Targeting Small G-Proteins in Triple-Negative Breast Cancer
Abstract
Breast cancer (BC) treatment is complicated by the fact that BC is not a single disease. Rather, BC is a collection of many subtypes requiring treatments that are tailored to each individual’s cancer. BCs that are positive for estrogen (ER) and/or progesterone receptors (PR) often respond to therapies that decrease activity of these receptors. Likewise, BCs that express HER2 can be treated with drugs such as trastuzumab that inhibit this receptor. These targeted treatments are powerful tools to individualize BC treatment and have improved survival for patients with hormone receptor-positive and HER2-positive breast cancers over the past decades. Unfortunately, for women with BC that is not positive for ER, PR, or HER2, there are currently no effective targeted therapy options. Because of this, management of these BCs is largely unchanged from the 1960s, with toxic chemotherapy as the only systemic treatment option. This subtype of BC is referred to as “triple-negative” (TNBC), a name reflective of the lack of therapeutic targets. Approximately 15% of all BCs are TNBC. This includes most BRCA1-mutant breast cancers and this percentage is higher in young women and women of African ancestry. TNBCs are frequently metastatic and patients with TNBC have the highest mortality among the BC subtypes. In order to improve treatment for women with TNBC, we must identify proteins that are not only essential for TNBC initiation, growth, and/or metastasis, but these proteins must also prove to be good therapeutic targets. We recently identified a protein, RalA, which is found at high levels in many TNBCs and predicts poor survival in these patients. In initial preclinical studies using human TNBC cell lines injected into mice, we found that RalA is required for TNBC cells to grow at primary and metastatic sites. We also found that RalB, which as its name implies is very similar in most ways to RalA, is found in normal mammary glands, but is decreased in TNBC. Intriguingly, we discovered that unlike RalA, RalB seems to inhibit TNBC metastasis. Thus, RalA and RalB, despite their apparent similarities, appear to have opposite roles in TNBC. By understanding the basis for this difference, we hope to gain important insight into why some TNBC do not metastasize while others do. In addition, there are experimental inhibitors that target both RalA and RalB. While these drugs are not yet ready to be used in the clinic, they are the prototypes that can be modified into a new, highly specific therapy for TNBC. If successful, this proposal will immediately supply clinicians with tools to distinguish which TNBCs are more likely to metastasize; thus, allowing patients and their treatment team to make more educated treatment decisions. Knowledge gained through this proposal will help us understand why some TNBCs never metastasize while others do. Finally, we will test existing preclinical Ral inhibitors against TNBC and use the insight gained through these studies to guide development of improved versions of these inhibitors to provide the first effective targeted therapy against TNBC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010047
Entities
People
- Steven T Sizemore
Organizations
- Ohio State University
- United States Army