Time Domian Electron Paramagnetic Resonance Imaging

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

IAssessment of physiologic changes in response to drugs targeting tumor stroma: In addition to the hypoxia and low pH in tumors caused by aberrant vasculature, extra stromal deposits such as collagen, hyaluronan impose high tumor interstitial fluid pressure (IFP). The elevated IFP causes further increases in hypoxia. The elevated IFP also imposes a hydrostatic barrier for drugs and antibodies to accumulate at the desired therapeutic levels. PEGPH20 is a pegylated hyaluronidase capable of degrading the tumor extrastromal content and allow accumulation of drugs. Though promising results were found in pre-clinical studies as well as Phase I and Phase II clinical studies, in Phase III studies no benefit was seen compared to standard treatments. We tested the hypothesis that prior imaging studies of changes in tumor physiology using molecular imaging techniques which can monitor tumor physiology in terms of pO2 and prefusion/permeability can select patients who can benefit from these treatments. EPR imaging of tumor pO2 in tumors expressing high content of hyaluranon vs tumors which do not were tested for changes in pO2 in response to treatment with PEGPH20. Our studies showed that tumors sensitive to PEGPH20 displayed enhanced perfusion and improvements in tumor oxygenation vs control tumors. Supporting this observation, enhanced tumor control in mice with tumors having high hyaluronan deposits was observed with radiation treatment following treatment with PEGPH20. These studies show the importance of integrating molecular imaging techniques to help select patients for treatment with PEGHP20. Effect of metabolic inhibitors on tumor pO2. The unique metabolic dependencies of tumors for energy provide pathways which can be targeted for therapy. The aerobic glycolytic and oxidative phosphorylation (OxPhos) dependent pathways are two main processes for energy generation the former being elevated in tumors. Targeting these two processes individually or in combination as well as adding other non-proliferation modalities are now being actively pursued. Inhibiting either of these processes may impact tumor physiology in terms of physiology and metabolism. Earlier studies have characterized the effect of NCI-006, an LDHA inhibitor and IACS-010759, an OxPhos inhibitor on metabolism. Presently we have evaluated the effect of these two agents on tumor oxygen status in collaboration with Dr. James Mitchell, RBB. We find that the LDHA inhibitor NCI-006 modestly but not significantly increased tumor hypoxia while administration of IACS-010759 significantly decreased hypoxia. The decrease in tumor hypoxia on treatment with IACS-010759 makes it potentially a useful radiosensitizer which was tested by DR. Mitchell's group. A significant enhancement of radiation effects were found with IACS-010759 supporting the use of this agent in chemoradiation settings. EPR Spectrometer Developments. The present Spectrometer is developed based on the modules integrated using coaxial SMA or BNC connectors. Several individual analog modules such as Frequency Generator, Transmitter, Pulse Control, Receiver etc are being used. These racks with external cabling to interconnect are prone to noise interference. To avoid a compact bench top system development is designed. In this system, the FPGA control system is used which is currently the state of art in electronics industry. In this compact system we use surface mount devices and interconnect are done in multilayer printed circuit boards. All the boards are interconnected through a back panel, so that environmental noise interference is minimized. The system will have flexibility to collect image data in multiple modalities allowing flexibility and improve detection sensitivity allowing high spatial and temporal resolutions.