TOMAS: revisiting PARP inhibitor combination therapy
Mené en Italie sur 50 patients atteints d'un sarcome osseux ou des tissus mous non résécable et de stade avancé, cet essai de phase Ib évalue la dose maximale tolérée, l'activité antitumorale et la toxicité d'un traitement combinant trabectédine, un antinéoplasique alcaloïde, et olaparib, un inhibiteur de PARP (durée médiane de suivi : 10 mois)
Olaparib is a member of a small molecule drug class that inhibits poly(ADP-ribose) polymerase-1 and polymerase-2 (PARP1/2) enzymes. PARP1 participates in the DNA damage response by poly-ADP-ribosylating (PARylating) DNA damage repair proteins, among other substrates. PARP inhibition is synthetically lethal in the setting of deficient homologous recombination because that pathway is required to remove inhibitor-induced PARP-DNA adducts. This functional aspect formed the rationale for PARP inhibitor development in BRCA1/ 2-mutated tumours. However, PARP inhibition was initially hypothesised to enhance the potency of drugs that damage DNA by inhibiting DNA damage repair. The first clinical example of this approach was the combination of the alkylating drug temozolomide and the PARP inhibitor rucaparib, which was hampered by dose-limiting myelosuppression.
The Lancet Oncology , commentaire, 2017