During the process of cancer transformation, cells hijack their internal metabolic pathways in order to utilize nutrients for the purpose of providing energy and building blocks required for rapid growth. In this V Foundation Award, we propose to use mass spectrometry to provide unprecedented insight into the activities of hundreds of metabolic enzymes in living cells as they become cancerous. We will use this information to identify unique metabolic vulnerabilities in cancer cells, essentially determining those metabolic processes that are required to sustain life and growth in cancer cells but not normal, non-cancerous cells. Ultimately, the work will allow us to design new dietary interventions and pharmacologic agents that selectively target the metabolism of cancer cells, including in breast cancer and colon cancer.
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.
