In Vitro Investigation Demonstrates IGFR/VEGFR Receptor Cross Talk and Potential of Combined Inhibition in Pediatric Central Nervous System Atypical Teratoid Rhabdoid Tumors

Curr Cancer Drug Targets. 2020;20(4):295-305. doi: 10.2174/1568009619666191111153049.

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.

Keywords: ATRT; Crosstalk; IGF-1R; VEGFR; anti-angiogenic therapies; drug combination..

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Axitinib / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Central Nervous System Neoplasms / drug therapy*
  • Central Nervous System Neoplasms / metabolism
  • Central Nervous System Neoplasms / pathology
  • Humans
  • In Vitro Techniques
  • Insulin-Like Growth Factor I / pharmacology
  • Molecular Targeted Therapy / methods
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor Cross-Talk / drug effects*
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptor, IGF Type 1 / metabolism
  • Rhabdoid Tumor / drug therapy*
  • Rhabdoid Tumor / metabolism
  • Rhabdoid Tumor / pathology
  • Signal Transduction / drug effects
  • Teratoma / drug therapy*
  • Teratoma / metabolism
  • Teratoma / pathology
  • Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism

Substances

  • IGF1R protein, human
  • Protein Kinase Inhibitors
  • Insulin-Like Growth Factor I
  • Axitinib
  • FLT1 protein, human
  • Receptor, IGF Type 1
  • Vascular Endothelial Growth Factor Receptor-1