Mechanistic and Therapeutic Implications of Spliceosomal Gene Mutations in ER+ Breast Cancer
Abstract
Among the major challenges facing breast cancer therapy is the limited understanding of what specific alterations or pathways are leading to the aberrant proliferation of an individual tumor. When scientists have been able to pinpoint the so-called “driver” in a specific cancer, it has enabled the development and application of much more effective therapies and ultimately improved the ability to induce long-term cures. One prominent example of this was the identification of the HER2/neu oncogene as overexpressed in ~15% of breast cancers, leading to the development of the HER2 antibodies trastuzumab and pertuzumab. The use of these drugs selectively in breast cancers “driven” by HER2 has led to major improvements in outcomes for this subgroup. We have noted that mutations in genes encoding RNA splicing factors occur in 5%-6% of breast cancer patients overall, with the most common event being a single mutation in a gene called SF3B1. SF3B1 is part of a complex of proteins that help with the normal processing of RNAs in the cell. Moreover, SF3B1 itself is more commonly mutated in certain forms of leukemia, and work we have done in this disease has led to the understanding that SF3B1 can help “drive” those cancers. Indeed, drugs targeting SF3B1 are now being actively studied for patients with SF3B1 mutant leukemias. However, the functions and significance of SF3B1 mutation for breast cancer are unknown. Although 5%-6% is a small percentage, research over the last 20 years suggests that in breast cancer, most tumors fall into such small subgroups. Major pharmaceutical companies have recognized this, and so drugs targeting AR, PARP, AKT1, and FGFR all have been developed specifically for subsets of breast cancer patients under 10%. In surveying the landscape of mutations in breast cancer for which a potential new drug therapy is available, SF3B1 is actually near the very top of the list in terms of frequency. Moreover, there may be additional ways that splicing is altered in breast cancer besides mutation in SF3B1 such that the drugs developed in this proposal may also prove beneficial. Thus, we believe the potential impact of this research is quite high – it may dramatically alter the course of therapy for an easily identified subset of patients. In this project, we propose to use the tools we developed for studying SF3B1 in leukemia and apply them for the careful study of the implications of SF3B1 for the growth and survival of different breast tumors. We will specifically determine whether mutation in SF3B1 can help initiate a breast cancer growth and whether SF3B1 mutation might cause breast tumors to become resistant to the most commonly used therapy, hormonal therapy. Lastly, we have been involved in the development of drugs against SF3B1 and will assess whether they are particularly effective in breast cancers with these mutations. Over the 3 years of this project, we will first learn if mutant SF3B1 is a “driver” of breast cancer growth. This is likely given our preliminary data. Second, we will ascertain how mutant SF3B1 can support tumor growth. This will help us understand the clinical context in which we mutant SF3B1 is working and provide the key insight into how we might develop trials for SF3B1 inhibitors. For instance, we may learn that the principal way that mutant SF3B1 works is to support one aspect of the estrogen stimulated growth program but that it cannot operate all by itself. This would then guide our decision to test combinations of SF3B1 inhibitors with antiestrogens. Finally, we will establish which specific inhibitors of splicing are most likely to be effective for breast cancer patients. Of note, each of the drugs we are studying is currently in Phase I clinical trials for other forms of cancer. At the end of this project, we believe we will be in a position to design a Phase 1/2, proof of concept for spliceosomal inhibition for breast cancer patients and thus anticip
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810383
Entities
People
- Omar Abdel-Wahab
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army