Real Time Metabolic Imaging to Interrogate Early Detection and Prevention of Pancreatic Cancer

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Project Summary Pancreatic ductal adenocarcinoma (PDAC) has a median 5-year survival of only 11%, and early diagnosis of PDAC is recognized as one of the highest priority areas by the NCI, with a focus on identification of more sensitive and specific biomarkers and imaging strategies in discernible preneoplastic lesions. The overarching goal of this proposal is to develop the capability of non-invasively detecting advanced pancreatic intraepithelial neoplasia (PanIN) precursor lesions in pancreas prior to invasive disease in human subjects using two magnetic resonance imaging-based tools: a) hyperpolarized metabolic imaging (HP MR) and b) acidoCEST MRI. Hyperpolarization increases the signal of conventional MRI by over 10,000-fold. AcidoCEST MRI uses a clinically approved contrast agent to quantitatively measure the extracellular pH (pHe) in the tumor microenvironment. The application of dual acidoCEST and HP MR is innovative as they interrogate two different but related biochemical features of PanINs: extracellular pH (pHe) and dynamic metabolic flux (HP lactate-to- pyruvate and HP alanine-to-pyruvate ratios), respectively. Together, this approach provides an exciting opportunity to identify and understand early metabolic aberrations and biomarkers associated with these early lesions, to enable detection of advanced pancreatic preneoplastic lesions as well as pancreatic cancer at the smallest size, for which no methods of detection currently exist. This is a transitional research proposal with multiple sponsors for the F99 phase. Including the laboratories of Pratip Bhattacharya, Ph.D. in the Department of Cancer Systems Imaging and Florencia McAllister, M.D. in the Department of Clinical Cancer Prevention, both at MD Anderson Cancer Center with the following two aims. Aim 1, the F99 phase, is to demonstrate and validate the sensitivity and specificity of dynamic hyperpolarized metabolic biomarkers in the detection and monitoring the progression of pancreatic premalignant lesions to PDAC and compare these to a chronic pancreatitis model. Aim 2, the K00 phase research direction, is to demonstrate detection of PanIN with a combination of HP MR and acidoCEST and to determine the efficacy of immunoprevention on PanIN models. The success of this proposal has the potential for leading to practice changing recommendations for non-invasively detecting and monitoring advanced PanIN lesions and incipient pancreatic cancer, as well as to non-invasively assess the immunopreventive measures for cancer prevention. Also included in this proposal is a fellowship training plan to be conducted in both the F99 and K00 phases. They include additional training in metabolomic data analysis, research skills in small animal handling, histological and imaging techniques, public speaking, and scientific writing during the F99 phase. For the K00 phase the training plan include establishing dual-imaging modalities, develop immunopreventative strategies, mentoring and teaching future scientists, and inter-departmental or institutional networking.