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...
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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 |
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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 & 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</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 & purification</subject><subject>Phosphoramide Mustards - pharmacology</subject><subject>Phosphoramide Mustards - therapeutic use</subject><subject>Prodrugs - administration & 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 - 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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 |
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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 |
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