Joel Garbow, Joseph Ackerman, Chong Duan, Liya Yuan, John Engelbach, Christina Tsien, Keith Rich

Glioblastoma (GBM) is a highly aggressive, malignant, primary brain tumor. Despite state-of-the-art standard-of-care treatment (surgery, chemotherapy, radiation), GBM inevitably recurs, usually in the peritumoral irradiated tumor/brain interface within two centimeters of the margins of the resection cavity. Anti-PD-L1 (immune checkpoint) inhibitors represent an important new class of cancer treatments, but have shown little efficacy in GBM. In a mouse glioma model, we demonstrate that late evolving effects of radiation blunt the therapeutic effectiveness of anti-PD-L1. Carbogen/O2 gas challenge experiments in these mice six weeks post-irradiation demonstrate that the brain microenvironment is physiologically modified, consistent with the observed blunting of immunotherapy.

Jin Li, Konstantinos Zormpas-Petridis, Andreas Heindl, Jessica Boult, Craig Cummings, Jeffrey Bamber, Yinyin Yuan, Ralph Sinkus, Yann Jamin, Simon Robinson

The relationship of magnetic resonance elastography-derived viscoelasticity quantified in vivo in nine pre-clinical tumour models exhibiting varying degrees of stromal density was compared with histological assessments of cellularity, collagen and vessel density. Both cellularity and collagen deposition were identified as important determinants of the relative tumour stiffness.

Dina Sikpa, Lisa Whittingstall, Jérémie P. Fouquet, Luc Tremblay, Réjean Lebel, Martin Lepage

We studied the effect of pre-existing inflammation on the genesis of brain metastases using MRI. Molecular MRI enhanced with VCAM-1 targeted microparticles of iron oxide enable the assessment of pre-existing vascular inflammation and then of metastasis implantation. The occurrence of brain metastases was increased by 2 fold when inflammation was present; this could be blocked with VCAM-1 antibody. This underlies the key role of VCAM-1 in tumor seeding to the brain, and suggests that preventive inflammation targeted treatment in cancer patients may minimize risks of brain metastasis. 

Ellen Ackerstaff, Natalia Kruchevsky, Ekaterina Moroz, H. Carl LeKaye, Kristen Zakian, SoHyun Han, HyungJoon Cho, Radka Stoyanova, Nirilanto Ramamonjisoa, Inna Serganova, Vladimir Ponomarev, Ronald Blasberg, Jason Koutcher

We characterized tumor vascularity, extracellular pH (pHe), and tumor lactate in various tumor models, focusing on prostate cancer. Spatial mapping demonstrated that vascular blood flow and permeability varied significantly in well-vascularized regions across tumor models and that the fraction of tumor necrosis was higher in the human than the murine models. The spatially most heterogeneous tumor type was characterized by the lowest lactate, a pHe of ~7.1 in well-vascularized regions, with lower pHe in less vascularized regions, and increasing lactate with decreasing vascular blood flow and permeability.

Donghan Yang, James Campbell III, Jenifer Gerberich, Heling Zhou, Ralph Mason

Tumor response to hypoxic gas breathing challenge was explored using oxygen-sensitive MRI in rat 13762NF breast tumors and compared with the more conventional hyperoxic gas breathing challenge. In viable tumor regions, blood oxygenation decreased with 16% O₂breathing (demonstrated by an increase in R₂*). A unique “on-and-off” pattern in T₁-weighted signal intensity, which was closely related to tumor hypoxia level, was triggered by 16% O₂ breathing but not 100% O₂ breathing. When combined with hypoxic gas breathing, oxygen-sensitive MRI may reveal tumor hypoxia threshold, which is important for assessing the efficacy of hypoxia-activated prodrugs.    

Devkumar Mustafi, Rebecca Valek, Michael Fitch, Victoria Werner, Xiaobing Fan, Erica Markiewicz, Sully Fernandez, Marta Zamora, Jeffrey Mueller, Suzanne Conzen, Matthew Brady, Gregory Karczmar

Breast cancer is the most commonly diagnosed malignancy among women in the US. Epidemiology shows that a high animal fat diet increases risk of triple-negative breast cancer (TNBC). Our previous work examined the effect of pre-pubertal exposure to high dietary animal fat in the SV40Tag mouse model of TNBC. We showed that a high animal fat diet changes mammary fat composition and increases incidence and aggressiveness of mammary cancers in this model. Here, we demonstrate using MR angiography that changes in fat composition and cancer incidence are paralleled by increases in vascular density in the mammary gland.

Henk De Feyter, Kevin Behar, Peter Brown, Douglas Rothman, Robin de Graaf

Deuterium Metabolic Imaging (DMI) is a novel approach providing high 3D spatial resolution metabolic data from both animal models and human subjects. DMI relies on ²H MRSI in combination with administration of ²H-labeled substrates. In a rat glioma model we show how DMI combined with administration of [6,6’-²H₂]-glucose and [²H₃]-acetate allowed spatial mapping of differences in metabolism between normal brain and glioma. DMI data after infusion of ²H-labeled glucose revealed high glucose uptake and lactate production but limited glucose oxidation in glioma. Furthermore, DMI revealed acute therapeutic effects of a drug (dichloroacetate) targeting glucose oxidation. 

Santosh Bharti, Paul Winnard Jr., Yelena Mironchik, Louis Dore-Savard, Balaji Kirshnamachary, Zaver Bhujwalla

Tumor interstitial fluid (TIF) contains the tumor secretome and forms a critical component of the tumor microenvironment. Cyclooxygenase-2 (COX2) mediates the inflammatory response of cells and is upregulated in cancers. In cancers, COX-2 expression has been related to increased invasion and metastasis.  Here, for the first time, using 1H MR spectroscopy we characterized changes in the metabolic patterns of TIF in tumors derived from triple negative SUM-149 human breast cancer cells with COX-2 overexpressed. COX-2 overexpression significantly altered several fundamental metabolic pathways. These data provide new insights into the role of COX-2 in tumor aggressiveness, and identify new metabolic targets.  

Georgios Batsios, Pavithra Viswanath, Anne Marie Gillespie, Elavarasan Subramani, Joanna Phillips, Russell Pieper , Sabrina Ronen

Mutant IDH1 produces the oncometabolite 2HG, which drives tumorigenesis in low-grade gliomas. One potential therapeutic option for such gliomas is treatment with a PI3K/mTOR inhibitor. Using cell models genetically-engineered to express mutant IDH1, we observed that PI3K/mTOR inhibition induced a reduction in 2HG levels in treated cells and tumors, that was associated with reduced cell proliferation and enhanced animal survival. The drop in 2HG was due to a reduction in its synthesis from both glucose and glutamine. Our study identifies MRS-detectable metabolic alterations that could serve as indicators of response for mutant IDH1 glioma patients undergoing treatment with PI3K/mTOR inhibitors.

Adam Berrington, Karisa Schreck, Christopher Whitlow, Roy Strowd, Peter Barker

Recent studies have focused on the use of ketogenic diet (KD) in the treatment of glioma since tumor cells are heavily glucose-dependent. Here, we assess the ability of MRS to monitor KD-therapy in glioma patients. Using a semi-LASER sequence at 3 T, with fully simulated basis for spectral fitting, we measured increases in acetone and β-hydroxybutyrate after KD in tumor and contralateral brain. NAA concentration decreased in contralateral brain and there was an observed elevation of β-hydroxybutyrate in IDH-mutated gliomas; potentially indicating differential response to KD. These results indicate a potential for MRS in monitoring KD-based therapy in glioma.