New PROTACs Targeting Tissue Transglutaminase in Ovarian Cancer
Abstract
Ovarian cancer (OC) is a highly lethal cancer and metastasis to abdominal organs is the most common cause of death. Over 13,000 women die from ovarian cancer annually and less than half of all women diagnosed with ovarian cancer will survive longer than 5 years. In particular, metastatic ovarian cancer has a dismal outlook, with a 5-year survival of only 17%. Current treatments for advanced OC typically rely on traditional chemotherapy that produces significant side effects and does not significantly prevent the spread of the tumor. While this approach can reduce OC tumors and provide benefit for many women, especially those with early-stage cancers, patients with advanced cancer that have spread have a poor prognosis. New treatments that reduce OC growth, while also preventing its spread, would provide a greatly improved therapeutic approach that addresses a key obstacle to effectively treating OC patients. Anti-metastatic OC approaches would be expected to contain the OC locally, where it can be treated more effectively, providing a substantial benefit to a large number of women. Importantly, extensive work by our laboratory and others has established that the protein TG2 plays an essential role in OC metastasis. The manner in which TG2 promotes OC metastasis is not entirely clear; however, TG2 possesses multiple functions as a transamidase enzyme, a fibronectin-binding partner, and a signaling protein. Past efforts at developing therapeutics targeting specific individual functions of TG2 have met with limited success because of the myriad ways in which TG2 promotes metastasis. An ideal TG2-targeting agent would therefore simultaneously inhibit all of its functions; however, no such inhibitor has been described to date. We have previously described a series of novel small molecules that inhibit the interaction of TG2 with fibronectin. These inhibitors have been shown to block various TG2-mediated signaling pathways and to inhibit cancer cell attachment to proteins present in the local tumor environment. However, because TG2 plays myriad roles in OC growth and metastasis, inhibitors that act by only this one mechanism are unlikely to produce a robust and clinically meaningful benefit for OC patients. We have used our novel inhibitors to develop them into TG2-targeted Proteolysis Targeting Chimers (PROTACs). These PROTACs bind to TG2 and recruit elements of the natural protein degradation machinery inside cells and cause the rapid degradation TG2. This leads to effective elimination of the entire protein along with all of its functions. For the first time, we have shown that a PROTAC is able to cause the degradation of TG2 in ovarian cancer cells, demonstrating that our approach is feasible. This strategy has been recently shown to be a powerful approach to therapeutically target other onco-proteins involved in breast and prostate cancer in a comprehensive way. For TG2, which possesses multiple functions, targeting it for degradation is expected to produce strong anti-tumor and anti-metastatic efficacy, as it will abolish all of TG2’s functions simultaneously. The goal of the present project is to continue the development of our unique series of TG2-targeting PROTACs. We will carry out medicinal chemistry to rationally develop improved compounds that can more-potently eliminate TG2. Using a variety of in vitro assays, we will thoroughly characterize their activity. Importantly, we will demonstrate that they are capable of inhibiting multiple key functions involved in ovarian cancer growth and metastasis. After evaluating their pharmaceutical properties in vivo, we will use our TG2 PROTACs to block the dissemination and growth of ovarian cancer metastases. These data will provide the first proof of concept that simultaneously targeting multiple TG2-dependent functions can be a viable therapeutic approach for ovarian cancer. Expected Outcomes: Population Served: The population that will be
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210470
Entities
People
- Gary E Schiltz
Organizations
- Northwestern University
- United States Army