Targeting Differential Apoptosis Regulation in Triple-Negative Breast Cancer
Abstract
Rationale: Approximately 15% of all breast cancers fall within a disease subtype known as triple-negative breast cancer, or TNBC. TNBCs are extremely aggressive tumors, and patients with this disease subtype show higher rates of relapse and shorter overall survival in the metastatic setting than other breast cancer subtypes. Further, in contrast to estrogen receptor-positive (ER+) or HER2 receptor-positive (HER2+) breast cancers, TNBCs lack therapeutically targetable molecular alterations. Thus, the standard-of-care for patients with TNBC is cytotoxic chemotherapy, which has dangerous side effects and, perhaps more importantly, does not cure advanced disease. Recently, we began searching for new therapeutic strategies for TNBCs by examining a process known as mitochondrial apoptosis, or programmed cell death. Specifically, building on several lines of evidence, we hypothesized that TNBCs might utilize unique mechanisms to prevent apoptosis. By identifying these mechanisms, we reasoned that we might uncover new therapeutic strategies to target cell death specifically in these tumors. Fortuitously, we found that this hypothesis was correct: Unlike normal cells in the adult body, TNBC cells are highly "primed" to undergo apoptosis, but they stay alive by expressing two key proteins, MCL-1 and BCL-XL, which block apoptosis. As such, drugs that directly or indirectly block the activities of MCL-1 and BCL-XL are specifically and synergistically toxic to TNBC cell lines and patient-derived tumors and cause dramatic regressions of established tumors in mouse models, even when used at low doses that do not affect normal cells. While BCL-XL inhibitors are already in clinical trials, no potent, bioavailable MCL-1 inhibitors have been developed. However, MCL-1 is controlled in TNBC by the AKT signaling pathway, and as such, AKT inhibitors (which are also in clinical trials) have the ability to potently suppress MCL-1 function. Thus, combinations of BCL-XL and AKT inhibitors have the potential to disrupt the current treatment paradigm in TNBC by replacing toxic and marginally effective chemotherapies with potent and selective tumor-targeted therapies. Objective/Aims: To maximize and accelerate the near-term translational potential of this discovery, we have assembled a team of world-leading breast cancer clinicians and biologists who will work together to examine three key aims. In Aim 1, we will use "gold standard" mouse models of patient-derived TNBC to examine the ability of combined, clinically available BCL-XL and AKT inhibitors to drive tumors regressions in vivo. In Aim 2, acknowledging the fact that cytotoxic chemotherapies are the backbone of current treatment regimens, and building on our finding that low doses of BCL-XL plus AKT inhibitors potently sensitize TNBCs to these chemotherapies, we will examine the anti-tumor effects of combined, low-dose BCL-XL/AKT inhibitors with chemotherapy in the same mouse models. Finally, in Aim 3, we will examine the breadth of responses to the therapeutic strategies from Aims 1-2 in diverse models of TNBC that represent the spectrum of patients with this disease to define mechanism-based biomarkers that identify patients most likely to respond favorably to these treatments. Applicability: By leveraging new insights into the biology of TNBC to develop potent, selective new therapeutic strategies, this work addresses two Breast Cancer Research Program overarching challenges: (1) Identify what drives breast cancer growth; determine how to stop it, and (2) revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective. Specifically, this work is expected to lead to new, safer, and more effective therapies for patients with TNBC, including both early- and late-stage disease. Although clinical trials will be necessary to determine the effectiveness and safety of these therapies in human patients, our st
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610703
Entities
People
- Kris C Wood
Organizations
- Duke University
- United States Army