O2M Webinar: Evaluating the Effects of Papaverine on Tumor Oxygenation and Radiosensitization in E0771 Breast Cancer and Primary Sarcoma Mouse Models Using JIVA-25 | Greg Palmer, Ph.D., Yvonne Mowery, M.D., Ph.D., & Ashlyn Rickard, Ph.D., Duke University
Evaluating the Effects of Papaverine on Tumor Oxygenation and Radiosensitization in E0771 Breast Cancer and Primary Sarcoma Mouse Models Using JIVA-25
Moderated by: Dr. Marty Pagel, MD Anderson Cancer Center
About the Speakers
Greg Palmer obtained his B.S. in Biomedical Engineering from Marquette University in 2000, after which he obtained his Ph.D. in BME from the University of Wisconsin, Madison. He is currently an Associate Professor in the Department of Radiation Oncology, Cancer Biology Division at Duke University Medical Center. His primary research focus has been identifying and exploiting the changes in absorption, scattering, and fluorescence properties of tissue associated with cancer progression and therapeutic response. To this end he has implemented a model-based approach for extracting absorber and scatterer properties from diffuse reflectance and fluorescence measurements. More recently he has developed quantitative imaging methodologies for intravital microscopy to characterize tumor functional and molecular response to radiation and chemotherapy. His awards have included the Jack Fowler Award from the Radiation Research Society.
Yvonne M. Mowery, MD, PhD, DABR is a physician scientist and the Butler Harris Assistant Professor or Radiation Oncology at Duke University, specializing in treating head and neck cancer with radiotherapy and studying novel combinations of radiation with immunotherapy. She received her MD and PhD in Pathology at Duke University in 2012, followed by completing an Internal Medicine internship and Radiation Oncology residency at Duke University in 2017. During residency, she joined the laboratory of sarcoma and genetically engineered mouse model expert David Kirsch, MD, PhD to initiate a new research project evaluating the combination of radiation therapy and immune checkpoint blockade in a novel carcinogen-induced and genetically engineered sarcoma model that she developed. Data from her preclinical studies supported initiation of SU2C-SARC032 (NCT03092323), a phase II trial evaluating anti-PD-1 antibody pembrolizumab in combination with neoadjuvant radiation therapy and surgery for high-risk soft tissue sarcoma of the extremity. Yvonne joined the faculty as an Assistant Professor of Radiation Oncology at Duke University in 2017 and continued her postdoctoral training through 2020 in the Kirsch laboratory. Supported by an ASCO Young Investigator Award and Duke School of Medicine Physician Scientist Strong Start Award, Yvonne continued her work studying radiation and immunotherapy and developed several novel primary mouse models of head and neck squamous cell carcinoma (HNSCC). Her laboratory focuses on studying head and neck cancer pathogenesis and mechanisms of overcoming radiation and immunotherapy resistance in HNSCC, with a particular interest in DNA damage response pathways. Yvonne also serves as the Associate Center Director for Radioimmunotherapy for the Duke Cancer Institute Center of Cancer Immunotherapy, and she was recently awarded a 2021 American Society for Clinical Investigation Young Physician-Scientist Award. She is the PI of an investigator-initiated phase I trial (NCT04576091) evaluating the ATR inhibitor BAY 1895344 with pembrolizumab and stereotactic body radiation therapy for recurrent HNSCC. Her research is supported by a K08 Career Development Award from the National Institute of Dental and Craniofacial Research, a Damon Runyon Clinical Investigator Award, a P30 Cancer Center Support Grant Supplement, and a U24 through the National Cancer Institute Co-Clinical Imaging Research Resources Program.
Ashlyn Rickard, PhD, received her doctoral degree in Medical Physics at Duke University in 2022, where she specialized in diagnostic imaging systems and radiation biology. In the Radiation Oncology laboratory of her PhD advisor, Gregory Palmer, PhD, she studies tissue-oxygen-imaging techniques using optical nanoprobes, Cherenkov emission imaging and electron paramagnetic resonance oxygen imaging. Because oxygen imaging has clinical implications in cancer research and radiation biology, most studies included radiation therapy and other anti-cancer therapies. At the time of writing, Ashlyn has published three first-author manuscripts; is a trainee member of the Duke Cancer Institute; is an active Scholar-in-Training and Education Committee member in the Radiation Research Society; received the Radiation Research Society Travel Grant in 2019, to present a talk on applying electron paramagnetic resonance oxygen imaging to oxygen microbubble radiosensitization therapy; received the Top 3 Poster Award at the Annual Retreat of the Duke Radiation Oncology and Imaging Program in 2018; served as a member of the Gordon G. Hammes Faculty Teaching Award Selection Committee at Duke University in 2019; received the Most Exciting New Imaging Technology Award at the Imaging Technology Fair at Duke University in 2017; and received the Chancellor’s Scholarship at Duke University. She intends to continue her training in the Radiation Oncology laboratory of Yvonne Mowery, MD, PhD who specializes in novel head and neck cancer treatments.
About the Webinar
Hypoxia, a prevalent characteristic of most solid, malignant tumors, contributes to diminished therapeutic responses and more aggressive phenotypes. The impact of hypoxia on radiotherapy response is significant: hypoxic tissue is 3x less radiosensitive than normoxic tissue. The major challenge in implementing hypoxic radiosensitizers is the lack of a high-resolution imaging modality that can directly quantify tissue oxygen concentration. A precommercial EPR oxygen-imager was used to quantify tumor hypoxia and investigate the hypoxia-modifying effects of the FDA-approved vasodilator papaverine (PPV). We aimed to quantify the change in absolute tumor hypoxia induced by papaverine in two murine tumor models: E0771 syngeneic mammary carcinoma and primary p53/MCA sarcomas. We hypothesized that 1) there is a PPV dose-related change in tissue pO2, 2) papaverine radiosensitizes tumors, increasing tumor control and survival probability, and 3) pre-screening tumors for baseline tumor hypoxia by EPR imaging predicts radiosensitization in response to PPV. We report that papaverine alters tumor hypoxia in the breast cancer model with an average 47.5% increase in median tumor pO2 and an average 7.8% decrease in tumor hypoxic fraction (<10mmHg); however, no radiosensitizing effect was apparent in either cancer model. We confirmed that hypoxic tumors are more radioresistant than normoxic tumors in the primary sarcoma model (p=0.0057) via oxygen quantification with EPR. Additionally, in a Cox Hazard Regression analysis for the sarcoma model, baseline hypoxic fractions proved to be a significant (p=0.0063) hazard in survivability. Papaverine’s effect on tumor vasculature (in combination with its oxygen consumption rate decrease) requires further study before concluding it is a hypoxic radiosensitizer.