Human Stringent Response as Novel Therapeutic Approaches for Breast Cancers
Abstract
Overarching challenge: Identify what drives breast cancer growth and determine how to stop it. Many breast tumor 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 growth of tumors and cell proliferation without many side effects. However, many of these tumor suppressor pathways cannot be readily turned on by small compounds 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 activate multiple brakes and stop tumor growth. In addition, the stringent response also kills tumor cells under hypoxia, a condition that is found in two-thirds of breast cancers. We call this system "the human stringent response"; it is a human version of a 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, scientists did not know that human cells also have a stringent response until recently. We have found the ability to activate this stringent response in tumor cells (and stop proliferation) by inhibiting an enzyme (MESH1 or HDDC3) that is the human version of a bacterial enzyme in the 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. One big difference from the bacteria is that human stringent response kills tumor cells under low oxygen (hypoxia) present in about two-thirds of breast cancers. What types of patients will it help and how will it help them? Although our understanding is still at an early stage, we think the patients with fast-growing and hypoxic tumors will benefit most from stringent response-targeting agents. For example, our data suggest that tumors driven by PI3K activation and hypoxia may be sensitive to inhibition by the stringent response. Since this therapeutic strategy is unique from chemotherapies, it may also be effective against tumors that have become resistant and are not responding to chemotherapies any more. It is possible that a subset of breast tumors has very low levels of the stringent response, so these tumor cells may not be effectively treated by inhibiting this pathway. By blocking Mesh1, we hope to apply a brake to stop the tumor cells from continuing to grow. 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 breast cancers. We envision that using an inhibitor to block the enzymatic activities of MESH1 will trigger the anti-tumor stringent response. Such a response may have a multi-pronged effect to halt the growth of human tumors, especially fast-growing tumors or with regions of hypoxia. 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 a corresponding low stringent response; these are the patients most likely to benefit from treatments targeting MESH1. Therefore, more studies are needed to understand how to best target the stringent response for therapeutic purposes. It is also not clear whether there are unknown toxicities associated with systemic activation of the human stringent response. These concerns will be addressed and clarified in the project. The projected time it may ta
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510486
Entities
People
- Jen-Tsan A Chi
Organizations
- Duke University
- United States Army