LCMS: From Pharmacokinetics to Metabolomics

Bernie Monaghan (BM): Could you tell us a little about the unit and group in which you work at Sutton? Florence Raynaud (FR): I work at The Institute of Cancer Research (ICR) in the Section of Cancer Therapeutics. Our
mission is to discover and develop new drugs to treat cancer. We have an impressive track record in drug discovery in oncology as four compounds (melphalan, chlorambucil, carboplatin and ralitrexed) originating from
the ICR have gained regulatory approval. In addition, we have several compounds in late clinical development (abiraterone, satraplatin and picoplatin). Six of our compounds are in early phase I/II clinical evaluations. They
include conventional antiproliferative agents that are selectively transported to tumours and molecularly targeted agents such as HSP90, HDAC and PI3K inhibitors. These compounds have been licensed to pharmaceutical
companies such as Novartis, Roche, Genentech and Onyx pharmaceuticals and some of them have been developed in partnership with biotechnology companies. We have an exciting pipeline which includes PKB inhibitors already licensed to Astra Zeneca, while B-RAF inhibitors, CHK1 and Aurora kinase inhibitors are all at licensing stage.

We are at a really exciting crossroad in oncology drug development as many compounds are targeting molecular abnormalities that drive cancer. This means that drug administration can be optimised by evaluating the target modulation rather than the maximum tolerability. In addition, it may be possible to select the patients that are most likely to respond to treatment, which leads to personalised therapy. This requires a large investment in biomarker development and analysis.

My team is involved in drug metabolism and pharmacokinetics of novel chemical entities and in the clinical pharmacokinetic evaluation of some of our agents, which have reached Phase I/II clinical trials at The Royal
Marsden Hospital. In addition, we are interested in the identification of novel biomarkers by LCMS metabolomics. We are focusing on the exploration of the exo-metabolome to circumvent difficulties in obtaining tumour specimens. Tumours are often not accessible, serial biopsies are invasive and, at best, only pre-treatment samples and posttreatment biopsies are obtainable. Circulating biomarkers are, therefore, highly desirable. We have so far initiated preclinical studies to evaluate the potential of metabolomics in identifying metabolomic biomarkers of signal transduction inhibitors. This is essential if you are developing a targeted agent as you have to prove, in the clinical context, that the compound modulated its target. We focus particularly on the inhibitors that we have developed in the Cancer Research UK Centre for Cancer Therapeutics at the ICR and which we have in clinical trials at The Royal Marsden hospital.