Development of O PROTACs-Based Novel EIF4G1 Degraders for Treatment of Non-Small Cell Lung Cancer
Abstract
Lung cancer is the number one killer among cancers in the United States with an estimated 154,050 deaths (83,550 in men and 70,500 in women) expected to occur in 2018. It is also the second most diagnosed cancer in the U.S. and is responsible for approximate 234,030 new cases in 2018. As a highly heterogeneous cancer, the majority of lung cancer patients doesn t respond well to conventional therapies, thus having a poor survival rate. More importantly, many studies have indicated higher rates of lung cancer incidence and mortality among Veterans than non-Veterans, probably because the active-duty military can have more chances to be exposure to many risk factors associated with lung carcinogenesis. As one component of the translation initiation complex, although EIF4G1 has been found overexpressed in a variety of cancers, its functional roles and therapeutic application in lung cancer remain largely unknown. Our studies will address two of FY22 LCRP Areas of Emphasis, Understand the molecular mechanisms of initiation and progression to clinically significant lung cancer and Identify innovative strategies for treatment of lung cancer. In the first Area, we plan to identify the signature of EIF4G1-controlled proteins in non-small cell lung cancer (NSCLC) cells, their individual function and clinical relevance in NSCLC patients; in the second Area, we plan to use newly developed O’PROTACs technology to design and synthesize EIF4G1 specific degraders, then screen and test the growth-inhibition effects of new degraders on a panel of NSCLC cell lines. Our final goal is to develop clinical trials of EIF4G1 targeted therapy (alone or combination with other therapies such as chemotherapy and immunotherapy) for NSCLC patients, prolonging their survival or improving their life quality. Based on high risks for developing lung cancer in military personnel and the size of lung cancer patients in VA population, we believe that a lot of military Service Members, Veterans, and their family members (as well as public population) suffering lung cancer will benefit from our studies eventually. Although our current project focuses on NSCLC, we will test the efficacy of our new compounds to other types of lung cancer in future studies. Also, based on the results from this project, we will further modify EIF4G1 degraders to create new compounds with better specificity and efficacy. To reach the goal of clinical application, in the current project, we will screen and identify the most effective EIF4G1 degraders against NSCLC. Moreover, we will determine which subtypes of NSCLC cells are more sensitive to our compounds. Considering lung cancer is a highly heterogeneous cancer, precision medicine is important to lung cancer treatment for achieving maximal therapeutic effects on every patient. The most effective EIF4G1 degraders from this study will be determined concerning their dosing safety, pharmacokinetics, and the in vivo efficacy of suppressing tumor progression in NSCLC xenograft mice models. These data are critically helpful to design future clinical trial for development of EIF4G1 targeted therapy in lung cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310083
Entities
People
- Zhiqiang Qin
Organizations
- United States Army
- University of Arkansas for Medical Sciences