About 12% of U.S. women will develop invasive breast cancer over the course of her lifetime. Despite advances in early diagnosis and treatment of the disease, breast cancer remains the most commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer death in American women. Acquisition of resistance to current therapies is a major challenge in everyday clinical practice, which significantly reduces the disease-free survival and overall survival in breast cancer patients. Thus, it is important to develop new therapeutic approaches for circumvention of resistance and also to identify predictive biomarkers for more effective treatment decisions. Our previous work found a protein called EZH2 as a very promising therapeutic target in metastatic breast cancer that becomes refractory to hormone therapy. Several highly selective inhibitors of EZH2 are currently being tested in phase I/II clinical trials in patients with B-cell lymphoma. In this study, we will evaluate the efficacy of these EZH2-targeting drugs in metastatic, endocrine resistant breast cancer. We further demonstrated that DNA methylation of one of EZH2-regulated target genes, called GREB1, is highly associated with EZH2 activity in advanced breast cancer. So we will test whether methylation of GREB1 can be used to identify patients who will respond to EZH2 inhibitors. Results from this clinical study provide a novel targeted therapy for advanced breast cancer and a biomarker for choosing the right treatment. Our work will pave the way for the development of personalized medicine as an alternative approach to fighting metastatic, endocrine therapy resistant breast cancer.
The overall goal of the University of Texas MD Anderson Cancer Center Ovarian SPORE is to prolong survival and to reduce the number of deaths from ovarian cancer through innovative research in the detection and treatment of ovarian cancer. The investigators funded by this grant have worked together to conduct five separate research projects. Project 1 has evaluated new biomarkers to create a blood test for early detection of ovarian cancer. When ovarian cancer is detected in stage I, up to 90% of women can be cured; however, only 20-25% of women are currently diagnosed at this stage. Detection of early stage disease in a larger number of women could improve the cure rate by 15–30%. Project 2 has tested drugs that can overcome the resistance that is developed to current therapy which targets the blood vessels that grow into and bring nutrients to ovarian cancer cells. Increasing the ability of drugs to eradicate the tumor blood supply will help kill the cancer cells. Project 3 has tested drugs for personalized therapy for low- grade cancer. Low-grade ovarian serous carcinoma is more common in younger women and it is a unique disease that is highly resistant to standard chemotherapy and difficult to manage. The goal of this project is to improve understanding of how low-grade ovarian cancer develops and progresses in order to identify new drug therapies that limit its growth. Project 4 has studied drugs for personalization of treatment for high grade ovarian cancers. Not all ovarian cancers will respond the same way or to the same extent to the chemotherapy drugs currently available or to the targeted therapies that are becoming the standard of care. This is due to molecular variation that exists from person to person and from cancer cell to cancer cell in the same patient. Finally, Project 5 has created modified cells that can be used to deliver a therapeutic agent directly to the ovarian tumors. Bone marrow-derived mesenchymal stem cells (MSC) are collected from an individual and modified in a test tube using recombinant DNA techniques. The modified cells are then injected into the patient and will move through the blood stream and ultimately integrate into the ovarian tumors. Once engrafted in the tumor, the modified MSC will produce a potent anti-tumor molecule which acts to reduce cancer cell growth.
