A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma
Tekijät: Jamieson SMF, Tsai P, Kondratyev MK, Budhani P, Liu A, Senzer NN, Chiorean EG, Jalal SI, Nemunaitis JJ, Kee D, Shome A, Wong WW, Li D, Poonawala-Lohani N, Kakadia PM, Knowlton NS, Lynch CRH, Hong CR, Lee TW, Grenman RA, Caporiccio L, McKee TD, Zaidi M, Butt S, Macann AMJ, McIvor NP, Chaplin JM, Hicks KO, Bohlander SK, Wouters BG, Hart CP, Print CG, Wilson WR, Curran MA, Hunter FW
Kustantaja: AMER SOC CLINICAL INVESTIGATION INC
Julkaisuvuosi: 2018
Journal: JCI Insight
Tietokannassa oleva lehden nimi: JCI INSIGHT
Lehden akronyymi: JCI INSIGHT
Artikkelin numero: ARTN e122204
Vuosikerta: 3
Numero: 16
Sivujen määrä: 18
ISSN: 2379-3708
DOI: https://doi.org/10.1172/jci.insight.122204
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/m(2) qw x 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.
