List of communications


Targeting commonly abrogated pathways in GBM: co-inhibition of the PI3K, MAPK and RB pathways

Mark C. de Gooijer, Department of Bio-Pharmacology/ Mouse Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Isabel Mayayo-Peralta, Department of Bio-Pharmacology/ Mouse Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Levi C.M. Buil, Department of Bio-Pharmacology/ Mouse Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Nishita Thota, Department of Bio-Pharmacology/ Mouse Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Ruud Weijer, Department of Bio-Pharmacology/ Mouse Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Jos H. Beijnen, Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute /Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands, Division of Drug Toxicology, Faculty of Pharmacy, Division of Biomedical Analysis, Faculty of Science, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands; Olaf van Tellingen, Department of Bio-Pharmacology/ Mouse Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands


GBM frequently harbors activated PI3K, MAPK and RB pathways and combined inhibition of all three pathways may be necessary for therapeutic efficacy. The blood-brain barrier (BBB) is a therapeutic hurdle for many CNS diseases. In particular, ABCB1 and ABCG2 restrict the entry of many targeted agents. Based on pharmacokinetics studies, we have selected buparlisib (PI3K), PD-0325901 (MEK) and palbociclib (CDK4/6) as best candidates to explore combinatorial treatment. By in vitro clonogenic and proliferation assays, FACS and western blot, we have interrogated how triple pathway inhibition can best be exploited. Importantly, mono-therapy target inhibition occurs at manifold lower concentrations than required for proliferation inhibition (IC50), suggesting that proliferation inhibition is due to off-target effects. Combinatorial treatment reduces the IC50 closer to that for target inhibition. Furthermore, caspase and β-galactosidase assays revealed that anti-proliferative effects of triple pathway inhibition occur through senescence but not apoptosis. We will now design in vivo combination therapy studies against orthotopic GBM. By applying smart dosing that results in sufficient brain exposure for target inhibition, we aim to enable that triple PI3K-MAPK-RB pathway targeting can be achieved in vivo with manageable side effects, hopefully thereby demonstrating its promise for clinical application in treatment of GBM.

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