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.
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.
The administration of a subset of human immune cells cultured in the laboratory and known as T lymphocytes that have been engineered to express a chimeric molecule that recognizes tumor cells has shown remarkable antitumor effects in patients with blood tumors. Although there is much promise in these therapies, there is still a need for improvement in safety and efficacy. This project is important to patients because it examines a considerable challenge with these therapies, e.g. their toxicities. The way toxicities are being addressed in this project is unique and holds the promise of alleviating many severe side effects experienced by patients. Additionally, controlling toxicities will be extremely important to the success of treating patients with solid tumors when normal tissues may be targeted. So, there are many advantages to the “safety switch” approach that we propose in this application to alleviate side effects.
Funded by the Stuart Scott Memorial Cancer Research Fund
Obesity and diabetes are associated with increased risk and worse outcomes for endometrial cancer (EC). African American (AA) women suffer a higher mortality from EC than Caucasian (CAU) women, and this may be in part due to greater rates of both obesity and diabetes among AA versus CAU patients. Metformin is a drug used in the treatment of type 2 diabetes. Our preliminary data finds that metformin has anti-cancer activity, due to its indirect effects within the body (decreased insulin/glucose) and direct effects on EC cells through inhibiting signaling pathways involved in metabolism, including suppression of fatty acid/lipid biosynthesis. Thus, it is logical that metformin may break the link between obesity and EC and emerge as a new targeted agent for the treatment of this cancer.
Our overall goal is to assess the contribution of indirect effects (via decreasing insulin and glucose levels) and direct effects (via inhibition of metabolic pathways and blunting of fatty acid/lipid biosynthesis) of metformin to its overall anti-cancer efficacy in (i) a clinically relevant EC mouse (obese/lean) model and (ii) an ongoing randomized phase 2/3 clinical trial evaluating metformin versus placebo, in combination with standard of care paclitaxel/carboplatin for the treatment of EC. We hypothesize that predictors of metformin response will include both molecular and metabolic biomarkers, specifically obesity, insulin resistance, upregulation of insulin/glucose signaling and heightened fatty acid/lipid biosynthesis, and this response may differ according to race. From this work, we hope to validate metformin as an innovative treatment strategy for obesity-driven EC.
