Glioblastoma (GBM) is a highly aggressive, malignant, primary brain tumor. Maximal neurosurgical tumor resection, followed by highly conformal radiation and concurrent chemotherapy, remains the standard of care for GBM patients. These tumors inevitably recur. Given the dismal prognosis, improved technologies are desperately needed to enable better treatment of recurrent GBM. An additional complicating factor is the diagnostic challenge of non-invasively discriminating recurrent GBM from radiation necrosis (RN). PARP-1, an enzyme involved in DNA repair, is selectively overexpressed in the nuclei of glioma cells. In recent years, radiolabeled PARP-1 inhibitors have been investigated for the non-invasive imaging of PARP-1 expression in glioma, as well as other tumors. Radiolabeled PARP-1 inhibitors have also been proposed for targeted radiotherapy, though, to date, there have only been two published reports. In this application, we propose to examine existing radiolabeled PARP-1 inhibitors and to synthesize and evaluate novel radiolabeled PARP-1 inhibitors, as theranostic agents for glioblastoma. Radionuclides of iodine and bromine are proposed for imaging and therapeutic studies. Herein, we will focus on positron-emitting radionuclides for PET imaging and Auger- emitting radionuclides for therapy. These studies will be supported by advanced MRI experiments aimed at characterizing the physiology of tumors and RN, and for assessing therapeutic response.
The aims of the proposal are to: i) synthesize various established and novel radiolabeled PARP-1 inhibitors, and evaluate their uptake and efficacy in vitro, ii) evaluate radiolabeled PARP-1 inhibitors for uptake in murine models of glioblastoma and experimental radiation necrosis, and iii) determine the therapeutic efficacy of the PARP-1 inhibitors in murine models of glioblastoma. This grant application will be led by a quality team of experts, specializing in models of experimental radiation necrosis and MR imaging (Dr. Joel Garbow); targeted radiation therapy and PET imaging (Dr. Buck Rogers); radioligand development and labeling (Dr. Dong Zhou); in vitro binding assays and autoradiography (Dr. Jinbin Xu); and radiolabeled PARP-1 inhibitors and glioma animal models (Dr. Thomas Reiner). If successful, our approach will provide a new technology driven paradigm for treating patients with recurrent glioblastoma.
The goal of this research project is to evaluate a novel, image-guided approach for the treatment of recurrent glioma, via Auger radiation therapy, using small-molecule inhibitors targeted to a DNA-repair enzyme. Potential inhibitors will be screened in vitro for high affinity binding to their target and cell killing. Tumor uptake of these inhibitors will be evaluated by in vivo PET and MR imaging that will guide their use as therapeutics, leading to identification of a candidate compound for future clinical evaluation.