Rhabdomyosarcoma (RMS) is the most common soft tissue cancer of childhood. Because RMS has features of skeletal muscle, we and others have been trying to understand how muscle development pathways inside the tumor cells have gone awry. This project will study the role of a protein called SFRP3, which although it takes part in normal muscle formation, is co-opted to support RMS tumor formation. We aim to understand in more detail how SFRP3 works in RMS, and how to block it. Our goal is to someday use SFRP3 blockade as a therapeutic intervention.
Dr. James M. Ford, M.D., is an Associate Professor of Medicine, Pediatrics and Genetics at Stanford University School of Medicine. He is the Director of the Stanford Cancer Genetics Clinic and the Stanford Clinical Cancer Genomics Program. A recipient of The V Foundation Translational Research grant in 2002, Ford joined the Scientific Advisory Committee in 2003.
Dr. Ford’s research goals are to understand the role of genetic changes in cancer genes in the risk and development of common cancers. He studies the role of the p53 and BRCA1 tumor suppressor genes in DNA repair, and uses techniques for high-throughput genomic analyses of cancer to identify molecular signatures for targeted therapies. Dr. Ford’s clinical interests include the diagnosis and treatment of patients with a hereditary pre-disposition to cancer. He runs the Stanford Cancer Genetics Clinic, that sees patients for genetic counseling and testing of hereditary cancer syndromes, and enters patients on clinical research protocols for prevention and early diagnosis of cancer in high-risk individuals.
Ford graduated Magna Cum Laude with a B.A. degree from Yale University in 1984 and earned his M.D. degree from Yale in 1989. He has been at Stanford ever since, serving as an intern, resident and fellow before earning his postdoc and becoming Assistant Professor in 1998.
Ovarian cancer is the 5th cause of cancer death in women. Older women with ovarian cancer have a markedly worse survival rate than for younger ones. This is likely due to a combination of biology and a treatment-related factors. In this project, we will study these older women using a two-pronged approach. First, we will look at gene array data and assess which gene expression patterns correlate with a more aggressive behavior in older women, how they are modified by chemotherapy, and whether a targeted therapy can help control these deleterious patterns. Secondly, we will investigate ways to improve the delivery of chemotherapy by factoring in body composition and the functional impact of side effects. We will proceed in three steps. In step 1, we will use the Total Cancer Care (TCC) database, which combines gene arrays and clinical data to identify promising patterns to be focused on. In step 2, we will conduct a prospective study and collect samples after preoperative chemotherapy, to see which genes fail to be inactivated by chemotherapy, and how body composition is related to the blood levels of chemotherapy. In Step 3, we will add a targeted drug therapy to the standard chemotherapy for ovarian cancer to try to thwart the resistance mechanisms we identified and improve response. In one of the arms, the chemotherapy will be adapted to body composition and functional impact of side effects. To have enough patients, Steps 2 and 3 will be multicentric studies conducted within the Moffitt Oncology Network and Total Cancer Care Partnership.
Fewer than 5% of adult cancer patients in the United States are enrolled in clinical trials. In addition, minorities constitute a small proportion of individuals participating in cancer studies. These strikingly low figures delay scientific advances, limit generalizability of trial results, and limit patient access to cutting-edge therapies. Proposed reasons for low accrual include lack of study availability, stringent eligibility criteria, physicians’ biases and lack of awareness, logistical issues, and patient mistrust.
Parkland Health and Hospital System (PHHS) serves as the safety-net hospital for Dallas County. Parkland, in partnership with the University of Texas Southwestern, provides medical care to a large population that disproportionately includes underserved minorities. Cancer patients presenting to Parkland are typically diagnosed at a more advanced stage and are more likely to have had delays in their care.
Based on our previous observations, we believe that the greatest potential impact lies in addressing specific and modifiable aspects of patient care. We therefore propose a Breast Cancer Clinical Research Navigator with a role distinct from research coordinators that will focus on early identification of trial candidates, expediting initial patient evaluation, and improving provider awareness of trial options.
We believe that engaging a Breast Cancer Clinical Research Navigator in the ways outlined above, will result in early and integrated consideration and presentation of trial options and will impact both patient and clinician interest in clinical trials, thereby augmenting accrual.
The promise of cancer therapies that target the mutationally activated “drivers” of malignant behavior is that highly selective drugs can be developed that will be effective with minimal side effects. However, that promise has not been achieved because most cancers rapidly develop resistance to these targeted therapies. Recent experience with the leukemias and lymphomas that respond to the drug ibrutinib provide a sobering example of both the successes and disappointments of these targeted approaches. Whereas many patients with malignancies of B-cells (Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL) or Diffuse Large B-Cell Lymphoma (DLBCL)) show a beneficial response to treatment with ibrutinib, the responses are generally incomplete and often are not durable. The goal of the collaborative research proposal from UVA and VCU is to elucidate the important mechanisms of intrinsic and adaptive resistance to therapies for B-cell malignancies, and use this understanding to develop RATIONAL combinations of drugs that target both the driver of malignancy and the resistance mechanisms. The two groups have over the past few years taken complementary approaches to tackling this problem, and some of these discoveries are now entering clinical trial. The UVA and VCU groups will utilize materials from these clinical trials, as well as preclinical models and patient samples to develop tools to match patients with the most appropriate drug combinations, and to develop additional combinations of targeted therapies that will have deeper and more long-lasting benefits.
