Myeloproliferative neoplasm (MPN) is a chronic leukemia characterized with no curative treatments other than bone marrow transplantation. MPN results from the acquisition of a mutation in a blood stem cell that drives the unrestrained production of myeloid blood cells. Mutations in the gene calreticulin have been recently identified in a large proportion of MPN patients, it is currently unknown how calreticulin mutations drive MPN. Our goal is to identify the mechanism by which calreticulin mutations cause the manifestations of MPN and to develop drugs targeting calreticulin to treat this disease.
Early detection of cancer represents a critically important goal in the improvement of survival outcome in common cancers. However, existing tests have shortcomings in sensitivity and accuracy, and false positive results often lead to additional expensive tests, risks inducing anxiety in patients and their families, and even potential harm if complications result from follow-up studies. To address these shortcomings, our proposal will develop a cutting-edge, highly-sensitive genome-wide approach for cancer screening and monitoring of tumor-derived DNA in easily-accessible body fluids. We will focus on developing this minimally-invasive “liquid biopsy” approach on non-small cell lung cancer (NSCLC), the leading cause of cancer death globally, and on Diffuse Large B-cell Lymphoma (DLBCL), the most common type of blood cancer. Once developed, we will apply this approach in populations at risk for NSCLC and lymphomas to validate early detection of these tumors. We thus anticipate that we can devise a sensitive method for early disease detection and monitoring that will be broadly applicable to many other cancers.
The reasons why cancer patients do or do not participate in cancer (clinical trials) research are complex. Often this is due to the lack of awareness of which studies are occurring by both the patient and their primary care clinicians.
Another very important reason is that patients, especially patients that do not speak English, are not invited to participate because the research team does not have non-English speakers or study materials in the patient’s language. We at the UC San Diego Moores Cancer Center (MCC) have the opportunity to better understand and address low clinical trials participation among our largest under-represented racial/ethnic group, Hispanics. Working with a multidisciplinary team of physicians and non-physician scientists we propose to inform key organizations in the South Bay of San Diego, a Hispanic-dense geographic area, about specific breast cancer clinical trials.
Further, we will assess the reasons (barriers) for study participation among Hispanic MCC breast cancer patients. By focusing on minority breast cancer patients, the V Foundation funds complement and expand our emerging efforts to increase minority clinical trials enrollment (accrual) and related outreach and inform how to intervene with MCC patients, providers, and leadership. We are particularly interested in targeting Hispanic breast cancer patients because they are the largest minority group in San Diego and Imperial counties, the regions served by the MCC, and our accrual data show that this is the single group that remains under-represented in our therapeutic clinical trials.
Funded by the 2015 V Foundation Wine Celebration Fund a Need, including $50,000 donated by the National Brain Tumor Society.
Children with high-grade gliomas continue to have a dismal prognosis, specifically when the tumor is located within the brainstem. Most children die from this disease and no significant change in outcome has been achieved over the last several decades. To improve the poor prognosis for these children, we will apply a precision medicine approach, which has never been explored in a comprehensive fashion for children with this diagnosis. We will conduct the trial through the Pacific Pediatric Neuro-Oncology consortium (PNOC). PNOC consists of 11 premier Children’s Hospitals within the US that all have internationally recognized brain tumor programs. We will profile each child’s tumor with state of the art next generation sequencing and determine a treatment plan based on the specific characteristics of the tumor. This precision medicine trial will answer if this approach results in clinical benefit. Additionally we will be able to address the question: if treatment fails, why it fails. To study this we will take biopsies from different parts of the tumor and assess if there are regional differences in the tumor’s genetic make-up, and compare molecular profiles of newly diagnosed and recurrent tumors. We will develop cell lines and animal models for each tumor that will be made available for preclinical testing to further explore mechanisms of treatment failure. Results of this trial may change how we approach these tumors and lay the groundwork for the next set of clinical trials for these children as these technologies continue to develop.
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.
V Scholar Plus Award- extended funding for exceptional V Scholars
Myeloproliferative neoplasm (MPN) is a chronic blood cancer without curative treatments. In MPN, blood stem cells obtain mutations that result in excessive numbers of blood cells. Mutations in a gene named calreticulin have been recently found in a large percentage of MPN patients. It is unknown how calreticulin mutations drive MPN. Our goal is to identify how calreticulin mutations cause MPN and to develop drugs targeting calreticulin to treat this disease.
V Scholar Plus Award- extended funding for exceptional V Scholars
Aggressive lymphomas are cancers of white blood cells. The most common type is called diffuse large B cell lymphoma (DLBCL). Most patients with DLBCL can be cured by chemotherapy, but some patients either do not respond to treatment or the disease comes back after a certain time (‘relapse’). If we can identify those patients likely to relapse earlier, we hope to improve their chance of survival. Circulating tumor DNA (‘ctDNA’) is DNA that comes from tumor cells and gets in the blood stream. CtDNA in the patient’s blood can be analyzed to get more information about the tumor. In this study, we developed a blood test to profile ctDNA at different stages of the disease and to identify patients at risk for relapse. We found that ctDNA in the patient’s blood contains information that can be used to tell how well the patients will do with chemotherapy. We also observed that analysis of ctDNA over the course of treatment could show how their lymphomas change over time. For example, we detected new mistakes (‘mutations’) in ctDNA that could be used as an early signal to predict that certain treatments would no longer work in these patients. Also, we found that ctDNA in the blood after treatment predicts disease relapse months earlier than any other clinical method. Our test can also give physicians early warning that the tumor is changing from a slow growing to a fast growing lymphoma type. All this information in ctDNA can be used to learn more about lymphoma biology and to find patient groups with high risk for relapse.
Each year in the United States over 30,000 patients with breast cancer are treated with a class of drugs known as the anthracyclines. The anthracyclines are one of the oldest and most effective chemotherapies for breast and other cancers. However, some patients do not benefit from this therapy for reasons that are not understood. Moreover, because the anthracyclines target TopoII isomerase (TopoII), a remarkable protein that is vital for normal cellular functions such as untangling DNA, they can have serious side effects. Recently, we have found that we can predict whether cancer cells will respond to TopoII inhibitors based on their genomic profile. Our over-arching goal is to spare patients treatment with this highly toxic class of drugs if they will not benefit from their use. By performing a simple genomic test on the patient’s tumor sample obtained at the time of diagnosis, we aim to predict which patients will benefit from anthracyclines and thereby inform treatment decision-making. In this manner, treatments can be personalized so that patients receive the best possible current therapy to treat their specific tumor, while being spared ineffective drugs and their side-effects.
This research will help us improve a new type of therapy for children with neuroblastoma. Neuroblastoma is a deadly tumor in the nervous system outside the brain. With this therapy doctors administer both chemotherapy and a protein (antibody) that attaches to tumor cells at the same time. This combination, a form of chemo-immunotherapy, was tested on children whose tumors had not decreased even after many rounds of chemotherapy. These children would have died, but chemo-immunotherapy literally melted the tumors off after a few rounds of treatment. The results of this study have not been published yet but are already being used by doctors to successfully treat these children.
Despite this great outcome, half of the children did not respond to the new treatment. There is still a lot to learn about chemo-immunotherapy. In this study, we will test patients’ tumors and find out how their blood cells change with chemo-immunotherapy. We hypothesize that chemo-immunotherapy is assisted by white blood cells destroying tumor cells. Our goal is to study how tumor cells stop or slow down the effect of this therapy. If we are successful, we can modify chemo-immunotherapy to work in all children with neuroblastoma.
A set of proteins are highly active in cancer. They can add small groups to a series of target proteins. These uncommon additions are often linked with tumors found in breast, liver, and other tissues. To date, it is still unclear how those aberrant proteins cause cancer. To answer this question, it is crucial to know all the targets that they act on in live cancer cells. But no method has been made available to resolve this key issue. In this project we are aimed to create an innovative platform to achieve this goal. Our research plan will use chemistry and biotechnology to make new tools for target identification. A particular member in this group will be chosen for this work. Because it shows much higher activities in diverse types of cancer. The full range of targets for this protein in live cancer cells will be clearly assigned for each specific type of cells. Moreover, the patterns, levels, and time courses of such additions in live cells can be directly viewed and precisely measured by our creative approach. These findings will lead to unveil the interaction networks of this cancerous protein to guide our further studies. The fundamental knowledge obtained from this work will advance our understanding of cancer. Importantly, it will foster the development of new approaches for cancer detection and treatment.
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