cell damage using Elispot analysis. Supervisor 2 is a global expert in immune reactions as part of the Centre for Drug Safety Science. Findings will be validated in patient plasma samples obtained by supervisor 3, who is a clinical academic who leads an immune-oncology department.

Overall value: As ICI administration continues to expand, optimising strategies that enhance their efficacy and reduce adverse events is crucial. The integration of SGLT2i could represent a significant advancement by minimising cardiotoxicity while enhancing the antitumour effect.

Student training: The student will receive comprehensive training in advanced techniques such as iPSC-CM generation/differentiation, immunology, mass spectrometry, cell imaging, Crisper/Cas 9 knockout analysis, flow cytometry, as well as quantitative skills in data analysis, including proteomics-driven statistics and bioinformatics. The research will be carried out at a university fully equipped with state-of-the-art equipment, including high-end imaging facilities, mass spectrometry suites, and cell culture facilities. They will also develop a range of transferable skills, including presentation, problem-solving, technical and lay writing, and project management. The student will have opportunities to present their work at lab meetings and conferences, both locally and internationally, with funding available for two local and one international conference.

Supervisors

Dr Parveen Sharma - psharma@liverpool.ac.uk

Prof Dean Naisbitt - D.J.Naisbitt@liverpool.ac.uk

Dr Anna Olsson-Brown - https://clatterbridgeprivate.co.uk/consultants/dr-anna-olsson-brown/