Targeting MCL-1 with Unique Peptide Inhibitors Delivered Intracellularly Using a Novel Nanoparticle Formulation
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive disease that has limited treatment options once it has spread to distant sites. Therefore, new therapies are needed for TNBC to address the Overarching Challenge of eliminating the mortality associated with metastatic breast cancer. Advances in our understanding of TNBC have shown that survival of these breast cancer cells is dependent on a protein known as myeloid cell leukemia-1 or simply MCL-1. In this way, MCL-1 has emerged as a highly attractive target for the treatment of TNBC. However, despite considerable efforts, there are presently no available agents that target MCL-1 for the treatment of TNBC in the clinic. Importantly, we have developed peptides that are potent inhibitors of MCL-1 and are potential clinical candidates for the treatment of patients with TNBC. Although highly encouraging, delivery of peptides to tumors in mouse models and in patients has been a challenge. To address this obstacle, we have also developed small particles, known as nanoparticles (NPs), for delivery of peptide drugs inside tumor cells. Partnering of the Keating lab at MIT (Massachusetts Institute of Technology) that works on MCL-1 inhibitor peptides with the Kufe lab at Harvard that works on NP delivery of peptides has thus provided a unique opportunity to develop novel agents that target MCL-1 in TNBCs. Our goal is thus to generate the preclinical information that would be needed to advance this approach to the clinic for the treatment of patients with metastatic TNBC. Our approach for targeting MCL-1 could also increase the sensitivity of TNBC cells to agents, such as taxol, that are now used for the treatment of this disease. Our timeline for the identification of an optimized MCL-1 peptide inhibitor that is formulated in NPs for clinical development is 2-3 years. A Phase I/II trial for patients with metastatic TNBC would then be initiated following the filing of an Investigational New Drug application and approval from the Food and Drug Administration. Our objective is to improve the treatment of metastatic TNBC. Notably, MCL-1 is overexpressed in other subtypes of breast cancer. Therefore, development of this approach for targeting MCL-1 may be effective more broadly for breast cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610671
Entities
People
- Amy Keating
Organizations
- Harvard University
- United States Army