“For the first time, we were able to directly monitor oxygen levels in human tumors growing in a mouse brain using EPR oximetry with implantable resonators,” explained Khan. “This provides exciting opportunities to evaluate and optimize various strategies being developed to improve oxygen levels in the glioma.”
Treatment of glioma has remained a challenge despite the options for surgical resection followed by chemotherapy and radiotherapy. Hypoxia, very low levels of oxygen in glioma, plays a crucial role in resistance to radiotherapy because oxygen must be present for optimal fixation of DNA damage induced by ionizing radiation. Hypoxic cells are relatively resistant to radiotherapy, requiring up to three times the radiation dose as normal cells to result in the same level of cell killing. Despite the profound effect of hypoxia in compromising the effectiveness of radiotherapy, techniques to directly and repeatedly quantify oxygen levels in glioma in order to develop optimal hyperoxic strategies are lacking.
Khan’s team set out to implement in vivo EPR oximetry using a method that employed implantable resonators for repeated measurement of oxygen levels in the glioma, and developed strategies to increase the levels to improve treatment outcomes. They have investigated temporal changes in oxygen levels of the normal brain and glioma in animal models subjected to breathing oxygen-enriched gases. They also investigated a new strategy to significantly inhibit glioma growth by rationally combining gemcitabine and MK-8776, a cell cycle checkpoint inhibitor.
“The treatment with gemcitabine and MK-8776 to inhibit glioma growth is a promising strategy that warrants further investigation,” said Khan. “Real-time knowledge of oxygen levels in gliomas will be extremely useful in developing oxygen guided optimal treatment plans for each patient in the clinic.”
The team is headed by Harold Swartz, MD, PhD, who is a leader in EPR technique and was recently awarded a five-year program project by National Cancer Institute (NCI) to investigate temporal changes in oxygen levels during tumor growth and treatment in patients. Together, these studies will provide essential evidence to inform therapies.
Collaborations such as these are common at Dartmouth’s Norris Cotton Cancer Center, where team science is a top priority. Khan, an expert in oximetry from the Department of Radiology, collaborated with Alan Eastman, PhD, from the Department of Pharmacology Toxicology, who brought expertise in the cell cycle. Huagang Hou, MD, Department of Radiology, contributed in the design and fabrication of the implantable resonators, and EPR measurements in this study.
Investigators at Dartmouth have extensive Shared Resources available for research and this team used the Pathology Shared Resource to evaluate cell cycle distribution in the glioma. These experiments were essential to understanding the effect of gemcitabine on cell cycle and the effective scheduling of checkpoint inhibitor for maximal malignant cell kill. The pre-clinical MRI Shared Resource was utilized to image glioma and monitor growth to determine treatment outcomes in this research.
Dartmouth’s Shared Resources are also available to outside investigators by arrangement.
Looking forward, Khan’s team plans to investigate treatment outcomes when radiotherapy is scheduled at times of an increase of oxygen levels in glioma. They will follow this approach to design a novel treatment plan by rationally combining gemcitabine with cell cycle checkpoint inhibitor, oxygen-enrich gas inhalation, and radiotherapy to significantly inhibit the growth of aggressive glioma.