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.
Ovarian cancer (OC) is the deadliest gynecological cancer. The standard treatment approach for epithelial OC is the combination of a platinum compound, mainly carboplatin and taxane. Although most women initially respond well to treatment, the vast majority experience disease recurrence within 2 years, resulting in a fatal relapse due to chemoresistance. Thus, the development of carboplatin resistance is a major barrier in OC treatment. To date, no effective approaches have been developed to overcome carboplatin resistance. We hypothesize that high expressions of some key proteins lead to carboplatin resistance in OC. Recently, we have developed the innovative validation-based insertional mutagenesis (VBIM) technique for novel gene discovery. In this proposal, our overall objective is to use the VBIM technique, in combination with bioinformatics and other advanced approaches, to identify key proteins that lead to carboplatin resistance in OC cells. Human OC cell lines and OC tumor tissues will be used as our research tools. Overall, our unique and comprehensive approach could yield a set of completely novel carboplatin resistance proteins which might not be discovered using traditional methods. The important findings generated from this work will guide physicians to design more rational and precise therapies with greater effectiveness in a specific OC patient. Moreover, this work could open future opportunities for reversal of carboplatin resistance by developing small molecule inhibitors. Therefore, this work would have a fundamentally transformative effect on OC chemotherapy.
Rhabdomyosarcoma is a connective tissue cancer with features of skeletal muscle, and the most common soft tissue cancer of childhood and adolescence. While most children with the embryonal variant of rhabdomyosarcoma are cured, there is a sub-group of children with high-risk features, making their chance of survival less than one in three. One hypothesis underlying these high-risk features is that there are rhabdomyosarcoma stem cells that can persist in the body despite current standard therapy. A goal of our research laboratory is to identify the cellular pathways that contribute to this persistence of rhabdomyosarcoma stem cells. Over the past several years we have observed that some cellular pathways active during normal skeletal muscle development have been hijacked by embryonal rhabdomyosarcoma cells. We even think that these development pathways communicate with one another to support and reinforce rhabdomyosarcoma stem cells. Our aim in this project is to understand how these cellular pathways communicate with one another, whether they can be inhibited by gene manipulations or pharmacologic agents, then test combinations of these treatments in rhabdomyosarcoma cells in culture and in laboratory mice. We hope to someday translate these findings to clinical trials, opening the door to new treatments for children with this disease.
V Scholar Plus Award- extended funding for exceptional V Scholars
Most cancers occur more often in males than in females. We don’t understand why. It isn’t explained by differences in cigarette smoking, for example. Males have two different “sex chromosomes,” called X and Y. Females have two copies of X, but no Y. We think that the X and Y chromosomes influence cancer risk and might explain why some cancers are more frequent in men. We studied cancer cells and were surprised to find that some patients had an excess of mutations in genes that “live” on the X chromosome. 100% of those patients were men. In this study, we will look at mutations on X and Y from thousands of patients with many types of cancer. Differences between men and women could explain some of the disparity in cancer incidence between the sexes. These findings may be relevant in cancers that are more frequent in men, including leukemia, brain tumors, kidney cancer, and bladder cancer. In addition, we will study these genes in the laboratory, comparing male and female cells. We will ask how sex differences in mutations on the X chromosome contribute to cancer. We hope that our research discovers new ways to prevent or treat cancer. Specifically, we want to understand why men and women might have different rates of developing cancer. This work might lead us to consider that men and women with the same type of tumor might best be treated differently.
V Scholar Plus Award- extended funding for exceptional V Scholars
Our lab is focused on improving treatment for patients with head and neck cancer. This project is studying cells that allow a cancer to spread to other parts of the body (i.e. metastasize). We believe that these same cells, termed cancer initiating cells or CICs, are also resistant to standard treatments. The first two years of V Foundation support has been very helpful. Using cells growing in plastic dishes and mice we have found a key pathway that CICs use to survive anti-cancer treatments. This same pathway also helps these cells to spread to other parts of the body. Our goal for the next year is to study these pathways in human cancers. We will study whether the genetic information that controls CICs in our models can be used to identify them in human tumors. We want to learn whether tumors with more CICs are more resistant to standard treatments. Finally, we will use tissues from actual patients to study whether patients whose tumors have more CICs are more likely to have aggressive cancers. These experiments will allow us to identify new ways to treat these cancers. We hope to improve our ability to select the right treatment for an individual patient.
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