Targeting the Nrf2 Pathway in Lung Cancer
Abstract
Rationale and Objective: New drugs are needed to treat lung cancer, as this devastating disease causes more deaths than breast, prostate, and colon cancer combined. Defects in genes that cause NRF2 to be turned on (activated) are found in approximately 30% of the 235,000 cases of lung cancers that are diagnosed in the United States each year, making it the third most frequent genetic change in lung cancer. The mutations that activate NRF2 drive the growth and metastasis of lung tumors and makes them resistant to the chemotherapy drugs normally used to treat lung cancer. No drugs are currently available to specifically treat patients who are resistant to chemotherapy because of the high NRF2 activity in their lung tumors. NRF2 activation in lung cancer also causes lung cancer to metastasize or spread from one lung to the other and to other organs, especially the brain, bones, and liver. We discovered a novel first-in-class inhibitor of NRF2, named MSU38225, that blocks the growth of lung cancer cells and tumors with NRF2 activation and found no toxicity in normal human lung cells and in mice. However, MSU38225 did not have the drug-like properties (stability, solubility) required to test it in patients with lung cancer. To overcome this challenge, we made a series of structural changes and have identified novel, improved NRF2 inhibitors. Several of our new inhibitors are more drug-like than MSU38225. These new inhibitors reduce the growth of lung cancer cells with high levels of NRF2 and can block tumor-like groups of lung cancer cells from moving and invading, which are important characteristics of lung cancer that spreads, or metastasizes. The objective of our project is to test whether our best new inhibitor, MSU146 can effectively treat lung cancer by reducing the high NRF2 levels that drive tumor growth and metastasis and to test whether MSU146 can make lung cancer chemotherapy drugs more effective. This objective directly addresses the DoD’s LCRP goal of identifying innovative strategies for the treatment of lung cancer. We have planned key experiments that will allow us to test how effective MSU146 is at stopping the growth of or killing human lung cancer cells that have high levels of NRF2. We will also confirm that MSU146 does NOT cause toxicity in normal cells. We will then test whether the combination of MSU146 with chemotherapy drugs currently used to treat lung cancer is better than the individual drugs. The most effective combination of chemotherapy drug with MSU146 will be used to treat lung tumors and monitor for unexpected side effects in two of the most relevant models available. We will first use patient derived xenograft (PDX) models, in which tumors from lung cancer patients with high NRF2 activity will be implanted into mice and treated with MSU146 and the chemotherapy drug. The PDX model is widely used to test new drugs before they advance to clinical trials in patients. The second model will use a mouse with a normal immune system, as has been done to test immunotherapy drugs now used to treat patients with lung cancer. Applicability: The ultimate goal of our drug discovery program is to develop MSU146 into an effective drug, that can be used either alone or in combination with chemotherapy, for the treatment of patients with NRF2-driven lung cancers. No drugs are currently available to treat patients with mutations that lead to activation of NRF2, so this project addresses a critical unmet medical need. If this project is successful, these studies will provide a compelling rationale to complete the safety studies required to advance MSU146 through the drug approval process required before new drugs can be tested in patients. With the expertise of an outstanding drug discovery team at MSU, we have defined a specific development plan to start clinical trials with MSU146 within 5 years. In addition, the proposed studies will advance the field of lung cancer research by pr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310273
Entities
People
- Karen Liby
Organizations
- Indiana University
- United States Army