V Scholar Plus Award- extended funding for exceptional V Scholars
Cancer is an abnormal state wherein cells become uncontrolled in their ability to divide, grow and cross tissue borders. These cellular processes are governed by an array of signaling proteins including KRAS. Mutations in the KRAS protein result in uncontrolled signaling leading to cancer. KRAS mutations are some of the most common causes of many types of cancer. However, researchers have struggled to discover ways of treating tumors driven by mutant KRAS. The goal of this project is to develop new drugs that directly target mutant KRAS proteins. We will focus on two mutations. One is common in lung cancer, KRAS G12C. The other is common in gastrointestinal cancers, KRAS G13D.
“Precision medicine” aims to develop better treatments by understanding the molecular causes of disease. This is essential in cancer because each type (breast, brain, or blood cancer, for example) represents dozens of different kinds of cancer at the molecular level. And each of these different molecular sub-types requires different treatments.
Based on research of the past twenty years, we understand a great deal about what drives cancers. Many drugs have been devised that specifically target these causes – molecular “smart bombs.” However, the cancer cells rapidly adapt and find escape routes. Drugs that seem to work ultimately fail. We get many hopeful responses but few cures.
Our research seeks to identify and block these escape routes. We look at the molecular changes inside cancer cells after drugs are applied, and we then use other drugs to “slam the door” so the cancer cannot escape treatment. Our approach is already proving successful: We are testing one of these combinations in people to treat Mantle Cell Lymphoma. We propose to look at similar cancers that might benefit from this approach. We also want to better understand ways that cancer cells might escape from our combination treatments. Our goal is to improve responses to therapy and turn temporary responses into real cures.
Funded by the Stewart J. Rahr Foundation PCF Challenge Award:
co-funded by The Prostate Cancer Foundation and
the 2016 V Foundation Wine Celebration Fund a Need
Nearly all patients with metastatic castration resistant prostate cancer (mCRPC) develop resistance to androgen targeting agents and ultimately succumb to their disease. Recent discoveries by our group and others have demonstrated that a significant proportion of these patients harbor somatic or germline genomic defects in DNA repair defects, and targeting this genomically defined subset with therapies affecting this pathway may impact patient care. The goal of this project is to definitively characterize the genomic and functional landscape of DNA repair defects in mCRPC, clinically test the hypothesis that tumors harboring DNA repair defects preferentially benefit from immune checkpoint blockade, and explore innovative strategies to augment the efficacy of these agents through genomic and preclinical approaches. The project described herein is the first to comprehensively bridge the DNA repair and immuno-oncology fields to directly impact patients with advanced prostate cancer. We propose an integrated strategy that leverages advances in clinical genomics, trial design, and preclinical modeling methodology pioneered by our team. Furthermore, our proposal will be the first to specifically enable immune checkpoint blockade treatment strategies for mCRPC. In summary, this project will catalyze our understanding of how DNA repair defects impact advanced prostate cancer, and how deep knowledge about these events may enable clinical development of a transformative new class of immunotherapies that are greatly needed for advanced prostate cancer patients.
This project attempts to use advanced analytical software (IBM’s Watson) to provide a comprehensive picture of our metastatic breast cancer patient population over a 5 year period at the Moffitt Cancer Center. The projects aims are to capture this dataset over the course of a year and enter in many different data points about the patients. These data points describe what this population of patients looks like from the perspective of an oncologist determining how many of them are eligible for any given trial that they have open. With this information we can use Watson to generate a detailed report to help us understand what types of patients we see, how those groups have changed over time, and most importantly what trials can we seek out to best match up with the patients we see at our center. The goal is to use data analysis to help us plan what mix of different trials we need to open in the future to best serve our patients’ needs.
Funded in honor of Nick Valvano by a challenge grant with
The University of North Carolina at Chapel Hill.
Personalized medicine for cancer patients is a current goal of biomedical research. A few gene expression-based assays have already proven to have clinical utility (i.e. value), especially for breast cancer patients (see 2016 ASCO biomarker guidelines). Therefore the continued discovery and clinical development of additional gene expression assays could be an important aspect for furthering personalized treatments. Here we propose to develop a new generation of gene expression-based assays for possible use in cancer care. The goal of this proposal is to further develop and test a genome-wide RNA-sequencing assay and it’s companion bioinformatics tool, for the automated classification of a tumor according to 300 different expression signatures. These signatures span a broad range of biological phenotypes including the microenvironment (immune cells, fibroblasts), tumor features (growth factor signaling pathways), and of cancer stem cells. Some of these 300 signature may eventually be of clinical value, and so in this proposal we will create a new technological platform with linked bioinformatics, to provide these signatures as new potential biomarkers for future clinical testing.
utilizing Stuart Scott Memorial Cancer Fund matching funds
While newer treatments for some types of lung cancers have improved patient survival, similar advances in squamous cancers of the lung, head and neck have been slow. Recent studies of the genes that characterize squamous cancers have revealed they are very complicated with no clear “smoking gun” way of attacking them. However the use of new therapies that activate the immune system has demonstrated exciting promise in squamous cancers.
We have found a new class of squamous cancers whose tumors take advantage of the immune system. We have created a list of genes that identifies patients with these types of cancers. This is the basis for a clinical trial we are developing. However, an important unmet need in North Carolina is an improved understanding of squamous cancers in black patients.
We believe that our list of genes will help determine whether black patients will benefit from immune therapies. We also believe that the amount of CD14 protein in their tumors, which is found on certain immune cells, will be helpful for a clinical trial we are creating. Building off of ongoing and upcoming clinical trials, the objectives of this proposal are to determine in black patients with squamous cancers whether our gene signature predicts for benefit to immune therapies already available to our patients. We also plan to find out whether the CD14 protein on these tumors will be useful for a clinical trial we are developing.
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.
V Scholar Plus Award- extended funding for exceptional V Scholars
Each year over 50,000 people develop a myeloid blood cancer in the United States alone. Some of these cancers have lost all or a portion of genetic material on chromosome 7 [known as -7/del(7q)]. These patients are difficult to treat. The survival for these patients is less then one year. -7/del(7q) also occurs in half of therapy-related myeloid cancers (t-MN), which arise as a side effect of cancer treatment. There is clearly an urgent need to develop new therapies for this disease. The long-term goal of the current work is to improve the outcome for patients with myeloid blood cancer. I used new technology to identify an important gene on chromosome 7, called CUX1. CUX1 normally puts the brakes on cell growth. My lab is identifying CUX1-regulated pathways that may be drug targets. We are establishing animal models of myeloid cancers for testing new therapies. The significance of this work is not limited to blood cancer. A wide range of tumor types also has CUX1 deletion. Thus, our work on CUX1 will guide our knowledge of the role of CUX1 in cancer in general.
This is a study to investigate the number and volume of injections necessary to achieve distribution throughout prostate cancer metastases and to assess the expression of the poliovirus receptor in prostate cancer. Men with metastatic castrate resistant prostate cancer and at least one bone, lymph node, or liver metastasis measuring between 2 and 8 cm will be enrolled in the study. Gadolinium, a standard type of MRI contrast, will be injected into one metastasis (bone, lymph node, or liver) per patient, and a follow-up MRI will be done to evaluate for distribution of the gadolinium throughout the metastasis. A biopsy of the metastasis will be obtained at the time of the gadolinium injection, and the biopsy specimen will be analyzed for expression of the poliovirus receptor. The results of this study will be used to plan the injections in a future prostate cancer clinical trial of an anti-cancer therapeutic vaccine.
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