TY - JOUR
T1 - Comprehensive Surfaceome Profiling to Identify and Validate Novel Cell-Surface Targets in Osteosarcoma
AU - Wang, Yifei
AU - Tian, Xiangjun
AU - Zhang, Wendong
AU - Zhang, Zhongting
AU - Lazcano, Rossana
AU - Hingorani, Pooja
AU - Roth, Michael E.
AU - Gill, Jonathan D.
AU - Harrison, Douglas J.
AU - Xu, Zhaohui
AU - Jusu, Sylvester
AU - Kannan, Sankaranarayanan
AU - Wang, Jing
AU - Lazar, Alexander J.
AU - Earley, Eric J.
AU - Erickson, Stephen W.
AU - Gelb, Tara
AU - Huxley, Philip
AU - Lahdenranta, Johanna
AU - Mudd, Gemma
AU - Kurmasheva, Raushan T.
AU - Houghton, Peter J.
AU - Smith, Malcolm A.
AU - Kolb, Edward A.
AU - Gorlick, Richard
N1 - Funding Information:
This work was funded by NIH/NCI grant 5U01CA199221-06, Swim Across America, the Foster Foundation, the Terry Fox Foundation, an Osteosarcoma Institute Translational and Preclinical Grant, and the Barbara Epstein Foundation. MD Anderson Cancer Center's Proteomics Facility was funded in part by NIH/NCI Cancer Center Support Grant P30CA016672, NIH High End Instrumentation program grant 1S10OD012304-01, and Cancer Prevention and Research Institute of Texas Core Facility Grant RP130397. MD Anderson Cancer Center's Flow Cytometry and Cellular Imaging Core Facility was funded in part by NIH/NCI Cancer Center Support Grant P30CA16672. NIH/NCI Cancer Center Support Grant P30CA016672 also supported the Clinical Trials Office and the Bioinformatics Shared Resource. Mass spectrometry was performed with help from David Hawke at UT MD Anderson Cancer Center's Proteomics Facility. Flow cytometry was performed at UT MD Anderson Cancer Center's Flow Cytometry and Cellular Imaging Core Facility. We thank Sunita Patterson, Senior Scientific Editor, Research Medical Library, for editing this article.
Funding Information:
This work was funded by NIH/NCI grant 5U01CA199221–06, Swim Across America, the Foster Foundation, the Terry Fox Foundation, an Osteosarcoma Institute Translational and Preclinical Grant, and the Barbara Epstein Foundation. MD Anderson Cancer Center’s Proteomics Facility was funded in part by NIH/NCI Cancer Center Support Grant P30CA016672, NIH High End Instrumentation program grant 1S10OD012304–01, and Cancer Prevention and Research Institute of Texas Core Facility Grant RP130397. MD Anderson Cancer Center’s Flow Cytometry and Cellular Imaging Core Facility was funded in part by NIH/NCI Cancer Center Support Grant P30CA16672. NIH/NCI Cancer Center Support Grant P30CA016672 also supported the Clinical Trials Office and the Bioinformatics Shared Resource. Mass spectrometry was performed with help from David Hawke at UT MD Anderson Cancer Center’s Proteomics Facility. Flow cytometry was performed at UT MD Anderson Cancer Center’s Flow Cytometry and Cellular Imaging Core Facility. We thank Sunita Patterson, Senior Scientific Editor, Research Medical Library, for editing this article.
Publisher Copyright:
© 2022 American Association for Cancer Research Inc.. All rights reserved.
PY - 2022/6
Y1 - 2022/6
N2 - Immunoconjugates targeting cell-surface antigens have demonstrated clinical activity to enable regulatory approval in several solid and hematologic malignancies. We hypothesize that a rigorous and comprehensive surfaceome profiling approach to identify osteosarcoma-specific cell-surface antigens can similarly enable development of effective therapeutics in this disease. Herein, we describe an integrated proteomic and transcriptomic surfaceome profiling approach to identify cell-surface proteins that are highly expressed in osteosarcoma but minimally expressed on normal tissues. Using this approach, we identified targets that are highly expressed in osteosarcoma. Three targets, MT1-MMP, CD276, and MRC2, were validated as overexpressed in osteosarcoma. Furthermore, we tested BT1769, an MT1-MMP-targeted Bicycle toxin conjugate, in osteosarcoma patient-derived xenograft models. The results showed that BT1769 had encouraging antitumor activity, high affinity for its target, and a favorable pharmacokinetic profile. This confirms the hypothesis that our approach identifies novel targets with significant therapeutic potential in osteosarcoma.
AB - Immunoconjugates targeting cell-surface antigens have demonstrated clinical activity to enable regulatory approval in several solid and hematologic malignancies. We hypothesize that a rigorous and comprehensive surfaceome profiling approach to identify osteosarcoma-specific cell-surface antigens can similarly enable development of effective therapeutics in this disease. Herein, we describe an integrated proteomic and transcriptomic surfaceome profiling approach to identify cell-surface proteins that are highly expressed in osteosarcoma but minimally expressed on normal tissues. Using this approach, we identified targets that are highly expressed in osteosarcoma. Three targets, MT1-MMP, CD276, and MRC2, were validated as overexpressed in osteosarcoma. Furthermore, we tested BT1769, an MT1-MMP-targeted Bicycle toxin conjugate, in osteosarcoma patient-derived xenograft models. The results showed that BT1769 had encouraging antitumor activity, high affinity for its target, and a favorable pharmacokinetic profile. This confirms the hypothesis that our approach identifies novel targets with significant therapeutic potential in osteosarcoma.
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UR - http://www.scopus.com/inward/citedby.url?scp=85131226363&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-21-0836
DO - 10.1158/1535-7163.MCT-21-0836
M3 - Article
C2 - 35312779
AN - SCOPUS:85131226363
SN - 1535-7163
VL - 21
SP - 903
EP - 913
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 6
ER -