Metabolic tumor imaging using magnetic resonance spectroscopy

Abstract

The adaptability and the genomic plasticity of cancer cells, and the interaction between the tumor microenvironment and co-opted stromal cells, coupled with the ability of cancer cells to colonize distant organs, contribute to the frequent intractability of cancer. It is becoming increasingly evident that personalized molecular targeting is necessary for the successful treatment of this multifaceted and complex disease. Noninvasive imaging modalities such as magnetic resonance (MR), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) are filling several important niches in this era of targeted molecular medicine, in applications that span from bench to bedside. In this review we focus on noninvasive magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) and their roles in future personalized medicine in cancer. Diagnosis, the identification of the most effective treatment, monitoring treatment delivery, and response to treatment are some of the broad areas into which MRS techniques can be integrated to improve treatment outcomes. The development of novel probes for molecular imaging--in combination with a slew of functional imaging capabilities--makes MRS techniques, especially in combination with other imaging modalities, valuable in cancer drug discovery and basic cancer research.

Figure 1

(A) Chemical structures of the choline phospholipid metabolites free choline (Cho), phosphocholine (PC), and glycerophosphocholine (GPC). (B) High-resolution ex vivo ¹H MR spectra of triple-negative human MDA-MB-231 breast cancer cell extracts (top) and in vivo ¹H MR spectra of the same cell line grown as orthotopic tumor (bottom). (C) High-resolution ex vivo ³¹P MR spectra of triple-negative human MDA-MB-231 breast cancer cell extracts (top) and in vivo ³¹P MR spectra of the same cell line grown as orthotopic tumor (bottom). Cho, free choline; GPC, glycerophosphocholine; GPE, glycerophosphoethanolamine; DPDE, diphosphodiester; NDP, nucleoside diphosphate; NTP, nucleoside triphosphate; Lac, lactate; Lipid-CH₂-, methylene groups of mobile lipids; Lipid-CH₃-, methyl groups of mobile lipids; PC, phosphocholine; PE, phosphoethanolamine; PCr, phosphocreatine; Pi, inorganic phosphate; tCho, total choline-containing compounds (Cho+PC+GPC). The ¹H and ³¹P nuclei in Cho, PC, and GPC and their respective ¹H and ³¹P signals in the MR spectra are color-coded to identify the MR signals that arise from the corresponding nuclei.

Figure 2

(A) Region of representative HR MAS >¹H MRS spectra selected for multivariate analysis, obtained from primary tumor tissue from patients with invasive ductal carcinoma grade III breast cancer. The top spectrum is derived from a patient diagnosed as hormone positive, with lymphatic spread, and the bottom spectrum from a hormone positive patient, without proven lymphatic spread. Glc, glucose; Lac, lactate; Cr, creatine; m-Ino, myo-inositol; Tau, taurine; GPC, glycerophosphocholine; PC, phosphocholine; Cho, choline. (B) Score plot of principal component 1 (PC1), principal component 2 (PC2), and principal component (PC3) from the principal component analysis of samples from 77 breast cancer patients. Samples from noninvolved adjacent tissue (0) are separated from the rest, thus demonstrating a marked metabolic difference from the malignant samples (+). However, invasive ductal carcinoma samples were interspersed, and there was no possibility to differentiate them from noninvolved adjacent tissue or cancer, emphasizing the need for more sophisticated analysis in order to achieve classification. Adapted with kind permission from Springer Science+Business Media: Bathen et al.

Figure 3

(A) Diagram of [1-¹³C]-pyruvate and its relevant metabolic pathways leading to [1-¹³C]-lactate and [1-¹³C]-alanine. (B) Peak height plots from hyperpolarized ¹³C spectra reveal the time course of hyperpolarized [1-¹³C]-pyruvate and its metabolic products following injection of 28 μmol of hyperpolarized [1-¹³C]-pyruvate at a constant rate from 0 to 12 s. (C) Axial T₂-weighted 1H MR image showing the primary tumor and a lymph node metastasis in a ‘transgenic adenocarcinoma of mouse prostate’ (TRAMP) mouse with a high-grade primary tumor, and (D) overlay of an interpolated hyperpolarized [1-¹³C]-lactate image following injection of 28 μmol of hyperpolarized [1-¹³C]-pyruvate. After spatially zero-filling and voxel-shifting the ¹³C MR spectra to maximize the amount of tumor in the voxels, (E) a subset of the spectral grid was selected and (F) displayed. The three-dimensional MRSI was acquired with a nominal voxel size of 135 mm³, zero-filled to 17 mm³. Substantially elevated lactate was detected in the high-grade primary tumor compared with adjacent normal tissue. In addition, the metabolite signal is significantly lower in the necrotic regions of the primary tumor. Lac, lactate; Ala, alanine; Pyr, pyruvate. Adapted with permission from the American Association for Cancer Research.

Figure 4

(A) Axial T₂-weighted 1H MRI section in a 68-year-old man with newly diagnosed Gleason 6 prostate cancer, serum prostate-specific antigen level of 4.6 ng/mL, and clinical stage of T2B. A large focus (arrows) of reduced T₂ signal intensity was observed in the left peripheral zone of the prostate. (B) Photomontage showing the axial T₂-weighted 1H MR image on the left side with an overlaid grid that corresponds to the MRSI spectral array on the right side. Voxels corresponding to the focus of reduced T₂ signal intensity displayed high total choline peaks (arrows), consistent with prostate cancer. (C) Axial T₂-weighted ¹H MRI section through the base of the prostate shows gross extracapsular extension of the tumor, with seminal vesicle invasion (stage T3B). The patient developed metastatic recurrence at 21 months after external beam radiotherapy. Adapted from Joseph et al with permission from Elsevier.

Figure 5

(A) A pre-therapy T₂-weighted sagittal fat suppressed 1H MR image including MRSI grid is shown that was measured in a patient with locally advanced breast cancer who responded to neoadjuvant chemotherapy (NACT). The ¹H MR spectrum on the left was obtained from a voxel with tCho signal prior to therapy. On the right, a post-therapy ¹H MR spectrum obtained from the voxel highlighted in the ¹H MR image is displayed that was obtained from the same patient after the third cycle of NACT and showed no tCho. (B) Pre-therapy T₂-weighted sagittal fat suppressed 1H MR image with MRSI grid of a patient with locally advanced breast cancer who did not respond to NACT. The ¹H MR spectrum on the left was obtained from a voxel highlighted in the above image showing tCho signal. On the right, a post-therapy T₂-weighted sagittal fat suppressed 1H MR image, including a ¹H MR spectrum obtained from the highlighted voxel, is displayed that was measured in the same patient after the third cycle of NACT showing tCho signal. These presented data suggest that the tCho signal can predict the response of breast cancer patients to NACT. Adapted with permission from John Wiley and Sons.

Figure 6

¹H/¹³C MRSI of ¹³C-labeled temozolomide ([¹³C]TMZ) in a human MCF-7 breast tumor xenograft, using the indirect detection technique, heteronuclear multiple-quantum coherence (HMQC). The same tumor was imaged using gadolinium(III) diethylene triamine penta-acetic acid (GdDTPA)-enhanced DCE-MRI. (A) The chemical structure of [¹³C]TMZ shows the ¹³C-labeled nucleus. (B) A significantly higher signal-to-noise (SNR) ratio was detected by indirect ¹H-detected ¹³C MRS detection of [¹³C]TMZ using HMQC as compared to direct ¹³C MRS detected [¹³C]TMZ. (C) The corresponding GdDTPA contrast uptake map shown in green was reconstructed as a difference map between pre- and post-contrast acquisitions. The grayscale image represents the tumor. (D) The intratumoral 3D distribution of GdDTPA-contrast uptake (green) was co-registered with the HMQC CSI detected 3D distribution of [¹³C]TMZ shown in red. Green and red channels indicate the GdDTPA uptake and distribution of [¹³C]TMZ, respectively, and reveal a partial overlap of the GdDTPA-enhancing regions with tumor areas of high temozolomide uptake. Adapted with permission from John Wiley and Sons.