Jesus Pacheco-Torres¹, Marie-France Penet^1,2, Flonne Wildes¹, Yelena Mironchik¹, Balaji Krishnamachary¹, and Zaver M Bhujwalla^1,2,3
1The Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States, ²Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States, ³Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University, School of Medicine, Baltimore, MD, United States

Expression of programmed death-ligand 1 (PD-L1) plays a significant role in creating an immune suppressive tumor microenvironment. We investigated the relationship between the aberrant choline metabolism observed in most cancers and PD-L1 expression in triple negative human MDA-MB-231 breast cancer cells. Using siRNA to downregulate Chk-a or PD-L1 or both, we identified a close inverse interdependence between Chk-α and PD-L1. We identified, for the first time, the role of PD-L1 in cancer cell metabolism. These results have significant implications for therapy and provide new insights into the relationship between metabolism and immune resistance in these breast cancer cells.

Kanchan Sonkar¹, Caitlin M. Tressler¹, and Kristine Glunde^1,2
1The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States, ²The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Triple negative breast cancer (TNBC) is a highly aggressive form of cancer that poses severe health care problem as no targeted therapeutics are available for its treatment. TNBC is treated with chemotherapeutic agents, including doxorubicin, paclitaxel, vinorelbine, 5-fluorouracil, melphalan and cisplatin , which are either used alone or in various combinations. Studies investigating the metabolic effects of chemotherapy in TNBC are still limited. Here we have used high-resolution ¹H MRS to study the metabolic profiles of TNBC cell lines MDA-MB-231 and SUM159 treated with these chemotherapeutic agents as compared to untreated controls. 

Laurie J Rich¹, Puneet Bagga¹, Gabor Mizsei¹, Mitchell D Schnall¹, John A Detre², Mohammad Haris³, and Ravinder Reddy^1
1Radiology, University of Pennyslvania, Philadelphia, PA, United States, ²Neurology, University of Pennyslvania, Philadelphia, PA, United States, ³Research Branch, Qatar University, Doha, Qatar

A key hallmark of malignant tissues is a metabolic shift from oxidative phosphorylation to glycolytic metabolism, leading to increased lactate production. Probing the kinetics of lactate production in vivo may play a key role in studying disease mechanisms and developing biomarkers of treatment response. Here, we developed a new approach for studying glycolytic metabolism in glioblastoma by combining ¹H MRS with infusion of deuterated glucose. Infusion of [6,6'-²H₂]glucose leads to downstream deuterium labeling of lactate, resulting in a reduction in the 1.33 ppm lactate peak on ¹H MRS and making it is possible to monitor the metabolic turnover of lactate.

Kavindra Nath¹, David Nelson¹, Jeffrey Roman¹, Sofya Osharovich¹, Saad Sheikh², Stepan Orlovskiy¹, Stephen Pickup¹, Dennis Leeper³, Yancey Gillespie⁴, Corrine Griguer⁵, Jay Dorsey², Mary Putt⁶, and Jerry Glickson^1
1Radiology, University of Pennsylvania, Philadelphia, PA, United States, ²Radiation Oncology, University of Pennsylvania, Philadelphia, PA, United States, ³Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, United States, ⁴Neurosurgery, University of Alabama, Birmingham, AL, United States, ⁵Radiation Oncology, University of Iowa, Iowa City, IA, United States, ⁶Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, United States

Standard of care for glioblastoma multiforme (GBM) patients, the Stupp protocol, involves radiotherapy concurrent with adjuvant temozolomide (TMZ) chemotherapy. Lonidamine (LND), an inhibitor of monocarboxylate transporters, mitochondrial pyruvate carrier and mitochondrial complex I & II, is shown to potentiate TMZ chemotherapy inhibiting the growth of U251 glioblastoma cells orthotopically implanted in mice. LND effects measured in vivo by ³¹P and ¹H MRS in subcutaneous U251 glioblastoma xenografts showed a sustained and tumor-selective decrease in intracellular pH, decrease in bioenergetics (βNTP/Pi) and an increase in lactate. Selective tumor acidification and deenergization induced by LND potentiated the TMZ response in U251 glioblastoma xenografts.

Georgios Batsios¹, Pavithra Viswanath¹, Celine Taglang¹, Robert Flavell¹, Joseph Costello², Russell O Pieper², Peder Larson¹, and Sabrina Ronen^1
1Radiology and Biomedical Imaging, UCSF, San Francisco, CA, United States, ²Neurological Surgery, UCSF, San Francisco, CA, United States

Telomerase reverse transcriptase (TERT) expression is essential for tumor proliferation and is also an attractive therapeutic target for gliomas. Imaging TERT can help monitor tumor development and response to therapy. TERT expression has previously been shown to enhance glucose flux via the pentose phosphate pathway in low grade glioma cells expressing TERT. Here, we show that hyperpolarized δ-[1-¹³C]gluconolactone metabolism to 6-phospho-[1-¹³C]gluconate is significantly higher in tumor compared to contralateral normal brain in TERT-expressing low-grade oligodendrogliomas, pointing to the utility of hyperpolarized δ-[1-¹³C]gluconolactone for non-invasive in vivo assessment of this critical tumor hallmark in gliomas.

Mor Mishkovsky¹, Olga Gusyatiner², Bernard Lanz¹, Cristina Cudalbu³, Irene Vassallo², Marie-France Hamou², Jocelyne Bloch², Arnaud Comment⁴, Rolf Gruetter^1,3,5,6, and Monika Hegi^2
1Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, ²Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland, ³Centre d'Imagerie Biomédicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, ⁴General Electric Healthcare, Chalfont St Giles, United Kingdom, ⁵Department of Radiology, University of Geneva (UNIGE), Geneva, Switzerland, ⁶Department of Radiology, University of Lausanne (UNIL), Lausanne, Switzerland

Glioblastoma (GBM) is the most malignant primary brain tumor in adults. Aberrant glucose metabolism is considered a hallmark of cancer, via the so-called ‘Warburg Effect’, however recent studies show distinct metabolic profile associated with the invasive phenotype in GBM, indicating active glucose oxidation. Hyperpolarized (HP) endogenous compounds, provides real-time metabolic information which is related to enzymatic activity. The aim of the present study was to apply HP ¹³C-glucose MRS in patient-derived GBM models and to investigate glucose metabolism in the infiltrative front of GBM, which potentially would enable to differentiate the invasive front of GBM from normal brain.

Leo L Cheng¹, Lindsey Vandergrift¹, Andrew Gusev¹, Shulin Wu¹, Mukesh Harisinghani¹, Chin-Lee Wu¹, and Adam Feldman^1
1MGH/Harvard, Boston, MA, United States

Prostate cancer (PCa) clinic is challenged by heterogeneously distributed and clinical insignificant diseases. Multiparametric (mp)-MRI, with a PI-RADS score, correlated to clinically significant cancer and its morphological variations to establish a biopsy Target, and ultrasound fusion-guided biopsy guided to the targeted area has increased detection of clinically significant cancer. We studied PI-RADS score according to tissue MRS-based metabolomics. Metabolic differences between Target and contralateral cores, regardless if Targets were Ca-positive or not, support the assumption that targeted areas fundamentally and metabolomically differ from non-targeted areas.

Geoffrey J. Topping¹, Irina Heid², Moritz Mayer², Lukas Kritzner², Florian Englert², Martin Grashei¹, Christian Hundshammer¹, Katja Steiger³, Katja Peschke⁴, Markus Schwaiger¹, Maximilian Reichert⁴, Franz Schilling¹, and Rickmer Braren^2
1Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany, ²Institute of Radiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany, ³Institute of Pathology, Technical University of Munich, Munich, Germany, ⁴Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

Multimodal imaging for characterization of pancreatic tumour cellularity and metabolism has potential to guide treatment. Murine orthotopically transplanted tumours were imaged with DWI, ¹³C-pyruvate CSI, and ¹⁸F-FDG PET, and endogenous tumours with DWI and CSI. Transplanted epithelial and mesenchymal tumours had similar cellularity, shown by ADC, but different metabolism, with higher mesenchymal AUC ratios and SUV. Compared with other endogenous tumour growth patterns, classical ductal had lower tumour cellularity (higher ADC), while solid had higher and more-variable AUC ratios. The combination of these methods can characterize tumour metabolism, including correcting for tumour cellularity, better than CSI alone.

Carlos Bilreiro¹, Rui V. Simões¹, Francisca F. Fernandes¹, Mireia Castillo-Martin¹, Kevin Harkins², Mark Does², Celso Matos¹, and Noam Shemesh^1
1Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal, ²Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States

Survival in pancreatic cancer resides on an early diagnosis, for which current imaging methods are insufficient. Here, we investigated which MRI contrast can reflect pancreatic pre-neoplastic lesions, particularly, pancreatic intraepithelial neoplasia (PanIN). To this end, we developed an ultrafast DWI-MGE pulse sequence and performed MR microscopy on pancreas extracted from transgenic mice with PanIN lesions (along with controls), and validated our findings using histology. PanIN lesions were clearly detected in the transgenic mice and differentiated from inflammatory changes at b=1000 sec/mm² and long TE. Our findings are encouraging for future detection of PanIN in vivo.