There is a low number of people involved in clinical studies. This is a national problem. This problem plays a part in poor health for people with cancer. It is even more of a problem for people of color who do not take part in clinical studies at the same rate as whites for several reasons. Some of these reasons include fear and not knowing about clinical studies. Also, some current and past research studies did not tell people of color the truth about the study and caused high rates of sickness and death in some cases. These reasons play a role in some people deciding not to take part in a study. Some people of color are not involved with clinical studies because they were not asked. Research teams may not ask people of color due to bias that they may not be aware of or concerns about trust. Studies show that most people who take part in a study do so because they were asked. The main reason people do not enroll in clinical studies is because they were not asked and did not know anything about it.
Studies suggest there is a need to teach research teams how to build skills in working with people of color. There is a need to build trust between patients and clinical staff as well as learn ways to increase the number of people of color enrolled in studies. The Just Ask: Diversity in Clinical Research Training Program works with patients, the community, and research teams to build skills and increase the number of people of color in clinical studies.
Funded in partnership with the Lung Cancer Initiative of North Carolina, utilizing Stuart Scott Memorial Cancer Fund matching funds
Lung cancer causes more deaths than the next three cancers combined, and small cell lung cancer (SCLC) is the most aggressive type. Lung cancer disproportionally affects African Americans. Existing therapies prolong life, but only by months, and at the cost of substantial side effects. Within the immune system, T cells are particularly important for fighting cancer, but in patients with SCLC, neither the native immune system alone, nor with augmentation with existing immunotherapy, controls cancer durably. CAR-T is an exciting new technology that modifies a patient’s own T cells to recognize and attack cancer cells that bare a particular marker. This technology has revolutionized the care of some lymphomas and leukemias, including cures.
We have made a CAR-T for the treatment of Glioblastoma Multiforme because it bears a particular marker, GD2. 60% of SCLC also has GD2 and so we hypothesize that for these patients, GD2-directed CAR-T could provide dramatic tumor regression. Our cancer center has committed funding to a clinical trial if we can provide the necessary data to support it. More specifically, we would like to treat animal models of human SCLC with the proposed therapy to see if it is safe and effective. We would study where the CAR-T cells go and how well they kill cancer cells. The CAR-T contains a safety switch in case of side effects; we would test to make sure that it works. During the resulting human trial, we also seek funding to assess where the T cells go.
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.
Prostate cancer is currently the second leading cause of cancer death in men in USA. Although surgical intervention and other first-line therapies for prostate cancer have improved over the past decades, there is still no effective cure for patients suffering from advanced/recurrent disease. Prostate cancer, like other cancers, is a heterogeneous disease such that individualized/precision medicine is likely to benefit patients. Our data indicate that a subset of prostate cancer exhibits reduced expression of a protein (cGAS) known to be involved in the response of cells to viral or bacterial infection. Importantly, lower expression of cGAS is correlated with prostate cancer recurrence, suggesting that loss of cGAS reduces efficacy of therapy. Interestingly, low cGAS is associated with poor outcome in lung cancer as well. In this proposal, we present preliminary data strongly supporting novel tumor suppressor roles of cGAS in prostate cancer functioning in individual cancer cells. We will fully investigate the underlying regulatory mechanisms and biological effects of the loss of cGAS in prostate cancer, along with the initial exploration of therapeutic vulnerabilities associated with this dysregulated pathway. We are hopeful that our studies will enable new therapeutic options for prostate cancer patients, with potential relevance to a subset of lung cancer.
“Spirit of Jimmy V” Award funded by the Dick Vitale Gala in honor of Holly Rowe
Fusion-positive rhabdomyosarcoma is driven by a specific fusion gene called PAX3-FOXO1 that acts as a powerful cancer driver. Unfortunately, this fusion gene is not yet able to be targeted directly with drugs. In fact, clinical trials over the past several decades have failed to improve the 5-yr overall survival rate for patients with fusion-positive rhabdomyosarcoma, which remains <50% for all-comers and <10% when metastatic. Prior work from our laboratory revealed that the Hippo pathway, a signaling network that in development ordinarily regulates the growth of organs and tissues, is turned off by PAX3-FOXO1. With Hippo turned off, pro-growth signals are left unchecked and cells become stimulated to proliferative. One of the main signals that gets activated by silencing of Hippo is TAZ, which is a powerful co-activator of cancer-promoting genes. We have seen that TAZ promotes resistance to chemotherapy and regulates the rhabdomyosarcoma cancer stem cell population. Our current studies, which utilize a variety of molecular biology and biochemical approaches in several cell culture and mouse model systems, aim to determine mechanisms by which TAZ controls chemoresistance and stemness. Ultimately, we are seeking to find vulnerabilities within the TAZ/PAX3-FOXO1 axis that can be exploited as novel therapies.
First year of this Vintner Grant funded by the 2018 V Foundation Wine Celebration in honor of Robin Lail
Triple negative breast cancer (TNBC) is breast cancer that lacks HER2 and ER/PR receptors. Because most treatments are based on having these markers, TNBC is hard to treat. Additionally, TNBC often spreads to the brain (brain metastasis), which is even harder to treat. Radiation therapy (RT) is a standard local therapy for TNBC brain metastases; however, survival is less than 6 months.
Immune cells (found throughout the body) fight invaders like viruses, bacteria and cancer. However, cancer cells are highly adept at hiding from immune cells. Immunotherapies are being tested to help immune cells fight cancer better. There have been promising results using immunotherapies to treat brain metastases. We have shown that TNBC brain metastases have a higher number of immune cells called tumor infiltrating lymphocytes (TILs) compared to TNBC in breasts. More importantly, we found that patients with a higher number of TILs in their brain metastases live longer. Adding RT to immunotherapies can help immune cells to fight cancer. We will use mouse models to test this strategy, which will lead to a clinical trial in humans. We expect immunotherapy will also treat cancer inside and outside of the brain at the same time, which will improve the lives of patients facing this disease. We also want to find more signals in brain metastases (biomarkers) that will guide selection of the right immunotherapy for each patient. New biomarkers will help us treat the right patient, at the right time, in the right way, with immunotherapies.
Breast cancer is the most common cancer among women in general and among older women in particular. Adjuvant chemotherapy has played a major role in improving survival in both younger and older patients, but in older women, especially, its associated toxicities can lead to declines in function, quality of life, and even survival. For clinicians treating older women with a breast cancer diagnosis, how their patients survive and thrive during and after adjuvant chemotherapy is as important as preventing cancer recurrence and prolonging life. Toxicities that result in decreased physical activity and increased fatigue can lead to chronic detrimental changes in body composition, including loss of lean body mass, loss of muscle mass, and an increase in adipose tissue. Interventions to decrease these risks are needed. The overall goal of this research is to identify whether a home-based physical activity program initiated during adjuvant chemotherapy can attenuate the molecular and clinical consequences of adjuvant chemotherapy on the aging process in a sample of breast cancer patients age 65 or older. Specifically, this study will investigate the impact of an exercise program-a simple walking program that can meet the exercise needs of older cancer patients-on changes pre-and post-chemotherapy: (1) in a gene that is a dynamic biomarker of aging (p16INK4a) and (2) lean body mass, physical function, fatigue, and quality of life. The study will also evaluate how data from a wireless activity tracker correlates with measures of physical function and quality of life during chemotherapy. if it is shown that this easy-to-implement physical activity intervention can maintain function and lessen toxicity among older breast cancer patients receiving chemotherapy, it would be ideal for incorporation into adjuvant treatment in both academic and community-based cancer care settings.
Recently, researchers in the program have discovered a synthetically accessible class of molecules that appear to increase the effects of novel anticancer drugs by several orders of magnitude. The overarching goal is to reduce the working concentrations of ALL anti-cancer drugs in order to mitigate serious side effects. Here, we propose to develop and screen our new molecules with both novel and existing chemotherapeutics against a variety of cancer cell lines in order to define the optimum combination treatment. Also we are working on tumor formation. The life and death of cells must be balanced if tissue homeostasis is to be maintained-there should neither be too much growth nor too little death. Normal cells accommodate this balance by invoking intrinsic programmed cell death, referred to as apoptosis. Apoptosis is triggered via three signaling pathways. If apoptosis does not occur correctly and cells do not die, then malignant tumors form. It is no surprise therefore that countless cancer therapeutics are being developed to control apoptosis. It is known that all three apoptosis signaling pathways route through a protein known as caspase-3. If caspase-3 fails to function, then cell death does not happen correctly and cancer occurs. It is known that a calcium-binding protein known as calbindin-D28K binds to caspase-3 and stops it functioning. If we can stop calbindin-D28K from interfering with caspase-3, apoptosis would occur normally and the risk of cancer developing would be significantly reduced. Consequently calbindin-D28K is a particularly powerful target for anticancer drug development.
Funded in partnership with the Buster and Kristen Posey Fund with support from Apple Gold Group
Despite numerous clinical trials for children with high grade glioma, including diffuse pontine glioma, either at initial diagnosis or recurrence, over the past 4 decades, there has been little improvement in patient outcome. In contrast, in the past few years major advances have been made in understanding the molecular underpinnings of these tumors. Specific, gene mutations in the genes encoding the histone H3.3 (H3F3A) and H3.1 (HIST1H3B, HIST1H3C) variants, along with BRAF V600E, mark distinct subgroups of disease in children and young adults. This proposal will combine our innovations in the clinic using the genetically recombinant poliovirus PVSRIPO with targeting technology aimed at these exploiting these mutations as targets.
In the currently accruing adult trials and the planned initial pediatric high grade glioma trial, PVSRIPO is administered by delivery into the tumor, via a surgical approach. In many pediatric glioma patients, diffuse infiltrating growth or location (e.g. diffuse intrinsic pontine gliomas; DIPG) precludes such intra-tumoral administration.
We plan to test a modified PVSRIPO technology for peripheral immunization with tumor-specific targets to create a viable alternative in pediatric brain tumors. We have recently developed robust technology to modify PVSRIPO for use as an immunization vector and have demonstrated PVSRIPO vectors do not require intratumoral administration and are able to generate tumor antigen-specific immune responses. These discoveries will enable us to develop virus based vaccination strategies for pediatric brain tumor patients where tumor-specific antigens are homogeneously expressed.
Funded in partnership with the Lung Cancer Initiative of North Carolina, utilizing Stuart Scott Memorial Cancer Fund matching funds and the Richard Jones Fund for lung cancer
Lung cancer remains a major cause of cancer mortality worldwide, and in 2017, 155,870 people are expected to die from lung cancer in US. African Americans have the highest lung cancer incidence and lung cancer-related death rate and develop the disease at an earlier age compared to other racial groups. African Americans also have poorer survival, because of limited access to lung cancer screening, adequate healthcare, and appropriate therapeutic interventions. Etiology studies suggest that such a disparity in lung cancer may be due to genetic susceptibility, in addition to environmental exposures to cigarette smoking, radon, asbestos, and arsenic. Recently, we identified a novel gene, DCAF4, through a large-scale meta-analysis in Caucasian populations, which is likely to be involved in cell-cycle control and DNA damage response that is relevant to African Americans as well. Our hypotheses are that dysfunctional DCAF4 impacts cancer initiation and progression by altering multiple cellular processes and that DCAF4 functional variants alter gene expression and tumor cell phenotypes, which may explain racial disparity in lung cancer. Therefore, we proposed to study the functions of this gene and its risk-associated genetic variants on cellular phenotypes in lung cancer cells, animals and human clinical samples of lung cancer. We will test the hypotheses that dysfunctional DCAF4 impacts cancer initiation and progression by altering multiple cellular processes and that DCAF4 functional variants alter gene expression and tumor cell phenotypes. By including clinical samples from both Caucasians and African Americans, we hope to identify genetic markers for disparity in lung cancer.
