Dissecting the Druggable PP2A Interactome for Colon Cancer Treatment
Abstract
Fiscal Year 2019 Peer Review Cancer Research Program Topic Area: This application is focused on novel treatments for colorectal cancer (CRC). Scientific Rationale and Objectives The clinical management of CRC presents significant challenges due to the lack of effective therapies for advanced disease. CRC is the second leading cause of cancer-related death in the United States in both men and women, accounting for more than 50,000 deaths annually. A 5-year survival rate for localized disease of 91% can be attributed to the success of surgical resection, but this rate drops to less than 14% for patients diagnosed with CRC that has spread to distant sites. Thus, there is a critical need for novel approaches for treatment of patients with disseminated disease. Protein phosphatase 2A (PP2A) is an enzyme with well-established functions as a tumor suppressor. Importantly, the tumor suppressive activity of PP2A is disabled in CRC by multiple mechanisms; thus, therapeutic reactivation of PP2A is likely to be a promising strategy for management of the disease. In this proposal, we will evaluate the potential of novel small molecule activators of PP2A, known as SMAPs, for the treatment of CRC. We have determined that SMAPs can reactivate PP2A in CRC cells that harbor common mechanisms of PP2A inactivation and that these agents are effective against CRC in tissue culture settings (in vitro). SMAPs are also effective in mouse models of CRC (i.e., in vivo), with minimal toxic side effects when administered at doses up to 40 times higher than those required to inhibit tumor growth and survival. Together, these findings point to a strong potential of these drugs for the treatment of CRC patients. However, the clinical development of SMAPs will require a better understanding of how they work to inhibit tumor progression. This understanding will enable selection of patients who are likely to respond to SMAP therapy, while providing indicators of drug efficacy. Understanding of the mechanisms of action of SMAPs will also facilitate the design of drug combination strategies for overcoming drug resistance and achieving maximal efficacy. Our studies with SMAPs have identified two previously unrecognized targets for these agents, both of which are altered in CRC cells to drive tumor progression: * 4E-BP1: A critical inhibitor of the production of many key proteins that drive tumor growth and dissemination. 4E-BP1 is frequently inactivated in CRC. * Cyclin D1: A molecule that potently drives cell division and tumor growth and is present at abnormally high levels in tumors. SMAPs are able to restore the function of 4E-BP1 and promote the loss of cyclin D1 in a manner that depends on their ability to reactivate PP2A. The objectives of our proposed studies are (a) to determine the mechanism(s) used by SMAPs to activate 4E-BP1 and downregulate cyclin D1, (b) to establish the importance of these effects in mediating SMAP antitumor activity, (c) to explore the ability of these proteins to predict response to SMAPs, and (d) to evaluate the potential of combining SMAPs with other anticancer agents to enhance antitumor effects. Individuals Helped by the Proposed Research The project is anticipated to help patients with advanced CRC, who have limited therapeutic options and a dismal prognosis. Clinical Applications The proposal aims to set the stage for the development of a novel therapeutic approach for the management of CRC patients. Although counter-intuitive based on its tumor suppressor function, 4E-BP1 is present at high levels in advanced CRCs, albeit in an inactive state. Similarly, cyclin D1 is aberrantly overexpressed in advanced disease. Thus, the ability of SMAPs to reactivate the tumor suppressor activity of 4EBP1 and downregulate cyclin D1 is expected to be of direct benefit for the treatment of disseminated CRC. Health and Welfare of Military Service Members and Their Families CRC is a leading cause of can
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010590
Entities
People
- Jennifer Black
Organizations
- United States Army
- University of Nebraska Medical Center