Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer
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....
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-09-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/17/4489 |
| id |
doaj-53bdcac7991a4b849db695f66547e9e1 |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Htoo Zarni Oo Zoltan Lohinai Nastaran Khazamipour Joey Lo Gunjan Kumar Jessica Pihl Hans Adomat Noushin Nabavi Hakhamanesh Behmanesh Beibei Zhai Robert Dagil Swati Choudhary Tobias Gustavsson Thomas M. Clausen Jeffrey D. Esko Jeffrey W. Allen Michael A. Thompson Nhan L. Tran Judit Moldvay Balazs Dome Ali Salanti Nader Al-Nakouzi Glen J. Weiss Mads Daugaard |
| spellingShingle |
Htoo Zarni Oo Zoltan Lohinai Nastaran Khazamipour Joey Lo Gunjan Kumar Jessica Pihl Hans Adomat Noushin Nabavi Hakhamanesh Behmanesh Beibei Zhai Robert Dagil Swati Choudhary Tobias Gustavsson Thomas M. Clausen Jeffrey D. Esko Jeffrey W. Allen Michael A. Thompson Nhan L. Tran Judit Moldvay Balazs Dome Ali Salanti Nader Al-Nakouzi Glen J. Weiss Mads Daugaard Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer Cancers NSCLC chondroitin sulfate glycosaminoglycan VDC-MMAE drug conjugate |
| author_facet |
Htoo Zarni Oo Zoltan Lohinai Nastaran Khazamipour Joey Lo Gunjan Kumar Jessica Pihl Hans Adomat Noushin Nabavi Hakhamanesh Behmanesh Beibei Zhai Robert Dagil Swati Choudhary Tobias Gustavsson Thomas M. Clausen Jeffrey D. Esko Jeffrey W. Allen Michael A. Thompson Nhan L. Tran Judit Moldvay Balazs Dome Ali Salanti Nader Al-Nakouzi Glen J. Weiss Mads Daugaard |
| author_sort |
Htoo Zarni Oo |
| title |
Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer |
| title_short |
Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer |
| title_full |
Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer |
| title_fullStr |
Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer |
| title_full_unstemmed |
Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer |
| title_sort |
oncofetal chondroitin sulfate is a highly expressed therapeutic target in non-small cell lung cancer |
| publisher |
MDPI AG |
| series |
Cancers |
| issn |
2072-6694 |
| publishDate |
2021-09-01 |
| description |
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 (<i>n</i> = 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. |
| topic |
NSCLC chondroitin sulfate glycosaminoglycan VDC-MMAE drug conjugate |
| url |
https://www.mdpi.com/2072-6694/13/17/4489 |
| work_keys_str_mv |
AT htoozarnioo oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT zoltanlohinai oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT nastarankhazamipour oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT joeylo oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT gunjankumar oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT jessicapihl oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT hansadomat oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT noushinnabavi oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT hakhamaneshbehmanesh oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT beibeizhai oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT robertdagil oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT swatichoudhary oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT tobiasgustavsson oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT thomasmclausen oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT jeffreydesko oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT jeffreywallen oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT michaelathompson oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT nhanltran oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT juditmoldvay oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT balazsdome oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT alisalanti oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT naderalnakouzi oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT glenjweiss oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer AT madsdaugaard oncofetalchondroitinsulfateisahighlyexpressedtherapeutictargetinnonsmallcelllungcancer |
| _version_ |
1717760618529816576 |
| spelling |
doaj-53bdcac7991a4b849db695f66547e9e12021-09-09T13:41:15ZengMDPI AGCancers2072-66942021-09-01134489448910.3390/cancers13174489Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung CancerHtoo Zarni Oo0Zoltan Lohinai1Nastaran Khazamipour2Joey Lo3Gunjan Kumar4Jessica Pihl5Hans Adomat6Noushin Nabavi7Hakhamanesh Behmanesh8Beibei Zhai9Robert Dagil10Swati Choudhary11Tobias Gustavsson12Thomas M. Clausen13Jeffrey D. Esko14Jeffrey W. Allen15Michael A. Thompson16Nhan L. Tran17Judit Moldvay18Balazs Dome19Ali Salanti20Nader Al-Nakouzi21Glen J. Weiss22Mads Daugaard23Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, CanadaDepartment of Tumor Biology, National Koranyi Institute of Pulmonology, 1122 Budapest, HungaryDepartment of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, CanadaDepartment of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, CanadaDepartment of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, CanadaDepartment of Cellular and Molecular Medicine, University of California, La Jolla, San Diego, CA 92093, USADepartment of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, CanadaDepartment of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, CanadaDepartment of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, CanadaDepartment of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, CanadaDepartment for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, DenmarkDepartment for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, DenmarkDepartment for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, DenmarkDepartment of Cellular and Molecular Medicine, University of California, La Jolla, San Diego, CA 92093, USADepartment of Cellular and Molecular Medicine, University of California, La Jolla, San Diego, CA 92093, USAKootenai Health, Post Falls, ID 83854, USAAurora Cancer Care, Advocate Aurora Health, Milwaukee, WI 53215, USADepartment of Cancer Biology, Mayo Clinic, Scottsdale, AZ 85259, USADepartment of Tumor Biology, National Koranyi Institute of Pulmonology, 1122 Budapest, HungaryDepartment of Tumor Biology, National Koranyi Institute of Pulmonology, 1122 Budapest, HungaryDepartment for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, DenmarkDepartment of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, CanadaMiRanostics Consulting, Oro Valley, AZ 85755, USADepartment of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, CanadaBroad-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 (<i>n</i> = 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.https://www.mdpi.com/2072-6694/13/17/4489NSCLCchondroitin sulfateglycosaminoglycanVDC-MMAEdrug conjugate |