Science at the Interface Between the Laboratory and the Clinic

Ryan Corcoran, MD, PhD, Massachusetts General Hospital Cancer Center, Boston, Massachusetts

Fellow summary authored by Yuki Kagoya, MD, PhD

Dr. Corcoran talked about how to integrate laboratory and clinical research to accelerate advances based on his own experience of translational research. While the BRAF inhibitor is effective against >50% of patients with melanoma, its response rate is only about 5% for patients with colorectal cancer (CRC). Dr. Corcoran first discovered inefficient inhibition of ERK phosphorylation by BRAF inhibition alone and showed that concomitant inhibition and BRAF and MEK improved response rate against CRC. He then demonstrated feedback reactivation mechanisms of MAPK signaling pathway through EGFR limits the efficacy of BRAF-MEK cascade inhibition. These basic research findings resulted in the development of a triple blockade approach (EGFR, MEK, and BRAF inhibition). Recently, his research focused on secondary resistance mechanisms following BRAF-MAPK inhibition therapy and demonstrated the importance of liquid biopsy to identify heterogeneous resistance mechanisms. Elucidation of resistance mechanisms through cell-free DNA (cfDNA) analysis at multiple time points enabled adaptation of targeted therapy in a real-time manner. He finally discussed recent advances in detecting residual cancer using circulating tumor DNA (ctDNA). These technologies will transform the standard of care for cancer. For example, the necessity of adjuvant chemotherapy can be determined based on the results of ctDNA analysis rather than clinical staging. In summary, his lecture clearly showed how basic research can transform clinical practice. At the same time, he also demonstrated that assessing the data on clinical specimens is essential to fuel the next discovery.