Targeting cMET and AXL kinase for treatment of resistant pancreatic cancer

Samenvatting

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among major malignancies, mainly due to resistance to current therapies, such as gemcitabine based combinations. We established unique primary PDAC cell cultures to evaluate the efficacy of innovative drugs, such as c-Met inhibitors. c-Met plays a pivotal role in regulation of cell proliferation and migration. Inhibitors such as crizotinib were effective in overcoming chemoresistance in these PDAC primary cells. However, these models do not completely reflect PDAC since in vivo the tumor also consists of stromal cells. Therefore 3-dimensional (3D) co-cultures of primary PDAC cells with pancreatic stromal cells will be established as a more realistic PDAC model. Pancreatic stellate cells (PSCs) are the major stromal cells that play a major role in promotion of tumor growth and invasiveness. Next to target these PSCs we also aim to target other “dominant nodes” in PDAC tumorigenesis. This innovative approach will greatly improve development of novel therapies. Dr. Firuzi has outstanding skills in the area of cancer drug discovery with the implementation of in vitro cell models, and his contribution to this NWO grant, will further enhance this research line in our laboratories by building up expertise on new cellular models to test novel targeted therapies.
In this 4 months project we will investigate novel inhibitors of the c-MET and AXL (another important receptor tyrosine kinase) pathways. To bypass potential resistance of downstream PI3K/Akt/mTor pathway we will also investigate inhibition of this pathway. We aim to study 2-3 novel inhibitors in each category in our cutting-edge in vitro models of PDAC. We will investigate inhibition of proliferation as well as migration by these inhibitors alone or in combination with gemcitabine by using a standard sulforhodamine-B assay and by scratch and transwell assays, respectively. The effect of the drugs in the 3D co-cultures will be examined by fluorescence microscopy by using primary PDAC cells transduced with mCherry and human PSCs transduced with GFP. This project will establish innovative in vitro models for discovery of novel personalized therapeutics for management of pancreatic cancer

Kenmerken

Projectnummer

040.11.609

Hoofdaanvrager

Prof. dr. G.J. Peters

Verbonden aan

Vrije Universiteit Amsterdam, VU Medisch Centrum Amsterdam, Medische Oncologie

Looptijd

01/08/2017 tot 01/12/2017