BupGPK global study
Customizing myeloablative conditioning regimes based on busulfan before allogeneic hematopoietic stem cell transplantation in children
Introduction:
Busulfan (Bu) is a chemotherapy drug that, in combination with other anti-cancer drugs, is given prior to hematopoietic stem cell transplantation (HSCT) in children. Bu is thus part of what is called the myeloablative conditioning regime, i.e. the treatment given to the patient in preparation for the transplant, and which consists in destroying the diseased bone marrow. The latter is then replaced by healthy marrow during HSCT. Bu has a narrow therapeutic window, i.e. the difference between its effective dose and its toxic dose is small. It is therefore necessary, once administered, to set up therapeutic monitoring of this medication in order to adjust its concentration in order to obtain an optimal therapeutic response, i.e. to avoid a relapse of the disease or graft rejection at too low concentrations or toxic effects at too high concentrations.
It is assumed that differences in genetic profiles inherited from a patient in proteins (also called enzymes) in drug metabolism and DNA repair proteins are one of the factors that could affect the effectiveness of Bu. Indeed, the proteins involved in the absorption, distribution, metabolism and excretion of Bu play an important role in determining its pharmacokinetics. A simple functional modification of one of these proteins may therefore be at the origin of the interindividual variability in plasma Bu levels observed. In order to identify new candidate genes linked to the toxicity of Bu, genomics and transcriptomics, hitherto applied in vitro research and in the clinic, could be applied to the pharmacogenomics of Bu. In parallel, the in silico analysis of the gene expression of proteins involved in specific functional signaling processes, induced by Bu, would also make it possible to identify target genes. Moreover, the functional genetic variants of these identified genes could be used as markers to predict the response to Bu in a personalized manner in order to obtain a therapeutic benefit.
Methods and results:
This study consists of the collection of clinical, pharmacokinetic and genetic information from children who have undergone stem cell transplantation, following a conditioning regime including Bu. The aim is to identify new candidate genes by transcriptomic analysis, to sequence the whole exome/genome, and to perform in vitro analyses to study more precisely the functionality of the variants of these new candidate genes.
Transcriptome and Bu cytotoxicity analyses are currently underway in order to identify new candidate genes. A similar multi-omic approach is also used to assess the cytotoxicity of other chemotherapies, such as treosulfan, used in the BupGPK study.
What does this study bring to patients?
The BupGPK study makes it possible to personalize busulfan-based chemotherapy treatments before hematopoietic stem cell transplantation for an optimal therapeutic response.
