Monitoring Chemotherapeutic Response by Hyperpolarized 13C-Fumarate MRS and Diffusion MRI

Abstract

Targeted chemotherapeutic agents often do not result in tumor shrinkage, so new biomarkers that correlate with clinical efficacy are needed. In this study, we investigated noninvasive imaging protocols to monitor responses to sorafenib, a multikinase inhibitor approved for treatment of renal cell and hepatocellular carcinoma. Healthy cells are impermeable to fumarate, so conversion of this metabolite to malate as detected by 13C-magnetic resonance spectroscopy (MRS) has been suggested as one marker for cell death and treatment response in tumors. Diffusion MRI also has been suggested as a measure of therapy-induced cytotoxic edema because viable cells act as a diffusion barrier in tissue. For these reasons, we assessed sorafenib responses using hyperpolarized 13C-fumarate, diffusion-weighted MRI (DW-MRI) in a xenograft model of human breast cancer in which daily administration of sorafenib was sufficient to stabilize tumor growth. We detected signals from fumarate and malate following intravenous administration of hyperpolarized fumarate with a progressive increase in the malate-to-fumarate (MA/FA) ratio at days 2 to 5 after sorafenib infusion. The apparent diffusion coefficient (ADC) measured by DW-MRI increased in the treated group consistent with cytotoxic edema. However, the MA/FA ratio was a more sensitive marker of therapeutic response than ADC, with 2.8-fold versus 1.3-fold changes, respectively, by day 5 of drug treatment. Histologic analyses confirmed cell death in the sorafenib-treated cohort. Notably, 13C-pyruvate-to-lactate conversion was not affected by sorafenib in the breast cancer model examined. Our results illustrate how combining hyperpolarized substrates with DW-MRI can allow noninvasive monitoring of targeted therapeutic responses at relatively early times after drug administration.

MARCH1 encourages tumour progression of hepatocellular carcinoma via regulation of PI3K‐AKT‐β‐catenin pathways

“…13 This study suggested that MARCH1 regulates cellular processes, not only in immunity, but also in cell signal transduction. [22][23][24]36 Previous studies have shown an ADC increase following targeted agent treatment with cisplatin in an ovarian cancer model, 37 sorafenib in breast cancer xenografts 38 and irinotecan in colon carcinoma xenografts. In this regard, here, we demonstrated that MARCH1 deletion does affect the biomarker of HCC tumours.…”

Simultaneous imaging of hyperpolarized [1,4‐13C2]fumarate, [1‐13C]pyruvate and 18F–FDG in a rat model of necrosis in a clinical PET/MR scanner

“…Increased conversion of pyruvate into lactate, also known as the Warburg effect, is a main hallmark of neoplastic activity, and has the potential to effectively monitor the response to treatment . The production of malate from fumarate has been proposed as a sign of necrosis, and it is expected that the degree of necrosis induced by treatment will be proportional to the amount of malate produced. The amount of malate observed in the 13 C spectrum also depends on the time of imaging following the intervention, as shown by the difference in malate signal between the two injections in the second rat.…”

“…This observation is referred to as the Warburg effect and it results from the fact that most cancer cells show elevated glycolysis even in the presence of sufficient oxygen. Moreover, magnetic resonance imaging (MRI) with hyperpolarized [1,4‐ 13 C 2 ]fumarate has been shown to allow the early detection of necrosis . The conversion of fumarate into malate is a normal step in the mitochondrial tricarboxylic acid cycle and is catalyzed by fumarase.…”

Assessing inflammatory liver injury in an acute CCl4model using dynamic 3D metabolic imaging of hyperpolarized [1-13C]pyruvate

“…Numerous studies have investigated metabolic imaging of hyperpolarized pyruvate (Pyr) in cancer and heart disease (see references in and ), and it has recently been applied in the first clinical trial of this methodology in prostate cancer patients . However, other than liver cancer , few studies have reported applications of hyperpolarized 13 C compounds in the diseased liver. Using a fatty‐liver mouse model of type 2 diabetes, Lee et al .…”

“…Numerous studies have investigated metabolic imaging of hyperpolarized pyruvate (Pyr) in cancer and heart disease (see references in 2 and 3), and it has recently been applied in the first clinical trial of this methodology in prostate cancer patients (4). However, other than liver cancer (5)(6)(7)(8)(9)(10), few studies have reported applications of hyperpolarized 13 C compounds in the diseased liver. Using a fatty-liver mouse model of type 2 diabetes, Lee et al (11) found increased hyperpolarized [1-13 C]Pyr to [1][2][3][4][5][6][7][8][9][10][11][12][13] C]alanine (Ala) labeling, which also correlated with ex vivo hepatic alanine transaminase (ALT) activity.…”