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Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer Oo, Htoo Zarni; Lohinai, Zoltan; Khazamipour, Nastaran; Lo, Joey; Kumar, Gunjan; Pihl, Jessica; Adomat, Hans; Nabavi, Noushin; Behmanesh, Hakhamanesh; Zhai, Beibei, 1978-; Dagil, Robert; Choudhary, Swati; Gustavsson, Tobias; Clausen, Thomas M.; Esko, Jeffrey D.; Allen, Jeffrey W.; Thompson, Michael A.; Tran, Nhan L.; Moldvay, Judit; Dome, Balazs; Salanti, Ali; Al-Nakouzi, Nader; Weiss, Glen J.; Daugaard, Mads

Abstract

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.

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Title
Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer
Creator
Oo, Htoo Zarni; Lohinai, Zoltan; Khazamipour, Nastaran; Lo, Joey; Kumar, Gunjan; Pihl, Jessica; Adomat, Hans; Nabavi, Noushin; Behmanesh, Hakhamanesh; Zhai, Beibei, 1978-; Dagil, Robert; Choudhary, Swati; Gustavsson, Tobias; Clausen, Thomas M.; Esko, Jeffrey D.; Allen, Jeffrey W.; Thompson, Michael A.; Tran, Nhan L.; Moldvay, Judit; Dome, Balazs; Salanti, Ali; Al-Nakouzi, Nader; Weiss, Glen J.; Daugaard, Mads
Contributor
Vancouver Prostate Centre; Vancouver Coastal Health Authority. Research Institute
Publisher
Multidisciplinary Digital Publishing Institute
Date Issued
2021-09-06
Description
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.
Subject
NSCLC; chondroitin sulfate; glycosaminoglycan; VDC-MMAE; drug conjugate
Genre
Article
Type
Text
Language
eng
Date Available
2021-10-05
Provider
Vancouver : University of British Columbia Library
Rights
CC BY 4.0
DOI
10.14288/1.0402439
URI
http://hdl.handle.net/2429/79889
Affiliation
Medicine, Faculty of; Non UBC; Urologic Sciences, Department of
Citation
Cancers 13 (17): 4489 (2021)
Publisher DOI
10.3390/cancers13174489
Peer Review Status
Reviewed
Scholarly Level
Faculty; Researcher
Rights URI
https://creativecommons.org/licenses/by/4.0/
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CC BY 4.0