Investigating Novel Biomarkers of Drug Resistance in Endometrial Cancer

Endometrial cancer (EC) is the 15th most common cancer worldwide, with increasing incidence and mortality predicted to continue. However, current treatment options have variable efficacy, highlighting the need for research into better options. Patient-derived explants (PDEs) offer a preclinical platform to evaluate patient-specific drug response to standard-of-care chemotherapy and immunotherapy, and to identify predictive and pharmacodynamic biomarkers by using multi-immunofluorescent (mIF) staining and digital pathology methods.Explants were derived from 51 tumours obtained from patients with EC. Samples were then cultured, with 24-hour treatment of Carboplatin and Paclitaxel, Pembrolizumab, or curcumin and resveratrol. Analysis was performed through mIF for key biomarkers including Ki67 (proliferation), cPARP (apoptosis) and CAM5.2 (tumour mask), alongside protein expression (MDR1, MRP1 and ABCG2). Cell viability and protein expression were then quantified for analysis.The cohort was reflective of the UHL population. Drug response was shown to be differential between patients, and with different treatment modalities, capturing the heterogeneity of EC tumours. Drug response was shown to be patient-specific, highlighting the importance of personalised medicine, with both curcumin and resveratrol achieving comparable drug responses to the chemotherapeutic SoC.ABCt protein expression was shown to be differential between patient and protein. Expression was stable with culture; however, drug treatment could induce a change in expression. Statistically significant correlations were found between ABCt expression and response to chemotherapy treatment, with further research needed to understand the mechanisms behind the effect of ABCt expression on drug response.Overall, this project has expanded on the use of EC PDEs in order to test response to novel drugs, and explore potential mechanisms of drug resistance to chemotherapy drugs in EC.