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| Cancers. 2021 Sep 6. pii: cancers13174489. doi: 10.3390/cancers13174489 |
| Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer. |
| Oo HZ1, Lohinai Z2, Khazamipour N3, Lo J4, Kumar G5, Pihl J6, Adomat H7, Nabavi N8, Behmanesh H9, Zhai B10, Dagil R11, Choudhary S12, Gustavsson T13, Clausen TM14, Esko JD15, Allen JW16, Thompson MA17, Tran NL18, Moldvay J19, Dome B20, Salanti A21, Al-Nakouzi N22, Weiss GJ23, Daugaard M24 |
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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 ( = 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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KEYWORDS: NSCLC, VDC-MMAE, chondroitin sulfate, drug conjugate, glycosaminoglycan |
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Publikations ID: 34503301 Quelle: öffnen |
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