Evaluation of In Silico-Designed mutP53 Anti-Misfolding Small Molecules in Lung Cancer
Abstract
Rationale: One of the reasons lung cancers are so dangerous is because, in such cancers, a gene called p53 is often modified in such a way as to affect the body’s ability to fight it (e.g., trigger cell death or growth arrest of tumors). Instead of being an anti-cancer gene, mutated p53 (mutP53) turns into a pro-cancer gene that does a variety of things to negatively affect treatment, one of which is to hijack various proteins to promote cancer progression. In fact, mutP53 protein has a distinct, misfolded shape that enables it to clump with itself and other cancer inhibitive proteins. These clumps of protein have additional unhealthful affects in fighting cancer. Objective: This project is attempting to discover and test new drugs able to stop mutP53 from clumping. Building on innovative work in designing anti-clumping drugs for other diseases that involve misfolded proteins (e.g., Alzheimer’s disease, ALS), we have used a computer-based model of misfolding proteins and some laboratory systems for looking at misfolding of mutP53 to discover starting points for drug discovery. We have discovered nine such starting points so far that can stop mutP53 from clumping and kill cancer cells carrying mutP53 on the one hand, while ignoring cells that have normal p53 on the other. Aims: 1. We will begin by testing our nine starting points, as well as some molecules that resemble them, to determine how effective they are at halting the clumping of mutP53 in a cell-free system. We will use a number of different methods to confirm that the anti-clumping effect is true. 2. We will then test the best molecules from Aim 1 in cell-based systems to show that they indeed work on cellular mutP53, as well as have an inhibitory effect on lung cancer cell growth, and that these anti-cancer effects are through mutP53 (as opposed to being just a coincidence). 3. We will, finally, test the best molecules from Aim 2 in animal models of cancer to confirm that anti- clumping molecules for mutP53 can indeed halt the growth of lung cancer cells in a living animal. Applicability: Overarching Challenge: There is an unmet medical need to develop a new therapy for lung cancer. The proposed study will revolutionize lung cancer treatment regimens by providing an innovative drug that will have the ability to slow the progression of the disease and improve treatment outcomes by minimizing the effects of mutP53 on lung cancer cells. Military Impact: While the Department of Defense spends over $1.6 billion per year in health-related outcomes due to tobacco use, the 5-year survival rate of those suffering from non-small cell lung cancer (NSCLC) remains despairingly low. Upon a successful completion of the proposed project, we expect to produce one or more small anti-cancer molecules with the ability to drastically improve survival and standard of living of those suffering from the disease. Translatability: Ultimately, a compound that treats misfolded mutP53 in cancer could be of value in other cancers that have misfolded mutP53. It could be added to current therapy with the potential to improve outcomes including longer progression-free survival and reduced metastatic potential. It is not a traditional chemotherapy and would not be expected to have the same kinds of serious side effects as most chemotherapy. It is, however, a new approach and will have to be carefully tested for safety. Translational Timeline: The potential drugs discovered in this project will still require several years of optimization post-project and animal testing before putting into clinical trials; but if successful, this work will establish a new way to attack cancer using anti-mutP53 misfolding agents, which is a significant advance that is directly on the pathway to new therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310426
Entities
People
- Donald Weaver
Organizations
- United States Army