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10.1172/jci.insight.169136
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Published February 22, 2023 - More info
Published in Volume 8, Issue 4 on February 22, 2023
Related article:
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.
Authors
Stephen M.F. Jamieson, Peter Tsai, Maria K. Kondratyev, Pratha Budhani, Arthur Liu, Neil N. Senzer, E. Gabriela Chiorean, Shadia I. Jalal, John J. Nemunaitis, Dennis Kee, Avik Shome, Way W. Wong, Dan Li, Nooriyah Poonawala-Lohani, Purvi M. Kakadia, Nicholas S. Knowlton, Courtney R.H. Lynch, Cho R. Hong, Tet Woo Lee, Reidar A. Grénman, Laura Caporiccio, Trevor D. McKee, Mark Zaidi, Sehrish Butt, Andrew M.J. Macann, Nicholas P. McIvor, John M. Chaplin, Kevin O. Hicks, Stefan K. Bohlander, Bradly G. Wouters, Charles P. Hart, Cristin G. Print, William R. Wilson, Michael A. Curran, Francis W. Hunter
×Original citation: JCI Insight. 2018;3(16):e122204. https://doi.org/10.1172/jci.insight.122204
Citation for this corrigendum: JCI Insight. 2023;8(4):e169136. https://doi.org/10.1172/jci.insight.169136
It has been brought to the authors’ attention that the STR profile of the head and neck squamous cell carcinoma line UT-SCC-54C presented in Supplemental Table 1 is markedly different from that of UT-SCC-54A and UT-SCC-54B, which originated from the same patient. Upon further investigation, the authors have determined that the UT-SCC-54C cultures used in this study almost exclusively comprise colon cancer–derived HCT116 cells, as demonstrated by STR, gene expression, and mutation profiling. The authors regret contamination of the UT-SCC-54C line reported here and confirm that uncontaminated UT-SCC-54C cultures are available from earlier frozen stocks. The authors have stated that the conclusions of the study are not affected.
Footnotes Version history Version 1 (February 22, 2023): Electronic publication
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