AG&M annual report 2018

AG&M Science Impressions 2018
Personalized Medicine in Rheumatoid Arthritis: Methotrexate Polyglutamylation
Revisited
Expert Review Precision Medicine and Drug Development 2018;3(6):331-334
Robert de Jonge and Ittai Muller
Personalized medicine of the anti-folate
methotrexate (MTX)
Prof. Robert de Jonge is an European Specialist in
Laboratory Medicine, head of the department of Clinical
Chemistry and vice chair of Division 9 (Laboratories).
His research focusses on one-carbon metabolism
(folate, vitamin B12). One of the research programs
focuses on individualized treatment of the anti-folate
Methotrexate (MTX) in auto-immune disease and
leukemia in order to obtain maximal efficacy with
minimal toxicity (medicijn op maat). In cross-sectional
and in prospective cohort studies together with partners
at Amsterdam UMC (Gastroenterology, Rheumatology,
Hematology), Reade, UMCU (Gastroenterology,
Rheumatology) and the Prinses Maxima Center Utrecht,
prediction models for clinical response and toxicity are
developed and pharmacokinetics/pharmacodynamics of
MTX is studied.
Methotrexate
MTX is a folic acid analogue drug that was discovered
in 1940’s as one of the first chemotherapeutic drugs
revealing potent activity in the treatment of acute
lymphoblastic leukemia. Since then, following its
success in cancer therapy, MTX has also been proven,
though at low doses, to be very effective for the
treatment for various chronic autoimmune disorders
such as rheumatoid arthritis, sarcoidosis, Crohn’s
disease and vasculitis. The mechanism of action of
MTX basically involves disruption of normal folate
metabolism, which is a crucial pathway for cellular
homeostasis as it provides essential nutrients (e.g.
purines, pyrimidines, amino acids) for DNA synthesis
and cellular proliferation and methylation reactions.
The important components in the cellular
pharmacology of MTX are well documented. Following
cellular uptake of MTX by specific transporters, one
of the critical factors for the therapeutic effects of
MTX involves the intracellular conversion into MTXpolyglutamates
(MTX-PGn). This process is catalyzed
by the enzyme folylpolyglutamate synthetase (FPGS),
which attaches multiple glutamate moieties (n=2-5,
depending on the MTX dose and duration of infusion/
treatment). MTX-polyglutamylation promotes the
intracellular retention of the drug, a process hijacked
from the intracellular retention of natural folates. The
mechanism of action of low-dose MTX treatment used
in autoimmune disorders relates to the inhibition of
key enzymes in purine de novo biosynthesis pathway
(i.e. 5-aminoimidazole-4-carboxamide ribonucleotide
transformylase; ATIC) by MTX-PGn and the downstream
release of the anti-inflammatory purine adenosine.
Although MTX is relatively safe and effective, still about
30-40% of RA patients discontinue MTX treatment due
to intolerance or inefficacy early in the treatment or
do not respond any more after 3-6 months of therapy
(MTX non-response or MTX resistance).
Therapeutic Drug Monitoring
The research in Robert de Jonge’s group focuses
on developing new analytical, molecular and
computational methods helping to predict and monitor
non-response and/or resistance to MTX in autoimmune
diseases and cancer treatment. Specifically, the MTXpolyglutamylation
process is revisited by employing
current state-of-the-art technologies to identify novel
predictive biomarkers and to sensitively and accurately
measure MTX-PGn levels in disease-relevant cell types
of patients.
Ittai Muller as PhD student and Marry Lin as
technician are the ones who are actively involved
in this project. Ittai obtained his Master’s degree
at the Vrije Universteit Amsterdam (Oncology)
during which he interned at Harvard Medical School
(Boston, USA), where he investigated potential
tumor microenvironment factors that predict breast
cancer metastasis. After his graduation, he became
coordinator of the Master Oncology and Master
Cardiovascular Research before transitioning into
academia to further his scientific career. He is currently
investigating novel predictive biomarkers for MTX nonresponse
in RA and leukemia under the supervision of
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