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.
Recipient of the V Scholar PLUS Award, a third year of grant support for V Scholars who have made exceptional progress in year 1 and 2 of their original grant
The precision oncology approach to the treatment of cancer bases treatment decisions on the biology of an individual’s cancer, most often using genetic alterations or mutations to inform therapy. This approach has been successful in a few cancer types, including lung cancer, melanoma, and chronic myelogenous leukemia where oral targeted therapies have led to both improved patient outcomes and fewer side effects compared to standard chemotherapy. However, this approach has not yet realized its full potential in these or other cancer types. In this proposal we plan to study new cancer-causing gene mutations involving the NTRK1, NTRK2 and NTRK3 genes, which are found in numerous types of cancer. We have already demonstrated that tumor cells treated with targeted therapies against this gene family can kill cancer cells in the laboratory. We have also observed early and dramatic tumor shrinkage in patients with different tumor types that share mutations in these NTRK genes. This proposal will focus on determining additional mutations of NTRK genes that may respond to therapy. The proposal will also study how cancer cells become resistant to targeted therapies and develop new laboratory models of NTRK+ cancer to develop new therapies for these cancers.
More children die from brain tumors than any other type of cancer, and the most common type of brain tumor in children is medulloblastoma. Children with medulloblastoma are treated with surgery, radiation, and chemotherapy, and more than 50% of patients survive into adulthood. However, the treatments used for medulloblastoma lead to many long-term side effects, including growth defects, hormone abnormalities, and impaired intelligence. Like all cancers, medulloblastoma is caused by uncontrolled cell growth. Approximately one-third of medulloblastoma cancers arise when a particular signal that tells brain cells to grow, called Hedgehog, gets stuck in the “on” position. We are interested in uncovering exactly how Hedgehog signals tell medulloblastoma cells to grow. To do so, we are investigating how the Hedgehog pathway is activated, and how Hedgehog activation regulates the expression of other signals to influence cell growth. In particular, we are using existing drugs to understand whether block critical mediators of Hedgehog effects blocks the growth of medulloblastoma. Understanding how Hedgehog signals cause cancer may show us how to turn off these signals, and potentially, lead to new therapies for medulloblastoma.
Funded by the 2015 Wine Celebration Fund a Need, including donations raised by the Dick Vitale Gala and Bristol-Myers Squibb
Recent research revealed that malignant gliomas in children often have common gene mutations in a molecule named H3.3, which is a component of the human genome. Approximately 30% of pediatric glioblastoma and 70% of diffuse intrinsic pontine glioma (DIPG) cases have the same mutation which causes a change in the H3.3 protein. The human immune system, such as T-lymphocytes (T-cells hereafter), do not normally react to normal proteins, but can recognize and attack cells that have abnormal proteins. Therefore, cancer-specific mutations can be suitable targets for cancer immunotherapy, such as cancer vaccines and adoptive T-cell transfer therapy (i.e., infusion of large number of T-cells). Indeed, immunotherapy using patients’ own T-cells that are engineered to recognize cancer cells have shown remarkable success in other cancers, such as acute lymphocytic leukemia in children. However, it is also important to ensure that those T-cells attack tumor cells but not normal cells. We recently found that the common mutation in H3.3 includes cytotoxic T cells which can kill glioma cells that have the mutation but not cells without the mutation. We are proposing two lines of translational studies. First, we will isolate genes for the T cell receptor which allows the specific recognition of mutated glioma cells. This will lead to a near future development of adoptive transfer immunotherapy. Concurrently, we will design and conduct a pilot vaccine trial using synthetic peptide for the mutated part of H3.3 in children with H3.3-mutated DIPG or high-grade glioma.
The last two decades have seen the development of increasingly effective cancer therapies that target different facets of transformed cells, including aberrant proliferation/survival, immune evasion, hyper-activated signaling pathways and dysregulated transcriptional programs. In a subset of cancers, including acute myeloid leukemia (AML) and non-small cell lung cancer with activating EGFR mutations, these therapies lead to dramatic clinical responses in a significant proportion of patients.
However, in the majority of AML and EGFR mutant lung cancer patients who respond to anti-cancer therapies, therapeutic relapse subsequently ensues, although often after a considerable interval, such that these responses do not lead to long-term cures. Often the relapsed tumors are infiltrated by adaptive immune cells (T cells). With the advances in immunotherapy, which utilize a patient’s own immune system to fight the cancer, it is possible to treat with immunotherapy after relapse. We are studying the T cell infiltrates before, during, and after relapse in both AML and NSCLC patients to determine if the response if the relapsed tumors have the characteristics of an immunogenic tum.
Tumors across different patients can be understood as independent evolutionary processes of clonal Darwinian evolution under distinct therapeutic evolutionary pressures. Different therapeutic strategies disrupt evolution in distinct ways allowing the inference of the order and co-mutation patterns specifically associated to these therapies. Inferring evolutionary patterns from large cross-sectional and longitudinal therapy specific cohorts will identify specific mechanisms of drug resistance, the genetic background of these mechanisms and will inform the dynamic model of the main routes of drug evasion.
First, using CAT(0) phylogenetic spaces, we will learn the statistics of phylogenetic processes associated specific drug mechanisms in breast cancer and melanoma. We conjecture that undisrupted evolutionary processes follow linear patterns and that specific therapies generate distinct branching patterns associated to number of alterations needed for relapse and effective size of the resistant population. Second, the highly branched processes associated to therapy allow to reconstruct the genetic alterations of ancestral clones allowing to order the genetic alterations. Combining cross-sectional information, one can elucidate the main routes of drug resistance, what alterations are selected under specific therapy and which is the mutational background in which they arise. As genomic data from clinical studies will be arriving we will generate first evolutionary models and integrate the results with the networks from dynamic modeling. By combining genomic data of longitudinal studies with state of the art network inference, we aim to uncover the main mechanisms of drug resistance and design combinatorial approaches.
Pancreatic ductal adenocarcinoma (PDAC) is a common and increasing cause of cancer death in the U.S.A. While attempts to harness the immune system to fight cancer has been successful in the treatment of many cancers, these strategies have to date been ineffective in PDAC. PDAC tumors contain not only cancer cells but a dense layer of fibrous tissue, called stroma. The stroma interferes with the immune systems ability to attack PDAC both by releasing substances that inhibit the immune system and by acting as a physical barrier to immune cells reaching the cancer cells. We have recently shown that Vitamin D can act on PDAC tumors to prevent the stroma from releasing immune inhibitory substances and to facilitate immune cell entry into tumors, potentially setting the stage for a more effective immune attack on PDAC. In this proposal, the post-doc/clinical fellow will work closely with a team of physicians, cancer immunologists, and computational biophysicists will work together to improve the effectiveness of immunotherapy for PDAC. The post-doc/clinical fellow will contribute toward the completion of two tightly coupled aims: first, novel theoretical and experimental tools will be used to characterize the patient-specific immunological environment of PDAC tumors; second, the detailed understanding of the immune environment in PDAC tumors will be used to develop novel immunotherapy strategies that will be tested in a new clinical trial. The clinical trial will use a combination of conventional chemotherapy, a potent Vitamin D analogue, a drug that activates immune cells, and surgery, in an effort to improve the outcomes of patients with pancreas cancer. The Penn post-doc will be the critical individual who supplies operative tissue to the diverse collaborators in the project, and correlates the different genomic and immunologic studies with patient outcomes. As such they will gain knowledge and experience in molecular phenotyping of tumors, immunotherapy, and clinical trials.
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