Deuterium MRSI characterizations of glucose metabolism in orthotopic pancreatic cancer mouse models

Abstract

Detecting and mapping metabolism in tissues represents a major step in detecting, characterizing, treating and understanding cancers. Recently introduced deuterium metabolic imaging techniques could offer a noninvasive route for the metabolic imaging of animals and humans, based on using 2H magnetic resonance spectroscopic imaging (MRSI) to detect the uptake of deuterated glucose and the fate of its metabolic products. In this study, 2H6,6′‐glucose was administered to mice cohorts that had been orthotopically implanted with two different models of pancreatic ductal adenocarcinoma (PDAC), involving PAN‐02 and KPC cell lines. As the tumors grew, 2H6,6′‐glucose was administered as bolii into the animals' tail veins, and 2H MRSI images were recorded at 15.2 T. 2D phase‐encoded chemical shift imaging experiments could detect a signal from this deuterated glucose immediately after the bolus injection for both the PDAC models, reaching a maximum in the animals' tumors ~ 20 min following administration, and nearly total decay after ~ 40 min. The main metabolic reporter of the cancers was the 2H3,3′‐lactate signal, which MRSI could detect and localize on the tumors when these were 5 mm or more in diameter. Lactate production time traces varied slightly with the animal and tumor model, but in general lactate peaked at times of 60 min or longer following injection, reaching concentrations that were ~ 10‐fold lower than those of the initial glucose injection. This 2H3,3′‐lactate signal was only visible inside the tumors. 2H‐water could also be detected as deuterated glucose's metabolic product, increasing throughout the entire time course of the experiment from its ≈10 mM natural abundance background. This water resonance could be imaged throughout the entire abdomen of the animals, including an enhanced presence in the tumor, but also in other organs like the kidney and bladder. These results suggest that deuterium MRSI may serve as a robust, minimally invasive tool for the monitoring of metabolic activity in pancreatic tumors, capable of undergoing clinical translation and supporting decisions concerning treatment strategies. Comparisons with in vivo metabolic MRI experiments that have been carried out in other animal models are presented and their differences/similarities are discussed.

Improving deuterium metabolic imaging (DMI) signal‐to‐noise ratio by spectroscopic multi‐echo bSSFP: A pancreatic cancer investigation

“…17 As a cancer imaging method, DMI has so far been tested in gliomas, EL4 (lymphoma cell line) models, 1,3 and now on PDAC. 18 Indeed, simulations, phantom, and in vivo comparisons confirm that higher SNR can arise from ME-bSSFP for DMI investigations, as compared to CSI. bSSFP had been used for spectroscopy within the context of hyperpolarized 13 C 40,43,44 and 31 P MRSI experiments 23 ; this study demonstrates that equal or larger gains could result for 2 H applications.…”

“…For the LSL‐Kras G12D/+ ; LSL‐Trp53 R172H/+ ;Pdx‐1‐Cre (KPC)‐based pancreatic cancer model 16 examined in this study, 17 ongoing studies have shown that DMI can also highlight these tumors’ locations, via enhanced localized production of 2 H 3,3’ ‐lactate ca. 60 min after injection of a 2 H 6,6’ ‐glucose bolus 18 . By contrast, little or no lactate is evidenced outside the tumor’s location.…”

“…60 min after injection of a 2 H 6,6' -glucose bolus. 18 By contrast, little or no lactate is evidenced outside the tumor's location. Our hypothesis was that the ME-bSSFP sequence could lead to substantially better SNR per unit time than CSI experiments performed at equal spatial resolutions, or provide increased resolution compared to CSI and greater insight into the metabolites' locations.…”

Pan-cancer imaging of TERT expression using deuterium magnetic resonance spectroscopy-based assessment of pyruvate metabolism

“…Our studies indicate that [U-2 H]-pyruvate flux to lactate is mechanistically linked to the TERT-mediated increase in NADH in cell and in vivo tumor models. 2 H-MRS recently emerged as a novel method of imaging the metabolism of 2 H-labeled substrates in vivo and studies have largely focused on assessing 2 H-glucose metabolism in normal rat brain and in tumor-bearing animals 22,23,[25][26][27] . Importantly, De Feyter et al have established the clinical feasibility of using 2 Hglucose to monitor tumor burden in vivo in glioblastoma patients 23 .…”

“…Recently, 2 H-MRS, in which the nuclear magnetic resonance of the 2 H moiety is interrogated, emerged as a versatile, innovative method of examining metabolic pathway activity in vivo 22 . Following administration of 2 H-labeled substrates such as glucose, acetate or fumarate, flux to metabolic products can be quantified in real-time in a noninvasive manner in preclinical tumor models in vivo [23][24][25][26][27] . Importantly, the feasibility of 2 H-MRS has been established in glioblastoma patients 23 , underscoring the clinical translatability of this method.…”