James B. Mitchell, Ph.D.
Dr. Mitchell’s primary research focus is identification of means to modify the radiation response of tumors and normal tissues. His research utilizes an array of agents to probe the radiosensitivity of cells/tissues including nitroxide-based antioxidants, chemical radiation protectors, and agents that target specific molecular pathways important in radiation responses.
As Branch Chief, Dr. Mitchell manages translational research initiatives involving radiation modification, the influence of tumor microenvironment on cancer treatment, and novel molecular imaging platforms to assess tissue metabolism.
1) radiation sensitization, 2) radiation protection, 3) redox processes, 4) oxidative stress,
5) nitroxide antioxidants, 6) chemoprevention
Modification of the Radiation Response
My research is directed toward the discovery of ways to modify the radiation response of both normal and tumor tissue. Such modification can be important for the improvement of cancer treatment using ionizing radiation either by protecting normal tissues or enhancing the sensitivity of tumor. Further, identifying means to protect normal tissues, particularly against radiation-induced late effects such as carcinogenesis, is important for countermeasure considerations of large populations exposed to radiation or in patients at risk for second malignancies following successful radiotherapy.
With respect to enhancing the effects of radiation damage to tumors, a number of approaches are being evaluated including molecularly targeted agents and cytotoxic chemotherapeutic agents. The overall objective here is to obtain a therapeutic gain by providing selective radiosensitization in tumors as compared to normal tissues. Admittedly, this has been and continues to be a difficult goal to achieve. We are presently evaluating in human tumor cell lines and xenografts inhibitors of JAK/STAT, CK2, Chk-1, a dual PI3K/mTOR inhibitor, the chemotherapy agent eribulin, and a hypoxia-mediated cytotoxin. Studies include the effects of the agent combined with radiation on survival, DNA damage repair, and cell cycle perturbations coupled with the effects of the combination on specific signal transduction pathways.
Our laboratory was first to identify nitroxides (lead compound Tempol) as catalytic antioxidants and radiation protectors providing protection against oxidative- and radiation-induced damage. Extensive pre-clinical studies are directed to normal tissue radioprotection using systemically or topically applied Tempol to protect against oral mucositis and salivary gland damage resulting from cisplatin-based chemoradiation in mice without interfering with tumor response. Studies are also directed to better define the mechanism of Tempol-mediated weight reduction in mice. Tempol has been shown to inhibit adipogenesis in 3T3-L1 cells resulting in a reduction in cellular lipid storage concomitant with HIF-1 induction. Tempol has been shown to delay the onset of cancer in various knock-out animal models (most recently in a Fanconi's anemia mouse model) prompting a study to determine if Tempol food supplementation could enhance survival and decrease radiation-induced carcinogenesis in mice receiving total body irradiation (TBI). Preliminary findings indicate that chronic supplementation of Tempol in the diet of mice over their life span can reduce body weight without toxicity, decrease cancer, and extend survival when administered immediately after non-lethal total body radiation (TBI). Delaying administration of the Tempol diet 1 month after TBI also enhanced survival and decreased carcinogenesis, suggesting that there may be a considerable "progression" phase of TBI-induced cancer induction that is amenable to modification and/or intervention.
Future studies will acquire gene expression and cytokine profiles on selected normal tissues taken from mice treated with various combinations of the Tempol diet and TBI (both at different times pre- and post-treatment) to gain insight as to the mechanism(s) of Tempol-mediated effects relative to TBI-induced carcinogenesis. Our research has demonstrated that nitroxides are a versatile class of antioxidants and our future studies will be centered on better understanding their mechanism of action as well as conducting the necessary studies to move them toward clinical trials where indicated.
Selected Recent Publications
Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy.Cell Rep. 30(6): 1798-1810, 2020. [ Journal Article ]
- J Clin Invest. 129(2): 489-91, 2019. [ Journal Article ]
Metabolic and Physiologic Imaging Biomarkers of the Tumor Microenvironment Predict Treatment Outcome with Radiation or a Hypoxia-Activated Prodrug in Mice.Cancer Res. 78(14): 3783-92, 2018. [ Journal Article ]
Abemaciclib, a Selective CDK4/6 Inhibitor, Enhances the Radiosensitivity of Non-Small Cell Lung Cancer In Vitro and In Vivo.Clin Cancer Res. 24(16): 3994-4005, 2018. [ Journal Article ]
SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2.Cancer Res. 76(18): 5442-54, 2016. [ Journal Article ]
Dr. Mitchell received his Ph.D. from Colorado State University in cellular radiation biology in 1978. He came to the NIH and the Radiation Oncology Branch of the NCI in 1979 and became an independent investigator in 1984. He served as chief of the Radiobiology Section and later as deputy branch chief of the Radiation Oncology Branch. In 1993, he was named chief of the Radiation Biology Branch. In 2009, the American Society of Therapeutic Radiation Oncology named Dr. Mitchell an ASTRO Fellow and in 2010 he received the Failla Award from the Radiation Research Society.
|Rajani Choudhuri Ph.D.||Biologist|
|John A. Cook Ph.D.||Staff Scientist|
|Janet W. Gamson||Biologist|
|Sangeeta Gohain||Laboratory Technician (Contr)|
|Askale Mathias Ph.D.||Biologist|
|Chandrasekhram Nagineni Ph.D.||Scientist (Contr)|
|Sarwat Naz Ph.D.||Postdoctoral Fellow (Visiting)|
|Lauren Shifflett||Program Staff (Contr.)|
|Anastasia L. Sowers||Biological Laboratory Technician|