Targeting Tumor-Specific Apoptosis Regulation in Advanced ER+ Breast Cancer
Abstract
Rationale: Approximately 75% of all breast cancers fall within a disease subtype known as estrogen receptor positive (ER+) breast cancer. Clinically, patients with metastatic, ER+ breast cancer are now treated with the combination of anti-estrogens (e.g., the selective estrogen receptor modulator [SERM] tamoxifen or the aromatase inhibitor [AI] letrozole) and CDK4/6 inhibitors (e.g., palbociclib), combination therapies that markedly delay disease progression relative to prior treatment regimens consisting of anti-estrogens alone. However, nearly all of these patients eventually develop progressive disease, leaving them with few proven therapeutic options. Recently, we began searching for new therapeutic strategies for breast cancers by examining a process known as mitochondrial apoptosis, or programmed cell death. Building on several lines of evidence, we hypothesized that breast tumors may 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, breast cancer 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 block the activities of MCL-1 and BCL-XL activate cell death, causing synergistic toxicity to breast tumors even when used at low doses that do not affect normal cells. While safe and effective, BCL-XL inhibitors are already in clinical trials, no potent, bioavailable MCL-1 inhibitors with evidence of in vivo activity and safety in humans have developed. Our 2015 Breast Cancer Research Program (BCRP) Breakthrough Award was therefore funded to discover and translate therapeutic strategies that combine BCL-XL inhibitors with drugs that inhibit MCL-1 activity via indirect regulatory mechanisms. Although the focus of that project is on triple-negative breast cancer (TNBC), in the course of those studies we made the surprising discovery that in about half of ER+ breast cancers (those with mutations in the PIK3CA gene), MCL-1 activity is tightly regulated by the mTOR/4E-BP signaling pathway. Thus, low dose combinations of BCL-XL and mTOR inhibitors yield tumor regressions in these tumors, activity that is maintained even after these tumors become resistant to standard of care, anti-estrogen plus CDK4/6 inhibitor therapy. Thus, combined low dose BCL-XL plus mTOR inhibitor therapy has the potential to provide a much needed, effective, and safe treatment for a large fraction of ER+ breast cancer patients with progressive disease. 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, progressive ER+ breast cancer to examine the ability of combined, clinically available BCL-XL and mTOR/4E-BP pathway inhibitors to drive tumors regressions in vivo. In Aim 2, acknowledging the fact that cytotoxic chemotherapies are the backbone of current treatment regimens for these patients, and building on our finding that low doses of BCL-XL plus mTOR inhibitors potently sensitize ER+ cell lines to these chemotherapies, we will examine the anti-tumor effects of combined, low dose BCL-XL/mTOR inhibitors with chemotherapy in the same mouse models. Finally, in Aim 3, we will combine structural and functional genomic techniques with analysis of tumor samples from ER+, PIK3CA mutant breast cancer patients enrolled in a Phase I trial of BCL-XL/mTOR inhibition at our institution to define the key, mechanism-based biomarkers of response to these treatments. Applicability: By leveraging new insights into the basic biology of ER+ breast cancer to deve
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910414
Entities
People
- Kris C Wood
Organizations
- Duke University
- United States Army