Innovative Cancer Imaging with Advanced MRI and New Tracers

Soft tissue sarcomas (STS) represent a heterogeneous group of malignant tumors that can occur at any age. STS arise in any of the mesodermal tissues of the extremities (50%), trunk and retroperitoneum (40%), or head and neck (10%). In order to facilitate complete tumor resections, patients are frequently treated with preoperative (neoadjuvant) chemotherapy. Several studies have shown that histopathological response to neo-adjuvant therapy predicts lower rate of local recurrence and improved survival. Standard response evaluation by Response Evaluation Criteria in Solid Tumors (RECIST) is not an accurate predictor of treatment efficacy in STS. Monitoring tumor glucose metabolism with 18F-2-fluoro-2-deoxy-D- glucose positron emission tomography/ computed tomography (18F-FDG-PET/CT) is significantly more accurate for assessment of response, but it associated with ionizing radiation and needs to be performed in addition to magnetic resonance imaging (MRI) which is the standard method for diagnosis, local staging and assessment of treatment response of STS. Hyperpolarized 13Carbon Magnetic Resonance Spectroscopic Imaging (13C HP MRSI) is emerging as novel imaging modality and allows a rapid, radiation-free, non-invasive investigation of tumor metabolism that can easily be integrated in routine MRI protocols. HP 13 C MRSI can detect both metabolized and non-metabolized contrast agents in the tumor whereas with 18F-FDG-PET/CT this differentiation is not possible. 18F-FDG-PET/CT allows only measurements of the total concentration of the radiotracer - metabolized and not metabolized- in the tumor. Therefore it can be expected that with HP 13C MRSI a more specific characterization of tumor metabolism in STS is possible. The goal of this proposal is to study the metabolism of STS with 18F-FDG-PET/CT and HP MRSI using 13C pyruvate as a hyperpolarized contrast agent. These studies will be performed in vitro on well-characterized sarcoma cell lines and in vivo on mouse models of soft tissue and bone sarcomas with varying degrees of sensitivity to chemotherapy. The study has two specific aims: 1) To study changes in tumor 18F-FDG uptake in response to cytotoxic chemotherapy using adriamycin as a model compound and compare these metabolic changes with HP MRSI using 13C pyruvate. 2) To determine how metabolic changes as measured with 18F-FDG-PET/CT and HP MRSI using 13C pyruvate differ in sarcoma models after exposure to targeted therapy with PI3K/mTOR kinase inhibitors. Data collected from the current study will be the basis for future clinical studies with HP MRSI using 13C pyruvate alone or a combination of HP MRSI using 13C pyruvate and 18F-FDG- PET/CT for monitoring treatment response in STS.

Hyperpolarized 13Carbon Magnetic Resonance Spectroscopic Imaging (13C HP MRSI) is emerging as novel imaging modality and allows a rapid, radiation-free, non-invasive investigation of tumor metabolism that can easily be integrated in routine MRI protocols. In contrast to 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography/ computed tomography (18FDG-PET/CT), HP 13C MRSI can detect both metabolized and non-metabolized contrast agents in the cancer. The PI3K-AKT-mTOR pathway is an intracellular signaling pathway that is important in regulating cell cycle. It is related to quiescence, proliferation, cancer, proliferation and the most frequently enhanced oncogenic pathway in breast cancer. The PI3K-AKT-mTOR pathway has prognostic and therapeutic implications, e.g. acquired resistance during endocrine therapy. Mutations in this pathway are associated with an increased glucose uptake in 18FDG PET/CT. In this study, we conducted 18FDG PET/CT and 13C HP MRSI in murine breast cancer models with and without mTOR mutations before and after treatment with targeted therapy for a more in-depth study of tumor metabolism. Untreated mutant breast cancer showed greater lactate signal with high signal-to-noise ratio than treated cancers indicative of vital tumor. In addition, experiments demonstrated that there is a decrease of glycolytic flux in mutant breast cancers at 96 hours of treatment with targeted treatment with rapamycin as depicted with 13C HP MRSI indicative of treatment efficacy. 13C HP MRSI findings agree with a reduction of tumor 18FDG uptake indicative of a decrease in total tumor glucose consumption. These preliminary results hint at the potential of non-invasive radiation-free HP MRSI as a valuable tool for assessment of effectiveness of targeted therapy in breast cancer.