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Synthesis and Characterization of Placental Chondroitin Sulfate A plCSA-Targeting Lipid-Polymer Nanoparticles
Published on: September 18, 2018
Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer
Htoo Zarni Oo1,2, Zoltan Lohinai3, Nastaran Khazamipour1,2
1Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
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.
Insights
Oncocofetal chondroitin sulfate (CS) is a promising target in non-small cell lung cancer (NSCLC). Targeting this biomarker with novel therapies, like VAR2-drug conjugates, shows potential for improved patient outcomes.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) requires novel broad-spectrum therapeutics.
- Proteoglycans with oncofetal chondroitin sulfate (CS) chains are expressed in many solid tumors.
- Recombinant VAR2CSA (rVAR2) proteins can target these oncofetal CS chains.
Purpose of the Study:
- To investigate the expression and targetability of oncofetal CS in human NSCLC.
- To evaluate oncofetal CS as a prognostic biomarker in NSCLC patients.
- To assess the efficacy of rVAR2-based therapeutics against NSCLC.
Main Methods:
- Analysis of oncofetal CS expression in clinically annotated NSCLC patient samples (n=493).
- Correlation of oncofetal CS levels with patient survival data (disease-free and overall survival).
- In vitro and in vivo studies using NSCLC cell lines and VAR2-drug conjugates (VDC-MMAE).
Main Results:
- High oncofetal CS expression is linked to shorter survival in Stage I/II NSCLC.
- Oncofetal CS is an independent prognosticator in male and smoker NSCLC patients.
- rVAR2 proteins effectively target oncofetal CS-modified proteoglycans in NSCLC cells.
- VDC-MMAE demonstrated efficient elimination of NSCLC cells in vitro and in vivo.
Conclusions:
- Oncocofetal CS is a significant prognostic biomarker in NSCLC.
- Oncocofetal CS represents an actionable glycosaminoglycan target for NSCLC therapy.
- rVAR2-based therapeutics, including VDC-MMAE, show therapeutic potential for NSCLC.
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