State: North Carolina

Funded by friends of TK and Virginia Wetherell

Metastatic castration resistant prostate cancer (mCRPC) – prostate cancer which is resistant to androgen deprivation therapy – can be often aggressive and lethal. The androgen receptor (AR) has an important role in the disease course of prostate cancer, since both enzalutamide and abiraterone acetate improve overall survival by exerting effects on the AR pathway. Our preclinical data shows that AR can increase proteins that are needed maintaining copper balance, such as the copper transporter protein, which we found in prostate cancer samples. To take advantage of the copper biology in prostate cancer, we performed a “conditional lethal” screen for drugs that exert their cancer-killing effects based on the presence of copper. This screen identified disulfiram “Antabuse”, as a potential drug for prostate cancer. Antabuse has been tested before in prostate cancer but never in the presence of copper. Mouse models of prostate cancer have shown that those cancer masses can shrink when Antabuse is given along with copper. Therefore, we propose to study the combination of Antabuse and intravenous copper, to find the safety profile for this combination of drugs. In addition, we will study the copper uptake of these patients’ prostate cancers using a radiolabeled copper PET scan. These studies will allow us to see whether the baseline copper uptake of a patient’s prostate cancer is linked to their response on the combination of Antabuse and intravenous copper.

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.

Funded in partnership with

the Lung Cancer Initiative of North Carolina

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.

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.

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.

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.

Funded in partnership with

the Lung Cancer Initiative of North Carolina

utilizing Stuart Scott Memorial Cancer Fund matching funds

Lung cancer is more common and deadly in African American patients compared to other racial groups. One reason for this difference may depend on the genetics of the tumor and how genes are expressed. We plan to study lung cancer samples to find differences in genes between African American and Caucasian tumors. We will also use a ‘Just Ask’ cultural training program to improve the engagement of African‐American lung cancer patients in research and tissue banking. Our hope is that this work will improve the understanding of reasons for racial differences in lung cancer. We hope that by studying the gene expression of tumors we will find new ways to treat patients with lung cancer in the future.

Funded by the Apple Gold Group

Neuroblastoma is the third most common childhood cancer. Unfortunately, despite intensive treatment, two-thirds of children with advanced neuroblastoma succumb to their disease. New treatment options must be developed to improve outcomes in this devastating disease. This requires a better understanding of how neuroblastoma cells survive in the face of these intensive therapies. N-Myc is a member of a family of proto-oncogenes (genes capable of leading to cancer development) implicated as a cause of several cancers. N-Myc plays a central role in the aggressiveness of neuroblastoma tumors. Children whose neuroblastoma tumors have extra copies of the N-Myc gene (N-Myc amplification) fare worse than children whose tumors have the normal number of N-Myc genes. However, it is unknown why extra N-Myc leads to poor outcomes. Mxi1 is a protein related to the Myc family, however, it counteracts the ability of N-Myc to cause cell growth. Mxi0 is a similar protein, but it does not inhibit N-Myc like Mxi1. In this proposal, we will test the hypothesis that the balance of Mxi1 and Mxi0 expression is important for maintaining normal growth, and that N-Myc alters this balance, leading to treatment resistance. To accomplish this, we developed a new kind of mouse which has its Mxi1 or Mxi0 genes removed. In this project, we will examine the impact of decreasing Mxi1 or Mxi0 expression on neuroblastoma tumor formation and response to treatment, with the overall goal of finding a mechanism to bypass the effects of N-Myc and improve the outcomes of children with neuroblastoma.