Sabine Mueller, M.D., Ph.D.

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.

Megan McNerney, M.D., Ph.D.

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.

Megan McNamara, MD and Daniel George, M.D.

Funded by friends of TK and Virginia Wetherell

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.

Tao Lu, Ph.D.

Funded by the Kay Yow Cancer Fund

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.

Corinne Linardic, M.D., Ph.D.

Funded by the Apple Gold Group

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.

Andrew Lane, M.D., Ph.D.

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.

Randy Kimple, M.D., Ph.D.

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.

Michael Kastan, M.D., Ph.D.

Funded by Genentech and matched funds from the V Foundation

The Duke Cancer Institute and the College of Veterinary Medicine at N.C. State University formed a Comparative Oncology Consortium (COC), taking advantage of their expertise and national leadership in their respective disciplines and their geographic proximity. The goals are to collaborate in pre-clinical and clinical cancer research activities in order to advance our understanding of both cancer causation (a high incidence of specific cancers in specific dog breeds provides opportunities to identify new cancer susceptibility genes and environmental factors in cancer causation) and of behaviors and genetics of specific tumor types, as well as to coordinate clinical trials in humans and canines so that novel therapies can be tested in both settings, with information gained in one setting informing the other. In addition to response outcomes of these cancer therapies, the ability to use biomarkers and pharmacology in the canine models can be a novel addition to the characterization of these new cancer therapies and these insights could result in significant enhancements of clinical trial designs (including dosing, scheduling, and combination therapies) when these treatments are tested in human clinical trials. Cost savings and improved clinical trials design would help encourage pharmaceutical companies to use the canine models as part of the assessment process and would benefit the canine patients by giving them access to these novel therapies.

Wenjun Guo, Ph.D.

V Scholar Plus Award- extended funding for exceptional V Scholars

Cancers are diseases caused by faulty genes. Finding these faulty genes will provide effective targets for treatment. To this end, researchers have discovered many gene mutations in all kinds of cancers. However, cancer cells can acquire random mutations, as they are highly unstable. Thus, it is critical to find out which mutations play a causal role in cancer.

To address this problem, we have developed a novel method for studying cancer mutations. We used stem cells to create breast cancer models carrying patient relevant mutations. Using these models, we will study which mutations are responsible for the resistance to cancer treatment. We focus on the treatment that block an important cancer gene, PI3 Kinase. Faulty activation of this gene has been found in many breast cancers. Thus, it is an important cancer target. We have found a specific gene mutation that causes the resistance to this treatment. In this project, we will understand how does this mutation cause the resistance. Based on our mechanistic finding, we will also develop new strategies to overcome the resistance. Thus, successful outcomes of our study will aid the development of effective cancer therapies.

Steven Grant, M.D.

Funded by Virginia Vine 2016

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.

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