Targeting mRNA Methyltransferase in Cancer Therapy
2022 Harrington Scholar-Innovator
Elevated oxidative stress and DNA replication stress are a double-edged sword in cancer cells. These intrinsic stresses promote tumor initiation and progression, but they also render cancer cells sensitive to radiation and chemotherapies. Dr. Lan and her colleagues are studying how cancer cells—specifically in breast and ovarian cancer—respond to oxidative and replication stresses through DNA repair pathways, and are developing new strategies to target these pathways.
Patients with breast and ovarian cancer are typically treated with chemotherapy drugs, including those that are platinum-based. Other cancer patients have benefitted from targeted therapy such as PARP inhibitors (PARPi). PARPi improves survival in homologous recombination (HR) deficient patients with mutations of certain HR genes. Unfortunately, only around 10 to 20% of patients benefit from targeted therapy and almost all of the patients develop drug resistance.
Dr. Lan's team recently discovered and delineated a novel DNA repair pathway—mRNA-mediated repair. They found that inhibition or loss of the RNA methyltransferase TRDMT1 kills cancer cells with selective markers, and sensitizes HR proficient cancer cells to PARPi and platinum. Therefore, it could convert PARPi and platinum-resistant patients into PARPi and platinum super responders.
“When we first identified this RNA dependent DNA repair pathway in 2015 the concept was too new to be accepted in the field,” Dr. Lan says. “Today many other groups have begun to see the importance of RNA in the DNA response.”
Dr. Lan's team has developed several lead compound TRMDT1 inhibitors; next steps include completing an IND application and testing the compounds' ability to suppress tumor growth in vivo.