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Nicholas Martin

Health Sciences, '16


Pharmacokinetic analysis of changes in temozolomide distribution after antiangiogenic treatment of glioblastoma

Mentor: Ciprian Catana, MD, PhD (Massachusetts General Hospital)

Glioblastoma (GBM) is a uniformly fatal tumor afflicting approximately 13,000 persons each year in the United States. Despite aggressive therapy with surgery, radiation and cytotoxic chemotherapy, average survival is less than 1 year and less than 4% of patients survive 5 years or more. Standard initial therapy for this tumor is maximal resection, combined daily temozolomide (TMZ) and radiation (chemoradiation) followed by monthly cycles of post-radiation temozolomide. Although the prognosis for newly diagnosed GBM patients has improved slightly with the advent of chemoradiation, the outlook is still grim in this patient population. Pathologic features of GBM include marked angiogenesis with microvascular proliferation and severe hypoxia with tumor necrosis. There is now some evidence to suggest that the anti-angiogenic agents are effective in GBM. However, the mechanisms by which these therapies exert an anti-tumor effect are not well understood. One hypothesis is that they change the delivery of chemotherapeutic agents such as TMZ. TMZ is a DNA alkylating agent used because of its excellent oral bioavailability. A spontaneous hydrolysis reaction causes the TMZ molecule to open up its heterocyclic ring at C4, producing carbon dioxide and MTIC, an unstable compound that degrades quickly into a reactive methylating compound, methyldiazonium ion. This compound can preferentially methylate a particular sequence on DNA, which causes a mismatch. Unless the methylation is completely removed, a mismatch is continually created and eventually, MutS, which a part of the DNA repair pathway, signals apoptosis in the cell. Magnetic resonance imaging (MRI) is firmly established as a diagnostic and assessment method for GBM patients, providing structural as well as functional (e.g. cerebral blood flow and volume, permeability) information. Positron emission tomography (PET) is a different imaging modality that offers complementary information about changes in tumor metabolism. Recently, a new method for efficient radiolabeling of TMZ was developed at the Martinos Center. This radiotracer ([11C]TMZ) can be used to monitor changes in TMZ distribution in the tumor during antiangiogenic treatment. Simultaneous MR-PET provides all the MRI-based metrics while imaging the delivery of [11C]TMZ to the tumor. Such data could be the means to provide answers to many important biomedical questions, including the very compelling question of how anti-angiogenic agents may be working. In this project, we will focus on the PET data analysis. This will include PET data processing, image reconstruction and pharmacokinetic analysis. The PET data were acquired for 90 minutes simultaneously with the MR data acquisition using the integrated Siemens 3T MR-BrainPET camera in GBM patients. As a first step, an MR-based attenuation map will be created using the widely available Statistical Parametric Mapping (SPM) software. Next, MR-based motion compensation will be performed to improve the PET data quantification. Motion correction will be applied separately to each of the dynamic frames before image reconstruction. The motion compensated images will be reconstructed using the OP-OSEM 3D algorithm. The reconstructed volume will consist of 153 slices with 256×256 pixels (1.25×1.25×1.25 mm3). Finally, spectral analysis will be used to study the pharmacokinetics of [11C]TMZ. This method is preferred for investigating radiolabeled drugs as opposed to the more constrained compartment model approaches (e.g. two tissue compartment models) as it better captures the heterogeneous nature of these tumors.

Multi-parametric PET/MR imaging in glioblastoma: FDG-PET and morphological MR image after administration of MR contrast agent (middle column). Parameters derived from the MR data (Ktrans, cerebral blood volume (CBV) and ADC) and the PET data (metabolic rate of glucose (CMRglu), K1, k3) in the region of interest (red contour) defined on the enhancing part of the tumor are shown in the left and right column, respectively. Images courtesy of Dan Chonde and Dominique Jennings. Source: