ABCG2 and TOP-1 as predictive biomarkers and targets for therapy in colon cancer
Authors: N. Brünner, J. Stenvang, V. Popovici, E. Budinska
Journal: Annals of Oncology (2018)

Introduction: There is a need for new and innovative solutions in the medical treatment of colon cancer since many of these patients eventually develop resistance to currently used drugs leading to untreatable cancer disease and death of the patients. We have by using our DEN50-R cell line based screening platform (isogenic pairs of drug sensitive and drug resistant human cancer cell lines), followed by testing in the PETACC-3 prospective randomized clinical study, identified ABCG2 and TOP1 mRNA expression as significant predictive biomarkers for irinotecan (a topoisomerase 1 inhibitor) resistance in the adjuvant treatment of colon cancer. Moreover, we have identified a new drug (SCO-101) that reverses irinotecan resistance in preclinical experiments (the DEN50-R platform). Here we present the clinical data with the biomarkers and data on SCO-101 including the clinical development plans for the drug. Methods: Biomarker studies: The study included 580 patients with mRNA expression data profiled from stage III colon cancer samples obtained from patients enrolled in the PETACC-3 study, which randomized patients to 5FUL +/- irinotecan. The primary end-points were recurrence free survival (RFS) and overall survival (OS). Median ABCG2 and the 75 percentile TOP-1 mRNA expression data were used to allocate patients into one of two groups: One with high ABCG2 expression (above median) and low TOP-1 expression (below 75 percentile) ("resistant") (n = 216) and another group including all other combinations of these two genes ("sensitive") (n = 364). Cox proportional hazards regression was used to estimate the hazard ratios and the association between variables and end-points and log-rank tests to assess the statistical significance of differences in survival between groups. Kaplan-Meier estimates of the survival functions were used for visualization and estimation of survival rates at specific time points. Reversal of irinotecan resistance: SCO-101 is a small molecule that as an oral formulation has passed 4 clinical phase 1 studies as monotherapy. SCO-101 is well tolerated with limited toxicity and a good PK profile. SCO-101 was tested alone and together with chemotherapy in the DEN50-R platform Results: Biomarker studies: Significant differences were found for both RFS (HR: 0.63 (0.44-0.92); p = 0.016) and OS (HR: 0.60 (0.39-0.93); p = 0.02) between the two biomarker groups when the patients received FOLFIRI. When considering only the MSS patients (n = 470), the differences were even more pronounced (RFS: HR: 0.57; 95% CI: 0.37-0.85; p = 0.006) and (OS:HR: 0.57, 95% CI: 0.35-0.92; p = 0.02). In contrast, no significant differences were observed between the groups when patients received 5FUL alone. Reversal of irinotecan resistance: In irinotecan (SN38) resistant colorectal cancer cell lines with upregulation of ABCG2, SCO-101 reversed the resistance and subsequent analyses showed that SCO-101 effectively blocked ABCG2 mediated drug efflux from the cancer cells. Conclusion: We will now initiate a clinical phase Ib study with the combination of SCO-101 and irinotecan in irinotecan resistant and ABCG2 high metastatic colorectal cancer patients.