Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma
| Autor: | Reidar Grénman, John Nemunaitis, Mark Zaidi, William R. Wilson, Courtney R. H. Lynch, Trevor D. McKee, Cho R. Hong, Peter Tsai, Charles P. Hart, Dennis Kee, Purvi M. Kakadia, John M. Chaplin, Tet Woo Lee, Bradly G. Wouters, Stephen M. F. Jamieson, Arthur Liu, Nicholas P. McIvor, Francis W. Hunter, Shadia I. Jalal, Cristin G. Print, Nicholas Knowlton, E. Gabriela Chiorean, Nooriyah Poonawala-Lohani, Way W. Wong, Kevin O. Hicks, Dan Li, Laura Caporiccio, Neil Senzer, Avik Shome, Michael A. Curran, Andrew Macann, Pratha Budhani, Maria Kondratyev, Stefan K. Bohlander, Sehrish Butt |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Adult
0301 basic medicine medicine.medical_treatment Cell Phases of clinical research Antineoplastic Agents Inhibitory Concentration 50 Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Exome Sequencing Biomarkers Tumor medicine Humans Prodrugs Papillomaviridae Response Evaluation Criteria in Solid Tumors Aged Evofosfamide Tumor hypoxia Squamous Cell Carcinoma of Head and Neck business.industry Human Papillomavirus Negative Chemoradiotherapy General Medicine Middle Aged medicine.disease ta3122 Xenograft Model Antitumor Assays Head and neck squamous-cell carcinoma Progression-Free Survival Nitrogen mustard Radiation therapy 030104 developmental biology medicine.anatomical_structure chemistry Drug Resistance Neoplasm Head and Neck Neoplasms Nitroimidazoles Gene Knockdown Techniques 030220 oncology & carcinogenesis Cancer research Female Phosphoramide Mustards business Research Article |
| Zdroj: | JCI Insight. 3(16) |
| ISSN: | 2379-3708 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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