State: North Carolina

Funded by the Kay Yow Cancer Fund

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.

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 treatment has dramatically changed, particularly with the introduction of immunotherapies aimed at jump starting a patient’s immune system to fight cancer. Along with the development of new treatments, biomarkers have become increasingly important to disease sub-typing and evaluation.  EGFR, ALK, and ROS1 are genes that can be mutated in patients with non-small cell lung cancer and serve as biomarkers.  An individual’s tumor may have one or many mutations. The mutational landscape of the tumor has been shown to be an important determinant of response to immunotherapy.  PD-L1 also serves as a biomarker, but there have been mixed results as to whether PD-L1 is appropriate for selecting immunotherapy treatment.  Microsatellite instability (MSI) and mismatch repair (MMR) are new markers and may also predict response to therapy.  Combinations of new and existing biomarkers may be better indicators of response to immunotherapies.

Many factors may contribute to the complex makeup of a patient’s immune response and each patient’s response may differ.  Factors that may influence response include the patient’s own baseline immune landscape, age, gender, race, or environment.

Assessing biomarkers from patient’s blood and tumor samples may guide immunotherapy selection and treatment duration to optimize overall patient benefit.  This study will assess the predictive utility of our blood immune response test to select patients appropriate for immunotherapy, as well as manage treatment over time.  Of importance, this study will assess samples across patient populations, including African Americans, longitudinally and will evaluate differences in immune landscapes and how biomarkers may determine treatment.

2017 C30 Program Grant

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.