Defining Tandem Duplicator Phenotypes in Triple-Negative Breast Cancer to Guide Therapeutic Interventions
Abstract
Rationale: Breast cancer remains a major public health threat. The challenge is that breast cancer is not a single disease, but a collection of diverse cancers with differing clinical presentations and outcomes. To improve breast cancer treatment success, we need better tools to distinguish between different cancers and to determine their distinct genetic causes. This will allow us to find the best ways to deploy treatments that already exist or to develop new effective therapies. One breast cancer type that exemplifies this challenge is triple-negative breast cancer (TNBC). TNBC accounts for ~15%-20% of all breast cancers and is associated with poor outcomes for patients, owing to its capacity for aggressive growth, high recurrence rate, and its insensitivity to therapies that target cancer-driving molecules such as HER2 and the estrogen receptor. TNBC tumors have complex and massive changes to their entire DNA makeup, also known as the cancer genome. By analogy, where a single change might be seen as a misplaced letter in a gene, many cancer genes in TNBC are misspelled, repeated wholesale, or deleted in many different places. Because it is much more difficult to read so many changes at once, it is also harder to identify those that are important for TNBC growth and sensitivity to treatment. We have used advanced computational methods to identify patterns among these complex changes and have uncovered findings that we believe will have a tremendous impact on our ability to cure TNBCs. In a recent study, we analyzed the whole genomes of >3,000 cancers using computational methods and identified a distinct genetic "fingerprint" in about 40% of TNBCs, called the "tandem duplicator phenotype" (TDP). This fingerprint is characterized by massive rearrangements of cancer genes collectively driving cancer growth. Our analysis also found, based on the genetic makeup of TDP TNBC, that a novel combination of chemotherapies -- distinct from what is used now in the clinic -- would be highly effective in shrinking TDP TNBC tumors. We confirmed these findings in cell lines in vitro and in mice engrafted with human TDP TNBC tumors. We also found that not all TDP TNBC tumors are the same. We now have strong preliminary data identifying subtypes of genetically different TDP TNBCs, and for each subtype we have found genes that likely drive these genetic differences and for which specific therapies are already Food and Drug Administration (FDA)-approved or in development. Our research shows that while TDP TNBC is highly complex, we have the tools to unpack this complexity in a way that creates unprecedented opportunities for better classifying, treating and curing TNBC cancers. Aims, deliverables, and goals of the proposal: The ultimate goal of our proposal is to bring a more precise approach for classifying and treating TNBC tumors to the clinic that is based on identifiable molecular mechanisms. We will do this by generating a TDP-based classification scheme that will serve to guide patient therapies and to identify candidate genes that cause differences in the TDP subtypes (Aim 1), to determine that these genes cause the genomic consequences characterizing TDP (Aim 2), and to determine relationships between TDP driver genes and drug sensitivity (Aim 3). Our proposal uses a range of molecular and computational tools, many of which have been pioneered or perfected by our laboratories, for the investigation of TNBC. Here, they come together as an integrated platform that we expect to deliver (1) a refined scheme for stratifying patients with TNBC; (2) a better mechanistic understanding of the formation of TDP subtypes; and (3) novel treatment regimens tailored to specific TDPs that will be ready for testing in a clinical setting. With this project, we hope to bring greater insight into the cause of this type of breast cancer and to develop refined diagnostic tools to optimize therapeutic combinations and ultimately a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710006
Entities
People
- Ralph Scully
Organizations
- Beth Israel Deaconess Medical Center
- United States Army