Oncofetal chondroitin sulfate is a highly expressed therapeutic target in non-small cell lung cancer

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Dokumenter

  • Htoo Zarni Oo
  • Zoltan Lohinai
  • Nastaran Khazamipour
  • Joey Lo
  • Gunjan Kumar
  • Jessica Pihl
  • Hans Adomat
  • Noushin Nabavi
  • Hakhamanesh Behmanesh
  • Beibei Zhai
  • Jeffrey D. Esko
  • Jeffrey W. Allen
  • Michael A. Thompson
  • Nhan L. Tran
  • Judit Moldvay
  • Balazs Dome
  • Nader Al-Nakouzi
  • Glen J. Weiss
  • Mads Daugaard

Broad-spectrum therapeutics in non-small cell lung cancer (NSCLC) are in demand. Most human solid tumors express proteoglycans modified with distinct oncofetal chondroitin sulfate (CS) chains that can be detected and targeted with recombinant VAR2CSA (rVAR2) proteins and rVAR2-derived therapeutics. Here, we investigated expression and targetability of oncofetal CS expression in human NSCLC. High oncofetal CS expression is associated with shorter disease-free survival and poor overall survival of clinically annotated stage I and II NSCLC patients (n = 493). Oncofetal CS qualifies as an independent prognosticator of NSCLC in males and smokers, and high oncofetal CS levels are more prevalent in EGFR/KRAS wild-type cases, as compared to mutation cases. NSCLC cell lines express oncofetal CS-modified proteoglycans that can be specifically detected and targeted by rVAR2 proteins in a CSA-dependent manner. Importantly, a novel VAR2-drug conjugate (VDC-MMAE) efficiently eliminates NSCLC cells in vitro and in vivo. In summary, oncofetal CS is a prognostic biomarker and an actionable glycosaminoglycan target in NSCLC.

OriginalsprogEngelsk
Artikelnummer4489
TidsskriftCancers
Vol/bind13
Udgave nummer17
Antal sider16
ISSN2072-6694
DOI
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
Funding: This work was supported by a grant from the Canadian Institutes of Health Research to M.D. (CIHR #153092). Z.L. was supported by the 2015 IASLC WCLC international mentorship program and the 2018 LCFA-BMS/IASLC Young Investigator Scholarship Award. Z.L. acknowledges funding from the Hungarian National Research, Development and Innovation Office (OTKA #124652 and OTKA #129664, Z). J.M. acknowledges funding from the Hungarian National Research, Development and Innovation Office (NAP2-2017-1.2.1-NKP-0002 and K129065). B.D. acknowledges funding from Austrian Science Fund (FWF I3977, I3522 and I4677). G.J.W. received funding from TGen Foundation, SHC Foundations and Flinn Foundation.

Funding Information:
This work was supported by a grant from the Canadian Institutes of Health Research to M.D. (CIHR #153092). Z.L. was supported by the 2015 IASLC WCLC international mentorship program and the 2018 LCFA-BMS/IASLC Young Investigator Scholarship Award. Z.L. acknowledges funding from the Hungarian National Research, Development and Innovation Office (OTKA #124652 and OTKA #129664, Z). J.M. acknowledges funding from the Hungarian National Research, Development and Innovation Office (NAP2-2017-1.2.1-NKP-0002 and K129065). B.D. acknowledges funding from Austrian Science Fund (FWF I3977, I3522 and I4677). G.J.W. received funding from TGen Foundation, SHC Foundations and Flinn Foundation.In memory of friend, husband, and father Kristian Nim, who lost the battle to NSCLC in 2015.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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