Hope S. Rugo, MD
Professor of Medicine
Director, Breast Oncology and Clinical Trials
UCSF Helen Diller Family Comprehensive Cancer Center
University of California, San Francisco
San Francisco, California
2013-2014 BCRF Project:
(The Delta Air Lines Award)
Novel immunotherapeutic approaches to combat breast cancer now include cell-based, DNA or peptide-based vaccines, as well as therapeutics that cripple cell-based pathways that inhibit tumor cell killing by CD8+ T cells. Dr. Rugo’s studies have identified several of these pathways and have thus led her team to examine macrophage-targeted therapies in clinical trials, in combination with chemotherapy, to improve overall survival for patients with breast cancer. In the coming year, Dr. Rugo intends to further these studies by examining macrophage-antagonists and chemotherapy, in combination with novel therapeutic agents that block “off signals” on CD8+ T cells in preclinical models of mammary cancer development. The goal is to identify the best agents to test in a subsequent clinical trial in combination with chemotherapy. Many breast cancers develop or have up-front resistance to the most effective chemotherapy agents, including paclitaxel or other taxane based therapies. Testing immune modulating therapies in tumors already resistant to standard chemotherapy is critical to inform appropriate clinical trials. Hence, Dr. Rugo’s team will develop relevant chemotherapy (paclitaxel)-resistant models of the major subtypes of breast cancer, specifically luminal A, luminal B, HER2+ and triple negative mammary tumors, in which to evaluate these novel immune-based approaches in combination with chemotherapy in recurrent metastatic disease in vivo.
Amplification of the MYC oncogene in triple negative breast cancers has been associated with a short time to recurrence and worse outcome. Inhibition of an enzyme called PIM1 kinase can kill these MYC positive cells, and PIM1 kinase is known to be involved with regulation of the immune system. Dr. Rugo’s team will evaluate the role of inhibition of PIM1 kinase in laboratory models of human triple negative breast cancer using several inhibitors of this enzyme and collaborate with her team to better understand the impact of PIM1 kinase inhibition on the tumor’s immune environment. The overall goal of these studies is to identify combinations of immune-based therapies that will provide durable tumor responses for patients with breast cancer.
Isolation and molecular analysis of CTCs offer a unique opportunity to monitor cancer progression and/or therapeutic efficacy of targeted therapies in a relatively non-invasive manner. However, since CTCs are extremely rare, isolating these tumor cells away from blood cells poses major technical challenges. Dr. Rugo’s group recently published a report describing a novel approach to isolate highly pure CTCs. They identified chromosome abnormalities that were common to these metastatic cells and showed that they were related to their corresponding primary tumors (before metastasizing). Comparison of the CTC HER2 status and the clinical HER2 status revealed differences in some patients, suggesting that HER2 status may change during cancer progression. They are now extending their work by characterizing genetic mutations in CTCs via new methodologies called next generation sequencing. Their preliminary data show that it is feasible to look at genetic changes in CTC at a very detailed level, down to a single nucleotide. With these studies, Dr. Rugo and colleagues hope to define the molecular events associated with breast cancer progression, and thereby provide a more detailed understanding of CTC-based biomarkers that can be used in clinical trials potentially therapeutic targets. Understanding the molecular changes in CTCs may allow clinicians to specifically target these cells in the context of a personalized treatment.
In her first aim, Dr. Rugo is focused on luminal B-type breast cancersm which respond poorly to neoadjuvant chemotherapy and are at high risk for metastatic recurrence within five years. Response to chemotherapy in breast cancer is partially mediated by cytotoxic T lymphocytes (CTLs); Dr. Rugo’s group has previously reported that this response is limited in luminal B-type cancers due to the presence of immunosuppressive immune cells (macrophages). They predict that simultaneously blocking macrophage-dependent immune suppression, while bolstering protective T cell responses will enhance efficacy of chemotherapy, thereby reducing recurrence and improving survival. To this end they are determining how CTL responses are regulated by macrophages and dendritic cells for development of new therapeutic approaches that foster durable anti-tumor immune responses to improve overall survival.
In a second aspect of her project, Dr. Rugo and team are using the latest cutting-edge next generation sequencing for molecular profiling of circulating tumor cells (CTCs). They demonstrate in a few patients the feasibility of next generation sequencing of CTC genomes, and envision that molecular characterization of CTCs may ultimately lead to the discovery of better prognostic or predictive markers for clinical decision making with the goal of customizing patient therapy in response to tumor heterogeneity.
Finally, Dr. Rugo’s group has identified the PIM1 kinase is a gene associated with worse outcome in patient with receptor triple negative breast cancer (TNBC). They thus sees to test the concept that inhibition of the PIM1 kinase, with small molecule drugs, may improve the outcome of patients with TNBCs. Specifically, they propose that inhibition of PIM kinases may alter the non-tumor cells associated with the cancer, thus preventing tumor growth and possibly blocking tumor metastasis. In the past three months they have established new models of breast cancer regulated by MYC that can be transplanted from one model into another. This powerful approach allows the researchers to generate sufficient models to study the role of PIM on the tumor-associated cells.
Dr. Hope S. Rugo is a Professor of Medicine in the Division of Hematology and Oncology at the Helen Diller Family Comprehensive Cancer Center of the University of California, San Francisco (UCSF), where she directs Breast Cancer and Clinical Trial Education. Her research interests include novel therapies for advanced breast cancer, immune modulation to restore chemotherapy sensitivity evaluation of circulating cells as novel markers of response and resistance to therapy, neoadjuvant therapy, and supportive care.
Dr. Rugo is an investigator in the Bay Area Spore at the UCSF Breast Cancer Center, the national multi-center ISPY2 trial, and is the principal investigator of a number of clinical trials. She serves on steering committees for national and international trials. Dr. Rugo is a member of the ALLIANCE Breast Core Committee and the Translational Breast Cancer Research Consortium, and serves on several committees for the American Society of Clinical Oncology. She has published many peer-reviewed papers and has given presentations on a variety of cancer related topics.
With a summa cum laude undergraduate degree from Tufts University. Dr. Rugo received her medical degree from the University of Pennsylvania School of Medicine and completed both a residency in internal medicine and fellowship in hematology and oncology at the UCSF. Additionally, she completed a two-year post-doctoral fellowship in immunology at Stanford University. She received the Cancer Care Physician of the year award in 2010.