Joseph J. Cullen, MD, FACS
Introduction
Adenocarcinoma of the pancreas is the fourth leading cause of cancer death in the United States and is increasing in incidence. Intravenous ascorbate (i.e., ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations, which are in the range that are cytotoxic to tumor cells. Studies from our currently funded 2 year U01 grant CA166800 "Ascorbate-induced radiosensitization in pancreatic cancer" have demonstrated that ascorbate, in doses achievable in humans, synergizes with ionizing radiation in decreasing viability and proliferation in all pancreatic cancer cell lines examined, via a H2O2–mediated mechanism. Our recently completed phase I study demonstrated that pharmacological ascorbate combined with gemcitabine is safe and well-tolerated and may lead to overall clinical benefit in patients with stage IV pancreatic cancer. This proposal focuses on improvement of the therapeutic ratio of a standard anti-cancer therapy (ionizing radiation) using a complementary approach (high dose ascorbate), in the treatment of pancreatic cancer. If pancreatic cancer cells (relative to normal cells) are more susceptible to ascorbate-induced cytotoxicity due to increased ascorbate auto-oxidation leading to increased H2O2 production, then ascorbate would be expected to be efficacious and well-tolerated adjuvant to chemo-radiation in patients. Furthermore, increasing the rate of auto-oxidation of ascorbate with redox active metal catalysts to generate more H2O2 should selectively increase ascorbate-induced radiosensitization and oxidative stress. Finally, ascorbate-induced radiosensitization would be expected to sensitize tumor cells to clinically relevant pharmacological agents that inhibit the removal of H2O2 The current proposal will test the hypothesis that production of H2O2 via the metal ion catalyzed auto-oxidation of ascorbate mediates ascorbate-induced cytotoxicity and chemo-radiosensitization in human pancreatic cancer. We will test our hypothesis with the following three Specific Aims. 1) Determine in a phase I trial the safety of administering pharmacological ascorbate during concurrent gemcitabine-radiation therapy for the treatment of non-resectable pancreatic cancer; 2) Determine if ascorbate-induced radiosensitization can be selectively enhanced by redox active metal catalysts; 3) Determine if the ascorbate-induced radiosensitization can be enhanced by clinically relevant pharmacological inhibitors of glucose and hydroperoxide metabolism. The phase I trial will quantify adverse events and determine changes in systemic parameters indicative of oxidative stress in patients. The preclinical studies will use biochemistry/molecular biology techniques to determine ascorbate-induced radiosensitization and oxidative stress and employ a non-invasive in vivo index of cell proliferation. If we can rigorously demonstrate that the radiosensitization mediated by pharmacological ascorbate induces preferential oxidative stress and subsequent cytotoxicity in human pancreatic cancer cells, then the results of this proposed research program will provide a foundation for the rational design of a novel combined modality cancer therapy.
Current Positions
- Professor, Gastrointestinal Surgery, University of Iowa
- Professor, Radiation Oncology, University of Iowa
- Staff Surgeon, Veterans Affairs Medical Center, Iowa City, Iowa
- Vice Chair for Research, Department of Surgery, University of Iowa
Education
- BS in Biology, Loras College, Dubuque, Iowa
- MD, University of Iowa Carver College of Medicine, Iowa City, Iowa
- Resident in General Surgery, University of Iowa, Iowa City, Iowa
- Fellow in Digestive Disease, NIH Research Fellow, Mayo Clinic, Rochester, Minnesota
Graduate Program Affiliations
Research Interests
- “Role of HIF-1α in EcSOD-induced growth inhibition of pancreatic cancer”
- “Ascorbate-induced radiosensitization in pancreatic cancer“
Licenses & Certifications
- Iowa Medical License, Iowa Board of Medicine, Iowa
- Board Certified, General Surgery, American Board of Surgery
- Fellow, American College of Surgeons
- Certified, Basic Life Support, American Heart Association
Selected Publications
- Bodeker KL, Smith BJ, Berg DJ, Chandrasekharan C, Sharif S, Fei N, Vollstedt S, Brown H, Chandler M, Lorack A, McMichael S, Wulfekuhle J, Wagner BA, Buettner GR, Allen BG, Caster JM, Dion B, Kamgar M, Buatti JM, Cullen JJ. A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer. Redox Biol. 2024 Oct 2;77:103375. DOI: 10.1016/j.redox.2024.103375. Epub ahead of print. PMID: 39369582.
- Chen GY, O'Leary BR, Du J, Carroll RS, Steers GJ, Buettner GR, Cullen JJ. Pharmacologic Ascorbate Radiosensitizes Pancreatic Cancer but Radioprotects Normal Tissue: The Role of Oxidative Stress-Induced Lipid Peroxidation. Antioxidants (Basel). 2024 Mar 18;13(3):361. DOI: 10.3390/antiox13030361. PMID: 38539894; PMCID: PMC10967795.
- Petronek MS, Monga V, Bodeker KL, Kwofie M, Lee CY, Mapuskar KA, Stolwijk JM, Zaher A, Wagner BA, Smith MC, Vollstedt S, Brown H, Chandler ML, Lorack AC, Wulfekuhle JS, Sarkaria JN, Flynn RT, Greenlee JDW, Howard MA, Smith BJ, Jones KA, Buettner GR, Cullen JJ, St-Aubin J, Buatti JM, Magnotta VA, Spitz DR, Allen BG. Magnetic Resonance Imaging of Iron Metabolism with T2* Mapping Predicts an Enhanced Clinical Response to Pharmacologic Ascorbate in Patients with GBM. Clin Cancer Res. 2024 Jan 17;30(2):283-293. doi: 10.1158/1078-0432.CCR-22-3952. PMID: 37773633.
- O'Leary BR, Kalen AL, Pope AN, Goswami PC, Cullen JJ. Hydrogen Peroxide Mediates Pharmacological Ascorbate Induced Radio-Sensitization of Pancreatic Cancer Cells by Enhancing G2-accumulation and Reducing Cyclin B1 Protein Levels. Radiation Research. 2023 Nov 1;200(5):444-455. doi: 10.1667/RADE-22-00182.1. PMID: 37758045; PMCID: PMC10699322 (available on 2024-11-01).
- Steers GJ, O’Leary BR, Du J, Wagner BA, Carroll RS, Doman FE, Goswami PC, Buettner GR, Cullen JJ. (2023). Pharmacologic Ascorbate and DNMT Inhibitors Increase DUOX Expression and Peroxide-Mediated Toxicity in Pancreatic Cancer. Antioxidants 12, no. 9: 1683. https://doi.org/10.3390/antiox12091683
- Carroll, R. S., Du, J., O'Leary, B. R., Steers, G., Goswami, P. C., Buettner, G. R. & Cullen, J. J. (2023). Pharmacological ascorbate induces sustained mitochondrial dysfunction. Free Radical Biology and Medicine 204 108-117. DOI: 10.1016/j.freeradbiomed.2023.04.023.
- Du, J., Pope, A. N., O'Leary, B. R., Wagner, B. A., Goswami, P. C., Buettner, G. R. & Cullen, J. J. (2022). The role of mitochondria in pharmacological ascorbate-induced toxicity. SCIENTIFIC REPORTS 12 (1). DOI: 10.1038/s41598-022-27185-9.
- Zaher A, Stephens LM, Miller AM, Hartwig SM, Stolwijk JM, Petronek MS, Zacharias ZR, Wadas TJ, Monga V, Cullen JJ, Furqan M, Houtman JCD, Varga SM, Spitz DR, Allen BG. (2022) Pharmacological ascorbate as a novel therapeutic strategy to enhance cancer immunotherapy. Frontiers in Immunology. 13:989000. doi: 10.3389/fimmu.2022.989000. PMID: 36072595; PMCID: PMC9444023.
- O'Leary, B. R., Ruppenkamp, E. K., Steers, G. J., Du, J., Carroll, R. S., Wagner, B. A., Buettner, G. R. & Cullen, J. J. (2022). Pharmacological Ascorbate Enhances Chemotherapies in Pancreatic Ductal Adenocarcinoma. Pancreas. DOI: 10.1097/MPA.0000000000002086. PMID: 36099493.
- Steers, G. J., Chen, G. Y., O'Leary, B. R., Du, J., Van Beek, H. & Cullen, J. J. (2022). Auranofin and Pharmacologic Ascorbate as Radiomodulators in the Treatment of Pancreatic Cancer. Antioxidants (Basel, Switzerland) 11 (5). DOI: 10.3390/antiox11050971. PMID: 35624835.