RNA Degradation Enzymes: Novel Targets in Non-Small Cell Lung Cancer
Abstract
Lung cancer is the number one cause of cancer death in the United States, and more than 80 percent of lung cancers are non-small cell lung cancer (NSCLC). Prognosis of the majority of NSCLC patients remains poor. Recently, a new group of cancer drugs, that, instead of targeting the tumor cells, target the immune cells in the tumor environment, have shown unprecedented success in the treatment of NSCLC patients. These findings suggest that targeting the tumor environment, rather than the tumor cells themselves, may be a successful strategy. Vascular endothelial cells in the tumor, or tumor endothelial cells (TECs), are important components of the tumor environment. TECs harbor a number of molecular and structural abnormalities and help the tumor grow and propagate in various ways. In this proposal we will study the utility of targeting a specific molecular abnormality in TECs. We have previously found that a small tumor suppressor gene, called microRNA-1 (miR-1), in TECs is important for tumor growth. In NSCLC patients the level of miR-1 is lower in TECs compared to the non-cancerous tissue, and patients with higher levels of miR-1 in their tumors survive longer compared to patients with lower levels. Also, raising miR-1 levels in animal models of NSCLC through artificial methods stops tumor growth. We have now found a group of enzymes (PAPDs) that brings down miR-1 level in nature. These enzymes are active in tumors and are increased in the tumors of NSCLC patients. In our preliminary studies, blocking these enzymes in animal models raised miR-1 levels and slowed down tumor growth, all suggesting that PAPDs control tumor growth by regulating miR-1 levels. In order to test this hypothesis we will: (1) Study the mechanism of PAPD4 effect on miR-1 in TECs. (2) Study the effect of PAPD blockers on tumor growth in NSCLC animal models. (3) Study the association between PAPD levels and survival in NSCLC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010673
Entities
People
- Seyedtaghi Takyar
Organizations
- United States Army
- Yale University