Triggering Human Antitumor Stringent Response to Target Recurrent Ovarian Cancer
Abstract
Rationale and Objective: Many cells have their own "brake" systems, or "tumor suppressor" genes and pathways that function to prevent unchecked cell growth. Some tumors develop because these brake systems are malfunctioning. For tumor cells, only when these brakes are turned off can they proliferate and expand. If we can learn how to turn these brake systems back on, they may effectively stop the cell proliferation and tumor growth without many side effects. However, we have so far been largely unsuccessful at defining ways to reactivate many of these brake systems to stop tumor growth. Here, we have found an entirely new controller of multiple brake systems that has the potential to be turned on by drugs to simultaneously engage multiple brakes and effectively stop tumor growth. We have also found that when this brake system is activated, tumor cells are killed when they are grown under condition of limiting oxygen (hypoxia), a condition found in the majority of ovarian cancers. We call this braking system "the human stringent response," a newly identified human version of the well-known "bacterial stringent response." As the name implies, the 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, scientists did not know that human cells also have a stringent response. We have found that we can activate this stringent response in tumor cells to stop their proliferation by inhibiting a specific enzyme called MESH1 (also known as HDDC3) that is the human version of the bacterial enzyme. 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. We will determine how this kind of cellular braking will help to eliminate ovarian cancer cells that are resistant to the commonly used chemotherapies. Critical Problem in Ovarian Cancer: This study addresses the critical problem of how to overcome ovarian cancer that has developed chemoresistance. By studying an entirely new way to activate tumor suppressor pathways, a mechanism that is evolutionarily conserved from bacteria, these studies may provide the means to overcome ovarian cancer chemoresistance, a near-ubiquitous feature of recurrent disease. New Paradigms, Insights, Technologies, or Applications in Ovarian Cancer: Because the human stringent response is a novel concept that has not been previously studied, this line of investigation may create a new paradigm for how ovarian cancer cells can be eradicated by activing the human stringent response. Since the stringent response can be activated by inhibiting Mesh1 enzymatic activities, our studies are expected to speed development of novel therapeutic approaches for ovarian cancers. Relevance to the Vision and Mission of the Ovarian Cancer Research Program: What types of patients will it help and how will it help them? Although our understanding is still at an early stage, we believe that patients with fast-growing and hypoxic tumors will benefit most from stringent response-targeting agents. For example, our data suggest that tumors driven by one important oncogene called PI3K activation and hypoxia may be most sensitive to inhibition by the stringent response. Since this therapeutic strategy is unique from chemotherapies, it may also be effective against ovarian tumors that are no longer responding to chemotherapy. We have also found that many ovarian tumors have very high levels of Mesh1, so these may not be effectively treated by inhibiting Mesh1 protein. By blocking Mesh1, we hope to apply a brake to stop the tumor cells from continuing to grow. We will take advantage of our discovery of a human version of the bacterial "stringent response" to treat ovarian cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710143
Entities
People
- Jen-Tsan A Chi
Organizations
- Duke University
- United States Army