A description of what we are funding at Memorial Sloan Kettering Cancer Center:
One major constraint that prevents cells from dividing and forming tumors is a “checkpoint” that blocks cell division when adequate nutrients and hormones are lacking. This checkpoint is often abrogated in breast cancers as a result of DNA mutations, causing cells to constitutively grow and divide. Recently, a powerful class of therapies designed to restore this checkpoint was approved after showing major benefit for patients with estrogen receptor positive metastatic breast cancer. The drugs are known as CDK4 inhibitors and, when added to standard hormonal therapy (letrozole or fulvestrant), nearly doubled how long patients could stay on the regimen before needing to change due to resistance. These drugs are now part of the standard of care for women with metastatic breast cancer.
Unfortunately, resistance to these drugs is commonplace and is not well understood. Our laboratory is taking a variety of approaches to develop an understanding of cancer resistance to these drugs. Our research on this area includes developing laboratory models of resistant cancer using patient-derived materials since most of the models currently available are NOT resistant these drugs. We are characterizing mutations that occur in the resistant cancers and testing both how they may promote drug resistance as well as strategies to overcome this. We are optimistic that by applying the latest technologies to these patient derived materials, key insights will emerge that enable us to develop even more effective therapies that delay or prevent drug resistance.
A description of the studies we are funding at Dana-Farber Cancer Institute:
An estimated 150,000 women and men in the U.S. are living with metastatic breast cancer, which is breast cancer that has spread beyond the tissues of the breast. More than 40,000 people in the U.S. die from metastatic breast cancer each year, accounting for 7% of all cancer deaths (and 14% of cancer deaths among women). Though treatments are improving, metastatic breast cancer is currently not curable.
Estrogen receptor positive (ER+) metastatic breast cancer is the most common breast cancer subtype, and the most common cause of breast cancer death. Though we have made many advances in the treatment of ER+ metastatic breast cancer using agents that target the estrogen receptor, patients invariably develop resistance to these therapies. Novel treatments and therapeutic strategies for ER+ metastatic breast cancer are urgently needed. The goal of this research is to increase our understanding of ER+ metastatic breast cancer using a variety of laboratory and genomic approaches. We will focus on two key areas:
1) Immunoprofiling of ER+ Metastatic Breast Cancer
Immunotherapy is a promising class of cancer therapy based on the idea that manipulating a patient’s immune system can enable the body’s immune system to fight cancer cells just as it would a hostile virus. Across multiple malignancies, including breast cancer, immunotherapy has the ability to induce long lasting responses even in patients with advanced disease. However, many questions remain about which patients will benefit from existing immunotherapy agents and how to develop new immunotherapies that can help a broader range of patients. In order to answer those questions, developing a better understanding of how the immune system interacts with a breast tumor will be very important, and that is the goal of our proposed work. Though ER+ breast cancer is the most common subtype of breast cancer, much of the work on immunotherapy has been done in the triple-negative breast cancer subtype. Further work is needed to better understand the immune environment in ER+ breast tumors in order to determine the best immunotherapeutic treatment strategies for this subtype. This research project will characterize the role of the immune system in ER+ metastatic breast cancer through genomic and molecular analysis of tumor samples from patients with advanced disease. Findings from this project this may ultimately help us to identify patients best suited for immunotherapies, and to build the most effective regimens combining standard therapies with immunotherapies. Our ultimate goal is to help pair the right immunotherapy approaches with the appropriate patient subgroups, so that the power of immunotherapy as a new therapeutic tool may be fully realized for patients with breast cancer.
2) The Role of HER2 mutations ER+ Metastatic Breast Cancer
Analysis of tumor samples from patients with ER+ metastatic breast cancer has shown that a subset of patients have mutations in HER2 that may be important for cancer progression. Characterization of some of these mutations has demonstrated that new drugs that target HER2 mutations, when combined with drugs that target the ER, may be particularly beneficial for patients with advanced ER+ breast cancer. The goal of this project is to improve our understanding of HER2 mutations in ER+ breast cancer by comprehensively characterizing mutations in HER2, including mutations that have been identified in patients as well as novel mutations that have not yet been seen in tumor samples. Once completed, we should be able to utilize this data to determine appropriate therapies and trials patients with ER+ metastatic breast cancer who have HER2 mutations.