Novel Therapeutic Approach to Target Lung Cancer Cells Expressing Mutant p53
Abstract
Objective/Rationale: Lung cancer has one of the lowest 5-year survival rates compared to other major cancers. The tumor suppressor p53 is mutated in up to 70% of lung cancers, most of which make the tumor suppressor p53 a cancer-causing protein. Studies using lung cancer mouse model and human lung cancer cells indicate that depletion of the cancer causing p53 eliminates the ability of cancer cells to develop tumor. Based on these observations, the proposed project plans to test the hypothesis that natural chemical agents that target the cancer causing p53 or its function may induce death of lung cancer cells that depend on the cancer causing p53 for their growth and survival. The objective of the present proposal is to screen natural chemical compounds for inhibitors of mutant p53 and determine their ability to inhibit proliferation of tumors with p53 mutation. Lung Cancer Research Program Areas of Emphasis: Identify innovative strategies for prevention and treatment of early and/or localized lung cancer. Ultimate applicability: Reports indicate that in many lung cancers p53 mutation is an early event. This proposal aims to identify natural chemical agents that could prevent growth (slowing down or death) of lung cancer cells expressing p53 mutants. If successful, the results will open avenues for treatment of a large number of lung cancer patients including those with localized and early lung cancer with p53 mutations. Thus, 30%-70% of lung cancer patients who have p53 mutations should benefit from the success of this research. Since p53 mutation is frequent in all types of lung cancer, screening of natural small molecule inhibitors to identify agents that would inhibit p53 mutant-dependent tumor growth will be performed in lung tumors and cells, but at the end the agents may function for all tumors with p53 mutation depending on the ability of the compound to be of favorable pharmacodynamics and bioavailability. Projected time to achieve a clinically relevant outcome: The proposed project of 1 year is designed to identify natural chemicals that can inhibit tumor formation by human lung cancer cells with p53 mutation or tumor formation in lung of lung cancer mouse model with p53 mutation but not inhibit growth of normal cells without p53 mutation. These compounds then can be vetted for toxicity, bioavailability, and pharmacodynamics in animal models and production for testing before entering clinical trial. Innovation: Due to the perceived loss-of-function role of p53 mutants in tumorigenesis, therapeutic approaches targeting p53 mutants have not been tried. The newly discovered addiction of human lung cancer cells or murine lung tumors to endogenous GOF p53 brings enthusiasm to develop a new line of therapy targeting GOF p53 to induce death of lung cancer cells addicted to the protein. To identify GOF p53 inhibitors, this proposal plans to employ a highly innovative experimental design utilizing mutant p53?s transactivation ability as a read-out, where uniquely constructed lung cancer cell lines that emits specific fluorescence in response to GOF p53 will be used to screen a natural chemical library. Impact: The design of this project utilizes the novel observation of dependence of lung cancer cells on their endogenous mutant p53 for growth and survival. Since p53 mutation is frequent in lung cancer, successful completion of the project would initiate treatment of a large number of lung cancer patients who have cancers with GOF p53 and would revolutionize the approach to treat lung cancer with p53 mutation. Military Relevance: Military Service members, Veterans, and their families are significantly affected by lung cancer incidence, although the incidences are somewhat more in veterans than in active duty personnel. Thus, success in the above research plan will equally benefit the active duty military members, Veterans, and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710181
Entities
People
- Swati Deb
Organizations
- United States Army
- Virginia Commonwealth University