A large multicenter trial performed by several international brain tumor and radiotherapy groups demonstrated a median survival in patients with newly diagnosed GBM of only 12.1 months with surgery/radiotherapy and 14.6 months when temozolamide therapy was added. This dismal prognosis for patients with malignant gliomas remains despite recent advances in diagnostic and therapeutic techniques. Even with the use of advanced MRI pulse sequences and PET radiopharmaceuticals, the true extent of tumor infiltration into surrounding normal brain is often inadequately characterized prior to surgical resection and radiation treatment. Moreover, following treatment, conventional MRI also has limitations in distinguishing pseudoprogression and treatment necrosis from tumor recurrence which can lead to false positive findings that may subject patients to unnecessary procedures and/or treatments. Clearly, new diagnostic and management strategies are needed for these patients. Our lab is developing radioiodinated NM404 as a diapeutic agent for the detection and treatment of a wide variety of solid tumors, including brain tumors. NM404 is a refined, second-generation, phospholipid ether analog that is characterized by preferential tumor uptake and prolonged tumor retention in 50/52 human xenograft, spontaneous and transgenic preclinical tumor models, including gliomas. The mechanistic basis for the selective uptake of NM404 is due to selective insertion into lipid rafts and resultant internalization into the cell. Malignant cells are now known to have greatly increased amounts of lipid rafts compared to normal cells. When labeled with the therapy isotope iodine-131, NM404, has produced significant prolongation of life following a single injection in a dozen human xenograft tumor models in mice. The goal of this imaging proposal is to first optimize the PET imaging parameters of 124I-NM404 in malignant brain tumor patients and then compare the tumor sensitivity and specificity of this agent with current state-of-the-art MRI imaging techniques and pathology. If NM404 PET/CT results prove superior to MRI in accurately defining the true extent of tumor infiltration, then this new technique may be used to guide preor intra-surgical biopsies, improve surgical and radiotherapy planning, monitor treatment response, and differentiate pseudoprogression or radiation necrosis from true tumor recurrence. This new diagnostic information could help significantly improve patient survival with current therapies. Additionally, if coupled with new 131I-NM404 systemic radiotherapy, patient survival may be dramatically improved.
This project investigates the utility of a new tumor imaging agent, NM404, to more accurately characterize malignant brain tumors in humans. If NM404 proves superior to current diagnostic methodologies in characterizing malignant brain tumors, then it will result in improved outcomes for patients with brain cancer.
|Clark, Paul A; Al-Ahmad, Abraham J; Qian, Tongcheng et al. (2016) Analysis of Cancer-Targeting Alkylphosphocholine Analogue Permeability Characteristics Using a Human Induced Pluripotent Stem Cell Blood-Brain Barrier Model. Mol Pharm 13:3341-9|
|Pointer, Kelli B; Clark, Paul A; Eliceiri, Kevin W et al. (2016) Non-torsadogenic human Ether-Ã -go-go Related Gene (hERG) inhibitors are associated with better survival for high hERG-expressing glioblastoma patients. Clin Cancer Res :|
|Clark, Paul A; Bhattacharya, Saswati; Elmayan, Ardem et al. (2016) Resveratrol targeting of AKT and p53 in glioblastoma and glioblastoma stem-like cells to suppress growth and infiltration. J Neurosurg :1-13|
|De, Ishani; Steffen, Megan D; Clark, Paul A et al. (2016) CSF1 Overexpression Promotes High-Grade Glioma Formation without Impacting the Polarization Status of Glioma-Associated Microglia and Macrophages. Cancer Res 76:2552-60|
|Swanson, Kyle I; Clark, Paul A; Zhang, Ray R et al. (2015) Fluorescent cancer-selective alkylphosphocholine analogs for intraoperative glioma detection. Neurosurgery 76:115-23; discussion 123-4|
|Morris, Zachary S; Weichert, Jamey P; Saker, Jarob et al. (2015) Therapeutic combination of radiolabeled CLR1404 with external beam radiation in head and neck cancer model systems. Radiother Oncol 116:504-9|
|Weichert, Jamey P; Clark, Paul A; Kandela, Irawati K et al. (2014) Alkylphosphocholine analogs for broad-spectrum cancer imaging and therapy. Sci Transl Med 6:240ra75|