Oncofetal chondroitin sulfate is a highly expressed therapeutic target in non-small cell lung cancer
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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; 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.
I: Cancers, Bind 13, Nr. 17, 4489, 2021.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Oncofetal chondroitin sulfate is a highly expressed therapeutic target in non-small cell lung cancer
AU - Oo, Htoo Zarni
AU - Lohinai, Zoltan
AU - Khazamipour, Nastaran
AU - Lo, Joey
AU - Kumar, Gunjan
AU - Pihl, Jessica
AU - Adomat, Hans
AU - Nabavi, Noushin
AU - Behmanesh, Hakhamanesh
AU - Zhai, Beibei
AU - Dagil, Robert
AU - Choudhary, Swati
AU - Gustavsson, Tobias
AU - Clausen, Thomas M.
AU - Esko, Jeffrey D.
AU - Allen, Jeffrey W.
AU - Thompson, Michael A.
AU - Tran, Nhan L.
AU - Moldvay, Judit
AU - Dome, Balazs
AU - Salanti, Ali
AU - Al-Nakouzi, Nader
AU - Weiss, Glen J.
AU - Daugaard, Mads
N1 - Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Chondroitin sulfate
KW - Drug conjugate
KW - Glycosaminoglycan
KW - NSCLC
KW - VDC-MMAE
U2 - 10.3390/cancers13174489
DO - 10.3390/cancers13174489
M3 - Journal article
C2 - 34503301
AN - SCOPUS:85114308055
VL - 13
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 17
M1 - 4489
ER -
ID: 280070467