Abstract
This study shows the use of hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) to assess therapeutic efficacy in a preclinical tumor model. 13C-labeled pyruvate was used to monitor early changes in tumor metabolism based on the Warburg effect. High-grade malignant tumors exhibit increased glycolytic activity and lactate production to promote proliferation. A rodent glioma model was used to explore altered lactate production after therapy as an early imaging biomarker for therapeutic response. Rodents were surgically implanted with C6 glioma cells and separated into 4 groups, namely, no therapy, radiotherapy, chemotherapy and combined therapy. Animals were imaged serially at 6 different time points with magnetic resonance imaging at 3 T using hyperpolarized [1-13C]pyruvate MRSI and conventional 1H imaging. Using hyperpolarized [1-13C]pyruvate MRSI, alterations in tumor metabolism were detected as changes in the conversion of lactate to pyruvate (measured as Lac/Pyr ratio) and compared with the conventional method of detecting therapeutic response using the Response Evaluation Criteria in Solid Tumors. Moreover, each therapy group expressed different characteristic changes in tumor metabolism. The group that received no therapy showed a gradual increase of Lac/Pyr ratio within the tumor. The radiotherapy group showed large variations in tumor Lac/Pyr ratio. The chemo- and combined-therapy groups showed a statistically significant reduction in tumor Lac/Pyr ratio; however, only combined therapy was capable of suppressing tumor growth, which resulted in low endpoint mortality rate. Hyperpolarized 13C MRSI detected a prompt reduction in Lac/Pyr ratio as early as 2 days post combined chemo- and radiotherapies.
Highlights
IntroductionThe most prevalent form of malignant brain tumors is glioma, which arises from glial cells [1]
Brain cancer is a challenging disease with very poor prognosis and outcomes
The radiotherapy and combined therapy groups had the highest mean survival time at 25 days followed by the chemotherapy group at 18 d and lastly the no therapy group at 17 days
Summary
The most prevalent form of malignant brain tumors is glioma, which arises from glial cells [1]. There are aggressive therapies available (ie, surgical resection, radiotherapy, and chemotherapy), patients diagnosed with the most aggressive (grade IV) malignant glioma have a disappointing 5year survival rate of 5.1% [2]. Despite aggressive treatment, these tumors almost inevitably recur [3]. Magnetic resonance imaging (MRI) is the preferred clinical diagnostic tool for brain tumor detection [4]; yet, it remains challenging to observe both the therapeutic response and efficacy during the course of the treatments. Because radiotherapy and chemotherapy affect tumors at the molecular level (DNA damage, blocking protein/ RNA), phenotypical changes (tumor size, diffusion, proliferation) that arise from therapies, can be challenging to detect during the early stages of treatment
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