The aim of the thesis is to assess response to modulations of the choline pathway in the context of the cholinic tumor phenotype. Conventional measurements like anatomically based endpoints may be inadequate to monitor the tumor response to targeted agents that usually do not result in tumor shrinkage while used in monotherapy. Therefore, the identification of more sensitively, non-invasive biomarkers are needed to optimize the schedule and dosage of novels therapeutics. The results illustrate that the assessment of total choline with 1H-MRS is able to confirm the inhibition of the target but is not sufficient to predict tumor response to the targeted treatment. Adding DW-MRI as a marker of tumor response to choline inhibition improves specificity of the monitoring. In addition, 13C-magnetic resonance spectroscopy and the detection of hyperpolarized 13C-fumarate to 13C-malate conversion has been suggested as a marker of cell death and treatment response in tumors. We showed here that hyperpolarized 13C-fumarate, detected by 13C-MRS, could constitute a new early in vivo marker of response to Sorafenib (MAPK inhibitor). The Sorafenib treatment targets a lot of kinases and its multi kinase action is closer to a non specific chemotherapeutic agent than to a very specific targeted treatment. It would be interesting to monitor the use of a more specific ChK inhibitor as MN-58b using 13C fumarate. However, using Sorafenib treatment, the level of tumor cell necrosis after treatment has been described as a good prognostic indicator for treatment outcome in the absence of any change in tumor size. Our results show that the net change in 13C-fumarate conversion into malate marker was even more sensitive than DW-MRI. In conclusion, our studies illustrate that: (i) the total choline 1H-MRS marker can constitute a pharmacodynamic marker of choline targeted therapies, but does not presume the actual response to therapy, (ii) the combination of diffusion MRI and choline spectroscopy can be considered as a marker of response to choline targeted therapies, and (iii) the follow up of the metabolic ratio of 13C-fumurate into 13C-malate can be considered as an emerging marker of response to targeted therapies, with an improved sensitivity while compared with Diffusion-MRI.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201
