Therapeutic Targeting of MESH1 in Renal Cell Carcinoma
Abstract
Scientific Objective and Rationale for the Proposed Project: Many human cells have their own "brake" systems, or "tumor suppressor genes/pathways," to limit cell proliferation and tumor growth. Some tumors develop because these brakes are broken. If we can learn how to turn these brake systems back on, they may effectively stop the cellular proliferation and tumor growth without many side effects. Here, we have found an entirely new brake system that has the potential to be turned on by drugs to stop tumor growth and wake up the immune system. We call this system "human stringent response;" it is a human version of the well-known "bacterial stringent response." As the name implies, the bacterial stringent response is a way for bacteria to cope with stringent (harsh) times when there is not enough food. Bacteria activate the stringent response to stop many energy-consuming processes to ultimately stop their growth. Although this response is well-known in bacteria, we have discovered that human tumor cells also have this hidden brake system and know to activate this stringent response. We found that once we inhibit this enzyme in human tumor cells, the tumor cells think they are lacking food and make many changes to "step on the brakes" and stop growing and dividing. These brakes also stop many growth-promoting pathways. In addition, we have found that the immune systems awaken, which may increase the efficacy of the immunotherapy. Area(s) of Emphasis: Treatments, Basic/Translation Science: Metabolisms and Gene Regulation Innovative Aspects of the Proposed Research Project: The innovative aspects of our proposal are to wake up a human version of stress antitumor pathways, which were thought to exist only in bacteria. We discovered that human cells also have this hidden brake system, which can be turned on by inhibiting MESH1 to stop proliferation and wake up immune systems. Ultimate Applicability of the Research: What types of patients will it help and how will it help them? Although our understanding is still at an early stage, we think most patients with all renal cell carcinoma may benefit from such treatments. Tumors with high MESH1 levels and TAZ-driven tumors may benefit most. Since this therapeutic strategy is unique from current therapeutics, it may be effective against renal tumors that have become resistant to current therapies. The Potential Clinical Applications, Benefits, and Risks: We will take advantage of our discovery of a human version of the bacterial "stringent response" to treat renal cancers, either alone or combined with immunotherapy. We envision that using an inhibitor to block the enzymatic activities of MESH1 will trigger the antitumor stringent response that would halt the growth of human tumors and wake up the immune response of tumor cells to sensitize cells to immunotherapy. Especially exciting is the potential to provide help to those patients whose cancers have been resistant to previous therapies. Technology already exists to identify tumors in patients that have high MESH1 levels and TAZ pathways; these are the patients most likely to benefit from treatments targeting MESH1. Because MESH1 KO mice do not have obvious side-effects, we do not expect significant toxicities. These concerns will be addressed in the project. The Projected Time It May Take to Achieve a Patient-Related Outcome: As part of this proposal, we will develop MESH1 inhibitors that may trigger the stringent response. Therefore, depending on the particular chemical structures and compounds we find, it will take approximate a decade to further refine agents to treat patients. Importantly, this study simultaneously will identify a way to predict which patients will respond better to these treatments, thus decreasing the amount of time between the lab bench and bedside use. Overall, the benefits are improving efficacy and reducing failure and resistance. What is the Likely Impact
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010907
Entities
People
- Jen-Tsan A Chi
Organizations
- Duke University
- United States Army