Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer

• Published in: Cancers Vol. 13; no. 17; p. 4489
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06-09-2021; MDPI
• Subjects: Antibodies; Cancer therapies; Cell surface; Chemotherapy; Chondroitin sulfate; Cytotoxicity; Digital video recorders; E coli; Epidermal growth factor receptors; Glycosaminoglycans; Immunotherapy; K-Ras protein; Lung cancer; Malaria; Metastasis; Mutation; Non-small cell lung carcinoma; Patients; Proteins; Proteoglycans; Small cell lung carcinoma; Solid tumors; Surgery; Therapeutic targets; Tumors; Xenografts; United States > US; Sweden; VDC-MMAE; NSCLC; glycosaminoglycan; chondroitin sulfate; drug conjugate
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13174489

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 (
= 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.