Identifying The Immune Related Metabolic Properties Of Pancreatic Cancer Using Nuclear Magnetic Resonance Spectroscopy And Dynamic Magnetic Resonance Spectroscopic Imaging With Hyperpolarized Pyruvate

Author

Joseph Weygand, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

0000-0002-1508-9162

Date of Graduation

8-2017

Document Type

Thesis (MS)

Program Affiliation

Medical Physics

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Pratip Bhattacharya

Committee Member

Richard Wendt

Committee Member

Florencia McAllister

Committee Member

Jason Fleming

Committee Member

Victor Krasnykh

Committee Member

Niki Millward

Abstract

Despite its relatively low incidence, pancreatic cancer was the fourth leading cause of cancer-related death in the US in 2015. This is due in part to pancreatic cancer’s natural resistance to both chemotherapy and radiotherapy. Immunotherapy presents an attractive potential treatment approach, but initial trials in mice have proved ineffective. Because cancer cells exhibit a significant increase in metabolic activity relative to normal tissue, an understanding of the metabolic function of tumors in systems with different levels of immunocompetence is a critical first step to develop an understanding of the immune-related metabolic properties of the tumor, which have potential application in assessing a tumor’s response to immunotherapy.

Magnetic resonance (MR) is an intrinsically low sensitivity technique, but dynamic nuclear polarization allows one to increase the MR signal by five orders of magnitude. As described by the Warburg effect, even in the presence of an ample amount of oxygen, tumors preferentially metabolize their energy via the inefficient process of glycolysis in which pyruvate is ultimately converted into lactate. Thus, by hyperpolarizing ¹³C-labelled pyruvate, one can spectroscopically observe the conversion of pyruvate to lactate in real time and quantify a tumor’s glycolytic conversion flux in vivo. In addition, the application of high-resolution ¹H nuclear magnetic resonance metabolomics allows one globally analyze the entire water-soluble metabolome and quantify the relative concentrations of each metabolite in an extracted tumor tissue sample. By applying MR spectroscopic imaging with hyperpolarized pyruvate and NMR metabolomics, this study identifies clear metabolic biomarkers that can facilitate the assessment of metabolic changes between pancreatic tumors in mice cultivated in both immunocompromised and immunocompetent environments.

Keywords

Hyperpolarization pyruvate lactate pancreatic cancer MRI NMR spectroscopy