The development of anti-cancer therapies has undergone a radical change over the last decades: from conventional cytotoxic drugs that don't discriminate between normal and tumor cells, to so-called targeted therapies which inhibit a specific target within a tumor cell.
The targets are mostly comprised of receptors or tyrosine kinases that have become aberrant in tumor cells, which can cause uncontrolled cellular signaling and growth.
Within our research group, we perform many phase I studies with inhibitors of these specific targets, both in the form of small-molecule inhibitors as well as monoclonal antibodies. Since this is the first time these anti-cancer therapies are administered to humans, the main goal of these studies is to characterize the safety and pharmacokinetic profile and to determine a recommended dose for further clinical development.
In recent years, it has become apparent that these targeted therapies have relatively modest anti-tumor activity, which is mostly due to the tumor cells developing resistance through mutations in parallel cellular signaling pathways. Thus, development of these compounds has steered more towards combining these compounds.
In support of clinical trials, our research group also focuses heavily on the development of pharmacodynamic assays, which could help us in diagnosis, but also in determining which patients benefit more from treatment.
These assays include the quantification of poly(ADP-ribose) polymerase (PARP) inhibition in peripheral blood mononuclear cells (PBMCs), which is currently validated in phase I clinical trials with the PARP-inhibitor olaparib, and circulating endothelial cells (CECs) in plasma.
Furthermore, we are in the process of validating a new assay to determine circulating tumor cells (CTCs) both in blood samples and in cerebrospinal fluid. With this assay, we could possibly detect signs of disease progression at an earlier stage.
Lastly, we are involved in optimizing assays for the determination of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) activity. These enzymes plays an important part in the metabolism and activity of fluoropyrimidines. Patients with decreased metabolism are at risk of developing serious toxicities and thus determining the DPD activity before starting treatment could warrant a dose adjustment.
In collaboration with our pharmacy department, our research groups conducts trials to test the safety and pharmacokinetics new oral formulations of intravenous anti-cancer drugs, such as docetaxel and paclitaxel.
Furthermore, to optimize treatment of tyrosine kinase inhibitors, we aim to develop and/or optimize therapeutic drug monitoring (TDM) for both new and existing anti-cancer treatments.
Additionally, the collaboration with the pharmacy also allows us to explore other types of pharmacological research, such as mass balance studies, measurements of intracellular metabolites of anti-cancer drugs and pharmacokinetic and pharmacodynamics modeling and simulation.