Targeting Lung Cancer with a Defect in PP2A-B55 Alpha
Abstract
Our studies address two Lung Cancer Research Program Areas of Emphasis: (1) Identify innovative strategies for the treatment of lung cancer and (2) Develop or optimize predictive markers to assist with therapeutic decision-making. Lung cancer is the most common cancer worldwide. Due to the possibility of exposure to risk factors during their military service, there is a higher incident rate of lung cancer and lower survival rate among Veterans than in the general population. Thus, the discovery of a novel treatment is especially urgent for Veterans. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer cases. Not every NSCLC is the same. Over 40% of patients have a deficiency of an important tumor suppressor gene called B55 alpha. The reduced expression of this gene is associated with poor prognosis. In this application, we will test the hypothesis that NSCLC with low expression of B55 alpha are sensitive to inhibitors targeting DNA damage response (DDR) proteins ATR and CHK1. Thus, reduced B55 alpha expression in NSCLC could be a biomarker to guide the use of ATR and CHK1 inhibitors by distinguishing those cancer cells likely to respond to treatment from those which are unlikely to respond. Most standard chemotherapy drugs work by killing cells in the body that grow and divide rapidly. Cancer cells proliferate rapidly, which is why these drugs often work against them. Unfortunately, conventional cytotoxic chemotherapy drugs can also affect normal cells in the body that divide rapidly, leading to serious side effects. Targeted therapy drugs do not work like chemotherapy drugs but target certain features of cancer cells that make them different from other cells. Currently, several new targeted therapies have been used in treating lung cancer. However, NSCLC remains the leading cause of cancer deaths worldwide despite the advancement in these new treatments because only a small proportion of lung cancer patients benefit from current therapies. Also, even if a cancer responds to a given therapy, the eventual development of resistance to this therapy is a concern. Therefore, there is still a dire need for more novel treatment strategies for this disease. Inhibitors targeting ATR and CHK1 that have similar functions in DDR are promising targeted therapy agents. ATR and CHK1 inhibitors are currently being tested in clinical trials as treatments for NSCLC as monotherapy or in combination with standard of care. However, these trials lack a precise molecular biomarker that can distinguish the responders from non-responders. This limitation may lead to a lower response rate in general. In addition, the non-responders will receive unnecessary treatment with physical suffering and extensive financial burden. Currently, the development of novel molecularly targeted cancer therapies remains slow (~10 years) and expensive, with many late-stage failures due to the lack of biomarkers as guidance. There is an urgent need to accelerate this process by improving early clinical anticancer drug evaluation through rational trial designs that incorporate predictive biomarkers. The success of our proposed studies will have a number of potential clinical applications. The anticipated results will reveal new approaches to specifically target B55-alpha deficient NSCLC. Given the high frequency of deficiency in this gene and the associated poor prognosis, identifying novel approaches to target this population could have a significant impact on patient survival. We will also provide a novel patient selection biomarker, which will significantly improve the treatment outcome with ATR and CHK1 inhibitors. Furthermore, the U.S. Food and Drug Administration recently emphasized that the development of every new drug should be accompanied by a biomarker. Identifying biomarkers will significantly improve the clinical applications of these agents, enhance response rate, reduce trial costs and patient
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010868
Entities
People
- Junran Zhang
Organizations
- Ohio State University
- United States Army