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

Htoo Zarni Oo; Zoltan Lohinai; Nastaran Khazamipour; Joey Lo; Gunjan Kumar; Jessica Pihl; Hans Adomat; Noushin Nabavi; Hakhamanesh Behmanesh; Beibei Zhai; Robert Dagil; Swati Choudhary; Tobias Gustavsson; Thomas M. Clausen; Jeffrey D. Esko; Jeffrey W. Allen; Michael A. Thompson; Nhan L. Tran; Judit Moldvay; Balazs Dome; Ali Salanti; Nader Al-Nakouzi; Glen J. Weiss; Mads Daugaard

doi:10.3390/cancers13174489

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

Htoo Zarni Oo, Zoltan Lohinai, Nastaran Khazamipour, Joey Lo, Gunjan Kumar, Jessica Pihl, Hans Adomat, Noushin Nabavi, Hakhamanesh Behmanesh, Beibei Zhai, Robert Dagil, Swati Choudhary, Tobias Gustavsson, Thomas M. Clausen, Jeffrey D. Esko, Jeffrey W. Allen, Michael A. Thompson, Nhan L. Tran, Judit Moldvay, Balazs DomeAli Salanti, Nader Al-Nakouzi, Glen J. Weiss, Mads Daugaard

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	4489
Journal	Cancers
Volume	13
Issue number	17
DOIs	https://doi.org/10.3390/cancers13174489
State	Published - Sep 2021

Keywords

Chondroitin sulfate
Drug conjugate
Glycosaminoglycan
NSCLC
VDC-MMAE

ASJC Scopus subject areas

Oncology
Cancer Research

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10.3390/cancers13174489

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Oo, H. Z., Lohinai, Z., Khazamipour, N., Lo, J., Kumar, G., Pihl, J., Adomat, H., Nabavi, N., Behmanesh, H., Zhai, B., Dagil, R., Choudhary, S., Gustavsson, T., Clausen, T. M., Esko, J. D., Allen, J. W., Thompson, M. A., Tran, N. L., Moldvay, J., ... Daugaard, M. (2021). Oncofetal chondroitin sulfate is a highly expressed therapeutic target in non-small cell lung cancer. Cancers, 13(17), Article 4489. https://doi.org/10.3390/cancers13174489

Oo, HZ, Lohinai, Z, Khazamipour, N, Lo, J, Kumar, G, Pihl, J, Adomat, H, Nabavi, N, Behmanesh, H, Zhai, B, Dagil, R, Choudhary, S, Gustavsson, T, Clausen, TM, Esko, JD, Allen, JW, Thompson, MA, Tran, NL, Moldvay, J, Dome, B, Salanti, A, Al-Nakouzi, N, Weiss, GJ & Daugaard, M 2021, 'Oncofetal chondroitin sulfate is a highly expressed therapeutic target in non-small cell lung cancer', Cancers, vol. 13, no. 17, 4489. https://doi.org/10.3390/cancers13174489

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

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.",

keywords = "Chondroitin sulfate, Drug conjugate, Glycosaminoglycan, NSCLC, VDC-MMAE",

author = "Oo, {Htoo Zarni} and Zoltan Lohinai and Nastaran Khazamipour and Joey Lo and Gunjan Kumar and Jessica Pihl and Hans Adomat and Noushin Nabavi and Hakhamanesh Behmanesh and Beibei Zhai and Robert Dagil and Swati Choudhary and Tobias Gustavsson and Clausen, {Thomas M.} and Esko, {Jeffrey D.} and Allen, {Jeffrey W.} and Thompson, {Michael A.} and Tran, {Nhan L.} and Judit Moldvay and Balazs Dome and Ali Salanti and Nader Al-Nakouzi and Weiss, {Glen J.} and Mads Daugaard",

note = "Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = sep,

doi = "10.3390/cancers13174489",

language = "English (US)",

volume = "13",

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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

PY - 2021/9

Y1 - 2021/9

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.

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KW - Drug conjugate

KW - Glycosaminoglycan

KW - NSCLC

KW - VDC-MMAE

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JF - Cancers

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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