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- Title
Mouse-human co-clinical trials demonstrate superior anti-tumour effects of buparlisib (BKM120) and cetuximab combination in squamous cell carcinoma of head and neck.
- Authors
Kim, Hye Ryun; Kang, Han Na; Yun, Mi Ran; Ju, Kwon Young; Choi, Jae Woo; Jung, Dong Min; Pyo, Kyoung Ho; Hong, Min Hee; Ahn, Myoung-Ju; Sun, Jong-Mu; Kim, Han Sang; Kim, Jinna; Yoo, Jinseon; Kim, Kyu Ryung; Koh, Yoon Woo; Kim, Se Heon; Choi, Eun Chang; Yoon, Sun Ock; Shim, Hyo Sup; Paik, Soonmyung
- Abstract
<bold>Background: </bold>Recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN) is a common cancer with high recurrence and mortality. Current treatments have low response rates (RRs).<bold>Methods: </bold>Fifty-three patients with R/M SCCHN received continuous oral buparlisib. In parallel, patient-derived xenografts (PDXs) were established in mice to evaluate resistance mechanisms and efficacy of buparlisib/cetuximab combination. Baseline and on-treatment tumour genomes and transcriptomes were sequenced. Based on the integrated clinical and PDX data, 11 patients with progression under buparlisib monotherapy were treated with a combination of buparlisib and cetuximab.<bold>Results: </bold>For buparlisib monotherapy, disease control rate (DCR) was 49%, RR was 3% and median progression-free survival (PFS) and overall survival (OS) were 63 and 143 days, respectively. For combination therapy, DCR was 91%, RR was 18% and median PFS and OS were 111 and 206 days, respectively. Four PDX models were originated from patients enrolled in the current clinical trial. While buparlisib alone did not inhibit tumour growth, combination therapy achieved tumour inhibition in three of seven PDXs. Genes associated with apoptosis and cell-cycle arrest were expressed at higher levels with combination treatment than with buparlisib or cetuximab alone.<bold>Conclusions: </bold>The buparlisib/cetuximab combination has significant promise as a treatment strategy for R/M SCCHN.<bold>Clinical Trial Registration: </bold>NCT01527877.
- Subjects
THERAPEUTIC use of antineoplastic agents; HEAD tumors; BIOCHEMISTRY; RESEARCH; BIOLOGICAL models; GENETIC mutation; RESEARCH evaluation; GENETICS; CLINICAL trials; HETEROCYCLIC compounds; RESEARCH methodology; ANIMAL experimentation; CELL physiology; APOPTOSIS; ANTINEOPLASTIC agents; MEDICAL cooperation; EVALUATION research; CELL cycle; TREATMENT effectiveness; PHENOMENOLOGY; COMPARATIVE studies; RATS; AMINOPYRIDINES; GENE expression profiling; NECK tumors; DRUG resistance in cancer cells; MICE
- Publication
British Journal of Cancer, 2020, Vol 123, Issue 12, p1720
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-020-01074-2