Development of ADGRF1 as Actionable Target in Lung Cancer
Abstract
Scientific Objective and Rationale: Lung cancer is the leading cause of cancer-related deaths in the United States and worldwide. Non-small cell lung carcinoma (NSCLC) accounts for 85% of lung cancer. For early stage NSCLC, lung resection remains the standard of care. However, disease recurrence has been seen in nearly 35% of stage I NSCLC within 5 years post-resection. More than half of NSCLCs, including KRAS mutant NSCLCs, have no known targets. Thus, research on new actionable targets in NSCLC is urgently needed to effectively treat this deadly disease. G Protein-Coupled Receptors (GPCR) are membrane receptors that constitute the largest family of druggable proteins. Very little is known about the function of the orphan GPCR, i.e., information is lacking regarding known endogenous, physiologic agonists or ligands. Adhesion G protein-coupled receptor F1 (ADGRF1), also known as GPR110, is a member of the family of orphan GPCR. GPR110 interacts with and activates Ga oncoproteins, Gaq and Ga11. YM254890, a cyclic depsipeptide, blocks the exchange of GDP for GTP in Gaq/11 and thus is a potent inhibitor of GPR110-Gaq/11 oncogenic signaling. This research project is designed to investigate the mechanism of GPR110 expression, test correlation between high GPR110 and advanced lung cancer, and develop a proof of concept that silencing GPR110 enhances the sensitivity of NSCLC to cytotoxic drugs. As such, this project will address two LCRP Areas of Emphasis: (1) develop or optimize prognostic or predictive markers to assist with therapeutic decision-making and (2) identify innovative strategies for the treatment of lung cancer. Ultimate Applicability of the Research: The anticipated outcomes of this research are the results showing that GPR110 expression is a predictive marker of NSCLC progression and that GPR110 silencing enhances tumor cell death and sensitivity to chemotherapeutic drug(s) in NSCLC. The near-term applicability of this research will be rapid clinical validation of GPR110 expression levels in large cohorts of military and civilian NSCLC cases and manipulation of GPR110 expression in the tumor xenograft models of NSCLC using GPR110-specific synthetic probes within the next 2-3 years. The military Service Members are particularly at a significantly high risk of developing lung cancer due to a high likelihood of exposure to environmental cancer-causing agents. This research may ultimately translate into an early detection of NSCLC and treatment of NSCLC with GPR110-specific drugs and, hence, accelerate progress toward eradicating deaths and suffering from lung cancer and improve quality of lives of many military Service Members, Veterans, and their families, as well as the American public.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110249
Entities
People
- Usha Kasid
Organizations
- Georgetown University
- United States Army