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
Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada.
Cancers (Basel). 2021 Sep 6;13(17):4489. 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.
非小细胞肺癌（NSCLC）对广谱治疗药物有需求。大多数人类实体瘤表达经独特的癌胚硫酸软骨素（CS）链修饰的蛋白聚糖，这些蛋白聚糖可用重组VAR2CSA（rVAR2）蛋白和rVAR2衍生的治疗药物进行检测和靶向。在此，我们研究了人NSCLC中癌胚CS表达及其靶向性。癌胚CS高表达与临床注释的I期和II期NSCLC患者（n = 493）较短的无病生存期和较差的总生存期相关。癌胚CS是男性和吸烟者NSCLC的独立预后指标，与突变病例相比，癌胚CS高水平在EGFR/KRAS野生型病例中更为普遍。NSCLC细胞系表达经癌胚CS修饰的蛋白聚糖，rVAR2蛋白可通过CSA依赖性方式对其进行特异性检测和靶向。重要的是，一种新型的VAR2-药物偶联物（VDC-MMAE）在体外和体内均能有效清除NSCLC细胞。总之，癌胚CS是NSCLC的一种预后生物标志物和可作用的糖胺聚糖靶点。
