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.