Title:In Vitro Investigation Demonstrates IGFR/VEGFR Receptor Cross Talk and Potential of Combined Inhibition in Pediatric Central Nervous System Atypical Teratoid Rhabdoid Tumors
VOLUME: 20 ISSUE: 4
Author(s):Halah Obaid, Sunand Kannappan, Mehul Gupta, Yibing Ruan, Chunfen Zhang, Pinaki Bose* and Aru Narendran*
Affiliation:POETIC Laboratory for Preclinical and Drug Discovery Studies, University of Calgary and the Division of Pediatric Oncology, Alberta Children’s Hospital, Calgary, Alberta, POETIC Laboratory for Preclinical and Drug Discovery Studies, University of Calgary and the Division of Pediatric Oncology, Alberta Children’s Hospital, Calgary, Alberta, POETIC Laboratory for Preclinical and Drug Discovery Studies, University of Calgary and the Division of Pediatric Oncology, Alberta Children’s Hospital, Calgary, Alberta, POETIC Laboratory for Preclinical and Drug Discovery Studies, University of Calgary and the Division of Pediatric Oncology, Alberta Children’s Hospital, Calgary, Alberta, POETIC Laboratory for Preclinical and Drug Discovery Studies, University of Calgary and the Division of Pediatric Oncology, Alberta Children’s Hospital, Calgary, Alberta, Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, AB, POETIC Laboratory for Preclinical and Drug Discovery Studies, University of Calgary and the Division of Pediatric Oncology, Alberta Children’s Hospital, Calgary, Alberta
Keywords:Crosstalk, ATRT, VEGFR, IGF-1R, drug combination, anti-angiogenic therapies.
Abstract:
Background: Atypical teratoid rhabdoid tumor of the central nervous system (CNS
ATRT) is a malignancy that commonly affects young children. The biological mechanisms contributing
to tumor aggressiveness and resistance to conventional therapies in ATRT are unknown. Previous
studies have shown the activity of insulin like growth factor-I receptor (IGF-1R) in ATRT tumor
specimens and cell lines. IGF-1R has been shown to cross-talk with other receptor tyrosine
kinases (RTKs) in a number of cancer types, leading to enhanced cell proliferation.
Objective: This study aims to evaluate the role of IGF-1 receptor cross-talk in ATRT biology and the
potential for therapeutic targeting.
Methods: Cell lines derived from CNS ATRT specimens were analyzed for IGF-1 mediated cell
proliferation. A comprehensive receptor tyrosine kinase (RTK) screen was conducted following
IGF-1 stimulation. Bioinformatic analysis of publicly available cancer growth inhibition data to
identify correlation between IC50 of a VEGFR inhibitor and IGF-1R expression.
Results: Comprehensive RTK screen identified VEGFR-2 cross-activation following IGF-1 stimulation.
Bioinformatics analysis demonstrated a positive correlation between IC50 values of VEGFR
inhibitor Axitinib and IGF-1R expression, supporting the critical influence of IGF-1R in modulating
response to anti-angiogenic therapies.
Conclusion: Overall, our data present a novel experimental framework to evaluate and utilize receptor
cross-talk mechanisms to select effective drugs and combinations for future therapeutic trials in
ATRT.
