Novel Manganese-Porphyrin Superoxide Dismutase-Mimetic Widens the Therapeutic Margin in a Preclinical Head and Neck Cancer Model.

Statistical modelling, data analysis.
Analysis of multiple observer studies.
Analysis of complex data.
Modelling tumor growth. Translation in drug discovery.
Statistical analysis of images: cellular and medical imaging.
Statistics of shape, structure and spatial arrangement.

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.

Laboratory Website:
https://radonc.duke.edu/research-education/research-labs/radiation-and-cancer-biology/palmer-lab

With a research background heavily weighted in drug delivery systems in the treatment of cancer, the focus of my work has shifted to vaccination delivery methods as potential anticancer strategies. The goal of my current funding is to identify and develop a vaccine strategy delivered via the intranasal (IN) route that induces a cytotoxic T lymphocyte (CTL) response adequate for the protection/prevention of metastatic lung cancer.

I am currently working under the mentorship of Dr. Herman Staats, and in addition to the cancer immunotherapy studies, I have a strong interest in mucosal immunization and maternal immunization studies, specifically in the rabbit model.

Intensity Modulated Radiotherapy optimization. Functional Image-guided radiotherapy (PET, SPECT). Modeling of Radiation-induced normal tissue complications (lung, cardiac) using neural nets, MART, self organizing maps, etc. Optimal selection of beam orientations for radiotherapy. Hyperthermia modeling.

Current Funded Grants:
NCI P01 CA042745-19: Hyperthermia and Perfusion Effects in Cancer Therapy Project 2: Real Time Modeling and Control Using Finite Elements and MRI (Program Director).
NCI 1R01 CA115748-01A1: Accurate Prediction of Cardiac and Lung Radiation Injury (Principal Investigator).
Varian Medical Systems: Incorporation of Functional Image-guidance in Radiotherapy Planning (Principal Investigator).

Graduate School Teaching:
MP322: Advanced Photon Beam Radiation Therapy Planning (Fall Semester)

Postdoctoral Research Associates (Past and Current):
Alan Baydush, Ph.D.
Shifeng Chen, Ph.D.
Kung-Shan Cheng, Ph.D.
Sarah McGuire, Ph.D.
Vadim Stakhursky, Ph.D.

We have successfully developed various rodent models of brain and spinal cord injuries in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma, subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression injury. We also established cardiac arrest and hemorrhagic shock models for studying multiple organ dysfunction.  Our current studies focus on two projects. One is to examine the efficacy of catalytic antioxidant in treating cerebral ischemia and the other is to examine the efficacy of post-conditioning on outcome of subarachnoid hemorrhage induced cognitive dysfunction.

Head and neck cancer has constituted both my principal clinical and research foci since I came to Duke University in 1987. I designed and led a single institution phase 3 randomized clinical trial, initiated in 1989, which was one of the first in the world to demonstrate that radiotherapy and concurrent chemotherapy (CRT) was more efficacious than radiotherapy alone (RT) for treating locally advanced head and neck cancer. CRT has since been established as the non-surgical standard of care for locally advanced head and neck cancer. Reduction of treatment-induced toxicity has also been a major interest of mine because more intensive therapeutic regimens improve efficacy but also increase morbidity. I was the principal investigator of the pivotal multinational randomized trial of amifostine in head and neck cancer, which established proof of principle for pharmacologic radioprotection and led to FDA approval of this drug for protection against radiation induced xerostomia in the treatment of head and neck cancer in 1999. I have also investigated role of recombinant human keratinocyte growth factor KGF in the amelioration of mucositis in both preclinical and clinical settings.
I have an ongoing commitment to the study of in situ tumor physiology and biology. I was one of the initial investigators to initiate direct measurement of tumor oxygenation in humans on a systematic basis. This work revealed a prognostic relationship between tumor hypoxia and local-regional failure and survival in head and neck. Parallel studies of tumor oxygenation in soft tissue sarcomas resulted in the first published literature to demonstrate that hypoxia at a primary tumor site was associated with a significant increase in the risk of subsequent distant metastatic recurrence after completion of treatment. We have also demonstrated that elevated lactate concentrations in head and neck cancer primary tumors is associated with an increased risk of metastatic failure in patients undergoing primary surgical therapy for head and neck cancer.
These interests and accomplishments provide the foundation for my present efforts, which are devoted to the development of functional metabolic imaging, both MRI and PET. We are using imaging to characterize the inherent, non-treatment induced variability of several physiologic and metabolic parameters in both tumors and normal tissues and to measure treatment induced changes in them. The long- term intent is to improve our abilities to predict treatment outcome, to better understand the relationships between physical dose delivery and the risk of toxicity, and to choose more customized treatment strategies for our patients that will increase the chances of cure and decrease the risks of serious side effects

            A major interest of mine has been in the design and synthesis of Mn porphyrin(MnP)-based powerful catalytic antioxidants which helped establish structure-activity relationship (SAR). It relates the redox property of metalloporphyrins to their ability to remove superoxide. SAR has facilitated the design of redox-active therapeutics and served as a tool for mechanistic considerations. Importantly SAR parallels the magnitude of the therapeutic potential of SOD mimics and is valid for all classes of redox-active compounds. Two lead Mn porphyrins are already in five Phase II clinical trials (reviewed in Batinic-Haberle et al, Oxid Med Cell Longevity 2021). Recent research suggests immense potential of MnPs in cardiac diseases. MnTE-2-PyP (AEOL10113, BMX-010) prevents and treats cardiac arrhythmia, while MnTnBuOE-2-PyP (BMX-001) fully suppressed the development of aortic sclerosis in mice. The latter result is relevant to the cancer patients undergoing chemotherapy. In addition to breast cancer, in collaboration with Angeles Alvarez Secord, MD, MHSc, we have recently shown the anticancer effects of Mn porphyrin/ascorbate in cellular and mouse models of ovarian cancer.

            In parallel with synthetic efforts, I have also been interested in the mechanistic aspects of differential actions of Mn porphyrins in normal vs tumor tissue. In-depth studies of chemistry and biology of the reactions of MnPs with redox-active agents relevant to cancer therapy – ascorbate, chemotherapy and radiation – set ground for understanding the role of thermodynamics and kinetics in the mechanism of action of Mn porphyrins. Mechanistic studies have been revealed in Batinic-Haberle et al, Antioxidant Redox Signal 2018, Batinic-Haberle and Tome, Redox Biology 2019 and Batinic-Haberle et al Oxidative Medicine and Cellular Longevity 2021. My research has resulted in over 230 publications, 18 268 citations and an h-index of 64. For my achievements, I have been awarded the 2021 Discovery Award from the Society for Redox Biology and Medicine, SfRBM.

Additional Training

• Postdoctoral fellowship with Professor Alvin Crumbliss in the field of Bioinorganic Chemistry, Department of Chemistry, Duke University
• Postdoctoral fellowship with Professor Irwin Fridovich in the field of Redox Biology, Department of Biochemistry, Duke University School of Medicine