MR evaluation of response to targeted treatment in cancer cells

Abstract

The development of molecular technologies, together with progressive sophistication of molecular imaging methods, has allowed the further elucidation of the multiple mutations and dysregulatory effects of pathways leading to oncogenesis. Acting against these pathways by specifically targeted agents represents a major challenge for current research efforts in oncology. As conventional anatomically based pharmacological endpoints may be inadequate to monitor the tumor response to these targeted treatments, the identification and use of more appropriate, noninvasive pharmacodynamic biomarkers appear to be crucial to optimize the design, dosage and schedule of these novel therapeutic approaches. An aberrant choline phospholipid metabolism and enhanced flux of glucose derivatives through glycolysis, which sustain the redirection of mitochondrial ATP to glucose phosphorylation, are two major hallmarks of cancer cells. This review focuses on the changes detected in these pathways by MRS in response to targeted treatments. The progress and limitations of our present understanding of the mechanisms underlying MRS-detected phosphocholine accumulation in cancer cells are discussed in the light of gene and protein expression and the activation of different enzymes involved in phosphatidylcholine biosynthesis and catabolism. Examples of alterations induced in the MRS choline profile of cells exposed to different agents or to tumor environmental factors are presented. Current studies aimed at the identification in cancer cells of MRS-detected pharmacodynamic markers of therapies targeted against specific conditional or constitutive cell receptor stimulation are then reviewed. Finally, the perspectives of present efforts addressed to identify enzymes of the phosphatidylcholine cycle as possible novel targets for anticancer therapy are summarized.

Choline metabolism in malignant transformation

“…The search for biomarkers to detect cancer and to non-invasively monitor the response to treatment has led to several clinical studies evaluating the non-invasive detection of tCho for these objectives. Similar to studies in cancer cells 10 , human tumour xenograft models 10 and excised tumour tissue 11,12 , clinical studies have confirmed the activation of choline metabolism in human tumours in vivo 10,13 .…”

Choline kinase alpha—Putting the ChoK-hold on tumor metabolism

“…These methods include conversion of PtdCho to free choline and phosphatidic acid (PA) by phospholipase D (PLD), and the coordinated activity of phospholipase A 2 (PLA 2 ), lysophospholipase (LPL) and glycerophospholipase:phosphodiesterase (GPC:PDE) to render free choline. These enzymes have been found to be differentially expressed in some but not all cancers, and much work is still required to fully elucidate their involvement in PC production [27,28]. A number of mitogenic second messengers are released as byproducts of PtdCho cleavage (Fig.…”

The Tumor Microenvironment Modulates Choline and Lipid Metabolism

“…Phosphatidylcholine (PtdCho), the most abundant phospholipid in eukaryotic cell membranes, contributes to proliferative growth and programed cell death (4). High levels of cellular phosphocholine (PC) and total choline-containing compounds [tCho: the sum of Cho, PC, and glycerophosphocholine (GPC)] have been consistently observed in cancer cells and tumor tissue and are closely related to malignant transformation, invasion, and metastasis (5–12). …”