Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Medical Biophysics

Supervisor

Dr. Robert Bartha

Abstract

Glioblastoma Multiforme (GBM) is the most aggressive and malignant form of primary brain tumor. In many tumors, increased intracellular pH (pHi) is a hallmark of aggressiveness. This increased pHi has been shown to be related to cell proliferation and evasion of apoptosis as well as resistance to chemotherapy. As such, monitoring pHi and the tumor pHi response to pharmacologic challenge, may aid in treatment planning and patient management for this deadly cancer. A magnetic resonance imaging (MRI) method called Chemical Exchange Saturation Transfer (CEST) has been used to detect changes in pHi. Our group has recently developed a CEST technique called amine and amide concentration independent detection (AACID), which was shown to be sensitive to pHi changes induced by the anticancer drug, lonidamine (LND). However, LND is not currently approved for use in humans. Our objective was to demonstrate that topiramate (TPM), an antiepileptic drug that is well tolerated in humans, could also induce tumor acidification. The goal this thesis was to quantify the changes in pHi induced by a single dose of TPM in a mouse model of brain tumor. CEST spectra were acquired using a 9.4T MRI scanner, before and 75 minutes after administration of TPM (dose: 120 mg/kg). A significant increase in the AACID CEST effect was observed within brain tumors with no change observed in contralateral tissue. The increase in AACID CEST corresponds to tumor acidification as expected. Therefore TPM induced a rapid measurable metabolic change in tumors that could provide valuable insight into cancer aggressiveness and aid in tumor detection.

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