Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical effi...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:JCI insight 2018-08, Vol.3 (16)
Hauptverfasser: Jamieson, Stephen Mf, Tsai, Peter, Kondratyev, Maria K, Budhani, Pratha, Liu, Arthur, Senzer, Neil N, Chiorean, E Gabriela, Jalal, Shadia I, Nemunaitis, John J, Kee, Dennis, Shome, Avik, Wong, Way W, Li, Dan, Poonawala-Lohani, Nooriyah, Kakadia, Purvi M, Knowlton, Nicholas S, Lynch, Courtney Rh, Hong, Cho R, Lee, Tet Woo, Grénman, Reidar A, Caporiccio, Laura, McKee, Trevor D, Zaidi, Mark, Butt, Sehrish, Macann, Andrew Mj, McIvor, Nicholas P, Chaplin, John M, Hicks, Kevin O, Bohlander, Stefan K, Wouters, Bradly G, Hart, Charles P, Print, Cristin G, Wilson, William R, Curran, Michael A, Hunter, Francis W
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page
container_issue 16
container_start_page
container_title JCI insight
container_volume 3
creator Jamieson, Stephen Mf
Tsai, Peter
Kondratyev, Maria K
Budhani, Pratha
Liu, Arthur
Senzer, Neil N
Chiorean, E Gabriela
Jalal, Shadia I
Nemunaitis, John J
Kee, Dennis
Shome, Avik
Wong, Way W
Li, Dan
Poonawala-Lohani, Nooriyah
Kakadia, Purvi M
Knowlton, Nicholas S
Lynch, Courtney Rh
Hong, Cho R
Lee, Tet Woo
Grénman, Reidar A
Caporiccio, Laura
McKee, Trevor D
Zaidi, Mark
Butt, Sehrish
Macann, Andrew Mj
McIvor, Nicholas P
Chaplin, John M
Hicks, Kevin O
Bohlander, Stefan K
Wouters, Bradly G
Hart, Charles P
Print, Cristin G
Wilson, William R
Curran, Michael A
Hunter, Francis W
description Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.
doi_str_mv 10.1172/jci.insight.122204
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6141174</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2092544109</sourcerecordid><originalsourceid>FETCH-LOGICAL-c402t-a84183574ac24aea346edff2d6d78862f261923487192e55a4f14d717b1775ba3</originalsourceid><addsrcrecordid>eNpVkU9r3DAQxUVoSJYkXyCHomMv3uifLe-lUMKmDQR6ac5iVh6tldrSRrIN_fZV2G1ITzOgeU_z5kfILWdrzrW4e7F-7UP2-35acyEEU2dkJaTeVFKz9tOH_pLc5PzCGONaCVa3F-RSMi5ryZsVwe0SXcwORt8hdTHRqUc6JYRpxDDR6Gg_jxDoAQ5-GOIIi09zrgLuYfIL0h6hoxA6GtD-pvl1hjHOmVocBmohWR-K5pqcOxgy3pzqFXl-2P66_1E9_fz-eP_tqbKKiamCVvFW1lqBFQoQpGqwc050TafbthFONHwjpGp1KVjXoBxXneZ6x7WudyCvyNej72HejdjZkiDBYA7Jj5D-mAje_P8SfG_2cTENV-Wqqhh8ORmk-Dpjnszo81sWCFhiGcE2olaKs00ZFcdRm2LOCd37N5yZN0SmIDInROaIqIg-f1zwXfIPiPwLBHKRwg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2092544109</pqid></control><display><type>article</type><title>Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Jamieson, Stephen Mf ; Tsai, Peter ; Kondratyev, Maria K ; Budhani, Pratha ; Liu, Arthur ; Senzer, Neil N ; Chiorean, E Gabriela ; Jalal, Shadia I ; Nemunaitis, John J ; Kee, Dennis ; Shome, Avik ; Wong, Way W ; Li, Dan ; Poonawala-Lohani, Nooriyah ; Kakadia, Purvi M ; Knowlton, Nicholas S ; Lynch, Courtney Rh ; Hong, Cho R ; Lee, Tet Woo ; Grénman, Reidar A ; Caporiccio, Laura ; McKee, Trevor D ; Zaidi, Mark ; Butt, Sehrish ; Macann, Andrew Mj ; McIvor, Nicholas P ; Chaplin, John M ; Hicks, Kevin O ; Bohlander, Stefan K ; Wouters, Bradly G ; Hart, Charles P ; Print, Cristin G ; Wilson, William R ; Curran, Michael A ; Hunter, Francis W</creator><creatorcontrib>Jamieson, Stephen Mf ; Tsai, Peter ; Kondratyev, Maria K ; Budhani, Pratha ; Liu, Arthur ; Senzer, Neil N ; Chiorean, E Gabriela ; Jalal, Shadia I ; Nemunaitis, John J ; Kee, Dennis ; Shome, Avik ; Wong, Way W ; Li, Dan ; Poonawala-Lohani, Nooriyah ; Kakadia, Purvi M ; Knowlton, Nicholas S ; Lynch, Courtney Rh ; Hong, Cho R ; Lee, Tet Woo ; Grénman, Reidar A ; Caporiccio, Laura ; McKee, Trevor D ; Zaidi, Mark ; Butt, Sehrish ; Macann, Andrew Mj ; McIvor, Nicholas P ; Chaplin, John M ; Hicks, Kevin O ; Bohlander, Stefan K ; Wouters, Bradly G ; Hart, Charles P ; Print, Cristin G ; Wilson, William R ; Curran, Michael A ; Hunter, Francis W</creatorcontrib><description>Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.</description><identifier>ISSN: 2379-3708</identifier><identifier>EISSN: 2379-3708</identifier><identifier>DOI: 10.1172/jci.insight.122204</identifier><identifier>PMID: 30135316</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Adult ; Aged ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Biomarkers, Tumor - analysis ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Cell Line, Tumor ; Chemoradiotherapy - methods ; Drug Resistance, Neoplasm ; Exome Sequencing ; Female ; Gene Knockdown Techniques ; Head and Neck Neoplasms - pathology ; Head and Neck Neoplasms - therapy ; Head and Neck Neoplasms - virology ; Humans ; Inhibitory Concentration 50 ; Middle Aged ; Nitroimidazoles - pharmacology ; Nitroimidazoles - therapeutic use ; Papillomaviridae - isolation &amp; purification ; Phosphoramide Mustards - pharmacology ; Phosphoramide Mustards - therapeutic use ; Prodrugs - administration &amp; dosage ; Progression-Free Survival ; Response Evaluation Criteria in Solid Tumors ; Squamous Cell Carcinoma of Head and Neck - pathology ; Squamous Cell Carcinoma of Head and Neck - therapy ; Squamous Cell Carcinoma of Head and Neck - virology ; Xenograft Model Antitumor Assays ; Young Adult</subject><ispartof>JCI insight, 2018-08, Vol.3 (16)</ispartof><rights>Copyright © 2018, American Society for Clinical Investigation 2018 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-a84183574ac24aea346edff2d6d78862f261923487192e55a4f14d717b1775ba3</citedby><cites>FETCH-LOGICAL-c402t-a84183574ac24aea346edff2d6d78862f261923487192e55a4f14d717b1775ba3</cites><orcidid>0000-0002-9930-9029 ; 0000-0003-0739-2484 ; 0000-0002-2744-1784 ; 0000-0003-4996-7207 ; 0000-0002-7959-6825 ; 0000-0003-1376-9209 ; 0000-0002-9970-8679 ; 0000-0002-9315-4062</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141174/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141174/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30135316$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jamieson, Stephen Mf</creatorcontrib><creatorcontrib>Tsai, Peter</creatorcontrib><creatorcontrib>Kondratyev, Maria K</creatorcontrib><creatorcontrib>Budhani, Pratha</creatorcontrib><creatorcontrib>Liu, Arthur</creatorcontrib><creatorcontrib>Senzer, Neil N</creatorcontrib><creatorcontrib>Chiorean, E Gabriela</creatorcontrib><creatorcontrib>Jalal, Shadia I</creatorcontrib><creatorcontrib>Nemunaitis, John J</creatorcontrib><creatorcontrib>Kee, Dennis</creatorcontrib><creatorcontrib>Shome, Avik</creatorcontrib><creatorcontrib>Wong, Way W</creatorcontrib><creatorcontrib>Li, Dan</creatorcontrib><creatorcontrib>Poonawala-Lohani, Nooriyah</creatorcontrib><creatorcontrib>Kakadia, Purvi M</creatorcontrib><creatorcontrib>Knowlton, Nicholas S</creatorcontrib><creatorcontrib>Lynch, Courtney Rh</creatorcontrib><creatorcontrib>Hong, Cho R</creatorcontrib><creatorcontrib>Lee, Tet Woo</creatorcontrib><creatorcontrib>Grénman, Reidar A</creatorcontrib><creatorcontrib>Caporiccio, Laura</creatorcontrib><creatorcontrib>McKee, Trevor D</creatorcontrib><creatorcontrib>Zaidi, Mark</creatorcontrib><creatorcontrib>Butt, Sehrish</creatorcontrib><creatorcontrib>Macann, Andrew Mj</creatorcontrib><creatorcontrib>McIvor, Nicholas P</creatorcontrib><creatorcontrib>Chaplin, John M</creatorcontrib><creatorcontrib>Hicks, Kevin O</creatorcontrib><creatorcontrib>Bohlander, Stefan K</creatorcontrib><creatorcontrib>Wouters, Bradly G</creatorcontrib><creatorcontrib>Hart, Charles P</creatorcontrib><creatorcontrib>Print, Cristin G</creatorcontrib><creatorcontrib>Wilson, William R</creatorcontrib><creatorcontrib>Curran, Michael A</creatorcontrib><creatorcontrib>Hunter, Francis W</creatorcontrib><title>Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma</title><title>JCI insight</title><addtitle>JCI Insight</addtitle><description>Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.</description><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biomarkers, Tumor - analysis</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Chemoradiotherapy - methods</subject><subject>Drug Resistance, Neoplasm</subject><subject>Exome Sequencing</subject><subject>Female</subject><subject>Gene Knockdown Techniques</subject><subject>Head and Neck Neoplasms - pathology</subject><subject>Head and Neck Neoplasms - therapy</subject><subject>Head and Neck Neoplasms - virology</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Middle Aged</subject><subject>Nitroimidazoles - pharmacology</subject><subject>Nitroimidazoles - therapeutic use</subject><subject>Papillomaviridae - isolation &amp; purification</subject><subject>Phosphoramide Mustards - pharmacology</subject><subject>Phosphoramide Mustards - therapeutic use</subject><subject>Prodrugs - administration &amp; dosage</subject><subject>Progression-Free Survival</subject><subject>Response Evaluation Criteria in Solid Tumors</subject><subject>Squamous Cell Carcinoma of Head and Neck - pathology</subject><subject>Squamous Cell Carcinoma of Head and Neck - therapy</subject><subject>Squamous Cell Carcinoma of Head and Neck - virology</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Young Adult</subject><issn>2379-3708</issn><issn>2379-3708</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU9r3DAQxUVoSJYkXyCHomMv3uifLe-lUMKmDQR6ac5iVh6tldrSRrIN_fZV2G1ITzOgeU_z5kfILWdrzrW4e7F-7UP2-35acyEEU2dkJaTeVFKz9tOH_pLc5PzCGONaCVa3F-RSMi5ryZsVwe0SXcwORt8hdTHRqUc6JYRpxDDR6Gg_jxDoAQ5-GOIIi09zrgLuYfIL0h6hoxA6GtD-pvl1hjHOmVocBmohWR-K5pqcOxgy3pzqFXl-2P66_1E9_fz-eP_tqbKKiamCVvFW1lqBFQoQpGqwc050TafbthFONHwjpGp1KVjXoBxXneZ6x7WudyCvyNej72HejdjZkiDBYA7Jj5D-mAje_P8SfG_2cTENV-Wqqhh8ORmk-Dpjnszo81sWCFhiGcE2olaKs00ZFcdRm2LOCd37N5yZN0SmIDInROaIqIg-f1zwXfIPiPwLBHKRwg</recordid><startdate>20180823</startdate><enddate>20180823</enddate><creator>Jamieson, Stephen Mf</creator><creator>Tsai, Peter</creator><creator>Kondratyev, Maria K</creator><creator>Budhani, Pratha</creator><creator>Liu, Arthur</creator><creator>Senzer, Neil N</creator><creator>Chiorean, E Gabriela</creator><creator>Jalal, Shadia I</creator><creator>Nemunaitis, John J</creator><creator>Kee, Dennis</creator><creator>Shome, Avik</creator><creator>Wong, Way W</creator><creator>Li, Dan</creator><creator>Poonawala-Lohani, Nooriyah</creator><creator>Kakadia, Purvi M</creator><creator>Knowlton, Nicholas S</creator><creator>Lynch, Courtney Rh</creator><creator>Hong, Cho R</creator><creator>Lee, Tet Woo</creator><creator>Grénman, Reidar A</creator><creator>Caporiccio, Laura</creator><creator>McKee, Trevor D</creator><creator>Zaidi, Mark</creator><creator>Butt, Sehrish</creator><creator>Macann, Andrew Mj</creator><creator>McIvor, Nicholas P</creator><creator>Chaplin, John M</creator><creator>Hicks, Kevin O</creator><creator>Bohlander, Stefan K</creator><creator>Wouters, Bradly G</creator><creator>Hart, Charles P</creator><creator>Print, Cristin G</creator><creator>Wilson, William R</creator><creator>Curran, Michael A</creator><creator>Hunter, Francis W</creator><general>American Society for Clinical Investigation</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9930-9029</orcidid><orcidid>https://orcid.org/0000-0003-0739-2484</orcidid><orcidid>https://orcid.org/0000-0002-2744-1784</orcidid><orcidid>https://orcid.org/0000-0003-4996-7207</orcidid><orcidid>https://orcid.org/0000-0002-7959-6825</orcidid><orcidid>https://orcid.org/0000-0003-1376-9209</orcidid><orcidid>https://orcid.org/0000-0002-9970-8679</orcidid><orcidid>https://orcid.org/0000-0002-9315-4062</orcidid></search><sort><creationdate>20180823</creationdate><title>Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma</title><author>Jamieson, Stephen Mf ; Tsai, Peter ; Kondratyev, Maria K ; Budhani, Pratha ; Liu, Arthur ; Senzer, Neil N ; Chiorean, E Gabriela ; Jalal, Shadia I ; Nemunaitis, John J ; Kee, Dennis ; Shome, Avik ; Wong, Way W ; Li, Dan ; Poonawala-Lohani, Nooriyah ; Kakadia, Purvi M ; Knowlton, Nicholas S ; Lynch, Courtney Rh ; Hong, Cho R ; Lee, Tet Woo ; Grénman, Reidar A ; Caporiccio, Laura ; McKee, Trevor D ; Zaidi, Mark ; Butt, Sehrish ; Macann, Andrew Mj ; McIvor, Nicholas P ; Chaplin, John M ; Hicks, Kevin O ; Bohlander, Stefan K ; Wouters, Bradly G ; Hart, Charles P ; Print, Cristin G ; Wilson, William R ; Curran, Michael A ; Hunter, Francis W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-a84183574ac24aea346edff2d6d78862f261923487192e55a4f14d717b1775ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biomarkers, Tumor - analysis</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Chemoradiotherapy - methods</topic><topic>Drug Resistance, Neoplasm</topic><topic>Exome Sequencing</topic><topic>Female</topic><topic>Gene Knockdown Techniques</topic><topic>Head and Neck Neoplasms - pathology</topic><topic>Head and Neck Neoplasms - therapy</topic><topic>Head and Neck Neoplasms - virology</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Middle Aged</topic><topic>Nitroimidazoles - pharmacology</topic><topic>Nitroimidazoles - therapeutic use</topic><topic>Papillomaviridae - isolation &amp; purification</topic><topic>Phosphoramide Mustards - pharmacology</topic><topic>Phosphoramide Mustards - therapeutic use</topic><topic>Prodrugs - administration &amp; dosage</topic><topic>Progression-Free Survival</topic><topic>Response Evaluation Criteria in Solid Tumors</topic><topic>Squamous Cell Carcinoma of Head and Neck - pathology</topic><topic>Squamous Cell Carcinoma of Head and Neck - therapy</topic><topic>Squamous Cell Carcinoma of Head and Neck - virology</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jamieson, Stephen Mf</creatorcontrib><creatorcontrib>Tsai, Peter</creatorcontrib><creatorcontrib>Kondratyev, Maria K</creatorcontrib><creatorcontrib>Budhani, Pratha</creatorcontrib><creatorcontrib>Liu, Arthur</creatorcontrib><creatorcontrib>Senzer, Neil N</creatorcontrib><creatorcontrib>Chiorean, E Gabriela</creatorcontrib><creatorcontrib>Jalal, Shadia I</creatorcontrib><creatorcontrib>Nemunaitis, John J</creatorcontrib><creatorcontrib>Kee, Dennis</creatorcontrib><creatorcontrib>Shome, Avik</creatorcontrib><creatorcontrib>Wong, Way W</creatorcontrib><creatorcontrib>Li, Dan</creatorcontrib><creatorcontrib>Poonawala-Lohani, Nooriyah</creatorcontrib><creatorcontrib>Kakadia, Purvi M</creatorcontrib><creatorcontrib>Knowlton, Nicholas S</creatorcontrib><creatorcontrib>Lynch, Courtney Rh</creatorcontrib><creatorcontrib>Hong, Cho R</creatorcontrib><creatorcontrib>Lee, Tet Woo</creatorcontrib><creatorcontrib>Grénman, Reidar A</creatorcontrib><creatorcontrib>Caporiccio, Laura</creatorcontrib><creatorcontrib>McKee, Trevor D</creatorcontrib><creatorcontrib>Zaidi, Mark</creatorcontrib><creatorcontrib>Butt, Sehrish</creatorcontrib><creatorcontrib>Macann, Andrew Mj</creatorcontrib><creatorcontrib>McIvor, Nicholas P</creatorcontrib><creatorcontrib>Chaplin, John M</creatorcontrib><creatorcontrib>Hicks, Kevin O</creatorcontrib><creatorcontrib>Bohlander, Stefan K</creatorcontrib><creatorcontrib>Wouters, Bradly G</creatorcontrib><creatorcontrib>Hart, Charles P</creatorcontrib><creatorcontrib>Print, Cristin G</creatorcontrib><creatorcontrib>Wilson, William R</creatorcontrib><creatorcontrib>Curran, Michael A</creatorcontrib><creatorcontrib>Hunter, Francis W</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>JCI insight</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jamieson, Stephen Mf</au><au>Tsai, Peter</au><au>Kondratyev, Maria K</au><au>Budhani, Pratha</au><au>Liu, Arthur</au><au>Senzer, Neil N</au><au>Chiorean, E Gabriela</au><au>Jalal, Shadia I</au><au>Nemunaitis, John J</au><au>Kee, Dennis</au><au>Shome, Avik</au><au>Wong, Way W</au><au>Li, Dan</au><au>Poonawala-Lohani, Nooriyah</au><au>Kakadia, Purvi M</au><au>Knowlton, Nicholas S</au><au>Lynch, Courtney Rh</au><au>Hong, Cho R</au><au>Lee, Tet Woo</au><au>Grénman, Reidar A</au><au>Caporiccio, Laura</au><au>McKee, Trevor D</au><au>Zaidi, Mark</au><au>Butt, Sehrish</au><au>Macann, Andrew Mj</au><au>McIvor, Nicholas P</au><au>Chaplin, John M</au><au>Hicks, Kevin O</au><au>Bohlander, Stefan K</au><au>Wouters, Bradly G</au><au>Hart, Charles P</au><au>Print, Cristin G</au><au>Wilson, William R</au><au>Curran, Michael A</au><au>Hunter, Francis W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma</atitle><jtitle>JCI insight</jtitle><addtitle>JCI Insight</addtitle><date>2018-08-23</date><risdate>2018</risdate><volume>3</volume><issue>16</issue><issn>2379-3708</issn><eissn>2379-3708</eissn><abstract>Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>30135316</pmid><doi>10.1172/jci.insight.122204</doi><orcidid>https://orcid.org/0000-0002-9930-9029</orcidid><orcidid>https://orcid.org/0000-0003-0739-2484</orcidid><orcidid>https://orcid.org/0000-0002-2744-1784</orcidid><orcidid>https://orcid.org/0000-0003-4996-7207</orcidid><orcidid>https://orcid.org/0000-0002-7959-6825</orcidid><orcidid>https://orcid.org/0000-0003-1376-9209</orcidid><orcidid>https://orcid.org/0000-0002-9970-8679</orcidid><orcidid>https://orcid.org/0000-0002-9315-4062</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 2379-3708
ispartof JCI insight, 2018-08, Vol.3 (16)
issn 2379-3708
2379-3708
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6141174
source MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central
subjects Adult
Aged
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Biomarkers, Tumor - analysis
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Cell Line, Tumor
Chemoradiotherapy - methods
Drug Resistance, Neoplasm
Exome Sequencing
Female
Gene Knockdown Techniques
Head and Neck Neoplasms - pathology
Head and Neck Neoplasms - therapy
Head and Neck Neoplasms - virology
Humans
Inhibitory Concentration 50
Middle Aged
Nitroimidazoles - pharmacology
Nitroimidazoles - therapeutic use
Papillomaviridae - isolation & purification
Phosphoramide Mustards - pharmacology
Phosphoramide Mustards - therapeutic use
Prodrugs - administration & dosage
Progression-Free Survival
Response Evaluation Criteria in Solid Tumors
Squamous Cell Carcinoma of Head and Neck - pathology
Squamous Cell Carcinoma of Head and Neck - therapy
Squamous Cell Carcinoma of Head and Neck - virology
Xenograft Model Antitumor Assays
Young Adult
title Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T23%3A27%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Evofosfamide%20for%20the%20treatment%20of%20human%20papillomavirus-negative%20head%20and%20neck%20squamous%20cell%20carcinoma&rft.jtitle=JCI%20insight&rft.au=Jamieson,%20Stephen%20Mf&rft.date=2018-08-23&rft.volume=3&rft.issue=16&rft.issn=2379-3708&rft.eissn=2379-3708&rft_id=info:doi/10.1172/jci.insight.122204&rft_dat=%3Cproquest_pubme%3E2092544109%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2092544109&rft_id=info:pmid/30135316&rfr_iscdi=true