Friederike Hesse¹, Alan Wright¹, Vencel Somai^1,2, Flaviu Bulat^1,3, and Kevin Brindle^1,4
1CRUK CI, University of Cambridge, Cambridge, United Kingdom, ²Department of Radiology, University of Cambridge, Cambridge, United Kingdom, ³Department of Chemistry, University of Cambridge, Cambridge, United Kingdom, ⁴Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom

Cell death is an important imaging target for assessing early tumour treatment response and the effectiveness of therapy. We show here that ²H-labelled fumarate can be administered orally to detect cell death and assess early tumour treatment response in a subcutaneous lymphoma (EL4) model. Following oral gavage, ²H spectra were acquired from tumors with a time resolution of 5 min. Within 48h after chemotherapeutic drug (etoposide) treatment the tumor malate/fumarate signal ratios increased similarly to those measured after intravenous injection.

Rui V Simoes¹, Rafael N Henriques¹, Beatriz M Cardoso¹, Francisca F Fernandes¹, Tania V Carvalho¹, and Noam V Shemesh^1
1Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal

Dynamic glucose-enhanced deuterium MRS (DGE ²H-MRS) coupled with Marchenko-Pastur PCA denoising has shown potential for in vivo quantification of glucose metabolism through glycolysis and mitochondrial oxidation in a mouse model of glioblastoma, and for assessment of pathway flux modulations according to tumor heterogeneity. Here, we extend this approach to immunocompetent mouse glioblastoma subtypes with marked differences in tumor cell metabolism and histopathologic features, to utterly demonstrate the potential of DGE ²H-MRS for non-invasive metabolic phenotyping of glioma, or other cancers with mitochondrial oxidation dependencies, according to key features of the tumor microenvironment such as cell proliferation.

Georgios Batsios¹, Celine Taglang¹, Meryssa Tran¹, Anne Marie Gillespie¹, Sabrina Ronen¹, Joseph Costello², and Pavithra Viswanath^1
1Radiology and Biomedical Imaging, UCSF, San Francisco, CA, United States, ²Neurological Surgery, UCSF, San Francisco, CA, United States

Telomerase reverse transcriptase (TERT) is essential for tumor proliferation and is an attractive therapeutic target. Non-invasive methods of imaging TERT can report on tumor proliferation and response to therapy. Here, we show that ²H-MRS following administration of [U-²H]pyruvate non-invasively monitors TERT expression in clinically relevant patient-derived glioma models. Importantly, imaging TERT using [U-²H]pyruvate provides a readout of response to targeted TERT inhibitors and standard of care chemotherapy in vivo, at early timepoints that precedes MRI-detectable anatomical alterations. Clinical translation of our results can enable non-invasive assessment of TERT expression in vivo and, thereby, aid in imaging response to anti-cancer therapies.

Donghyun Hong¹, Marina Radoul¹, Noriaki Minami¹, Anne Marie Gillespie¹, Russell O. Pieper¹, Joseph Costello¹, Pavithra Viswanath¹, and Sabrina M. Ronen^1
1University of California, San Francisco, San Francisco, CA, United States

Mutant IDH1 inhibitor treatment is currently in clinical trials for glioma patients. Therefore, in vivo biomarkers are needed to assess early therapeutic responses. Here we treated mutant IDH1-expressing cells and animals with patient-derived mutant IDH1 brain tumors with the emerging inhibitor BAY-1436032. Using ¹H MRS we found a significant decrease in 2HG that was accompanied by an increase in glutamate and phosphocholine, and using ¹³C MRS we detected a significant decrease in 2HG and a significant increase in glutamate produced from hyperpolarized [1-¹³C] α-ketoglutarate in cell and animal models.

Sourav Bhaduri¹, Jack Sharkey¹, Soham Mukherjee¹, Edward J Delikatny², Sungheon G Kim³, and Harish Poptani^1
1Centre for Preclinical Imaging, University of Liverpool, Liverpool, United Kingdom, ²Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States, ³Department of Radiology, Weill Cornell Medical College, New York, NY, United States

This study investigates the effect of JAS239 on GL261 mouse glioblastoma using MRS. Higher reduction in Cho concentration and Cho/Cr ratios were observed in the tumour region than the contralateral normal brain after JAS239, indicating high sensitivity of MRS in as a pharmacodynamic marker of ChoK inhibition in glioblastomas with a potential of being an alternative treatment method.

Natalie J Serkova¹, Jane S Manalo², Jenna L Steiner², Andrea M Griesinger², Angela Pierce², Mark S Brown², and Nicholas F Foreman^3
1Radiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States, ²University of Colorado Anschutz Medical Campus, Aurora, CO, United States, ³Children's Hospital Colorado, Aurora, CO, United States

We report on an advanced mpMRI protocol for characterizing the cellular and vascular phenotype in an orthotopic mouse model of pediatric ependymoma (EPN). Using diffusion-weighted based cell-size imaging, iron-oxide based vessel-size imaging and quantitative T2-maps, we report on an EPN-specific phenotype, characterized by an increased cell size (S=14 microns), increased vessel density index (Q=0.54), and low ADC values (0.63x10-3). Radiation treatment (10 Gy) in combination with 5-fluorouracil chemotherapy resulted in a decrease of gross tumor volumes, tumor necrosis with decreased cell sizes and increased ADC values, as well as a dramatic vascular-inflammatory response (highly decreased Q and DT2 values).

Sourav Bhaduri¹, Jack Sharkey¹, Clémentine Lesbats², Claire L. Kelly¹, Soham Mukherjee¹, Edward J Delikatny³, Sungheon G Kim⁴, and Harish Poptani^1
1Centre for Preclinical Imaging, University of Liverpool, Liverpool, United Kingdom, ²Division of Radiotherapy and Imaging, Institute of Cancer Research, London, United Kingdom, ³Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States, ⁴Department of Radiology, Weill Cornell Medical College, New York, NY, United States

This study was designed to monitor changes in DCE-MRI based parameters K^trans, v_e, τ_i and F_p in pre-clinical GBM models in response to choline kinase inhibition using a cluster analysis approach. The study demonstrates that region-based clustered pharmacokinetic parameters obtained using DCE-MRI can be used for detecting and assessing tumour heterogeneities which may be useful in assessing therapeutic response.