Mismatch repair is considered a classic tumor suppressor, loss of which is common in nonpolyposis human colorectal cancer (HPNCC). In 2017, FDA approved Pembrolizumab, an anti-PD-1 antibody, in treating cancer patients with mutations in mismatch repair genes or with microsatellite instability. This is the first approval in FDA history based on molecular target irrelative of cancer types. We found that MSH2 and MSH6, two important proteins involved in mismatch repair, are highly elevated in BLBC and their expression significantly correlates with shorter patient survival. We believe that this mismatch pathway could be important for BLBC progression and want to study their roles in BLBC. In collaboration with Maria Spies from Biochemistry and Meng Wu from Pharmacy, we are screening for small inhibitors for this pathway with a purpose to develop targeted therapy for BLBC patients. In addition, these inhibitors could be also potentially used in inducing the mutation loads hence the sensitivity to immunotherapy.
- Le et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jun 8. pii: eaan6733. doi: 10.1126/science.aan6733. [Epub ahead of print].