Mouse–human co-clinical trials demonstrate superior anti-tumour effects of buparlisib (BKM120) and cetuximab combination in squamous cell carcinoma of head and neck

Autor: Jong Mu Sun, Jinseon Yoo, Kyoung Ho Pyo, Byoung Chul Cho, Se-Heon Kim, Sun Ock Yoon, Hye Ryun Kim, Dong Min Jung, Yoon Woo Koh, Eun Chang Choi, Han Na Kang, Hyo Sup Shim, Kyu Ryung Kim, Kwon Young Ju, Tae Min Kim, Han Sang Kim, Soonmyung Paik, Jae Woo Choi, Min Hee Hong, Mi Ran Yun, Myoung Ju Ahn, Jinna Kim
Rok vydání: 2020
Předmět:
Male
Oncology
Cancer Research
Buparlisib
Aminopyridines
Cetuximab
Apoptosis
Mice
SCID
Mice
chemistry.chemical_compound
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
Medicine
Head and neck cancer
Head and neck
Aged
80 and over
0303 health sciences
Middle Aged
Progression-Free Survival
Up-Regulation
Treatment Outcome
Head and Neck Neoplasms
030220 oncology & carcinogenesis
Female
medicine.drug
Adult
medicine.medical_specialty
DNA Copy Number Variations
Combination therapy
Cell Survival
Morpholines
Mice
Nude
Article
03 medical and health sciences
Internal medicine
Animals
Humans
Basal cell
Aged
030304 developmental biology
Whole Genome Sequencing
Squamous Cell Carcinoma of Head and Neck
business.industry
Gene Expression Profiling
Reproducibility of Results
Cancer
Cell Cycle Checkpoints
medicine.disease
Clinical trial
chemistry
Drug Resistance
Neoplasm
Mutation
business
Neoplasm Transplantation
Zdroj: British Journal of Cancer
ISSN: 1532-1827
0007-0920
DOI: 10.1038/s41416-020-01074-2
Popis: Background 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). Methods 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. Results 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. Conclusions The buparlisib/cetuximab combination has significant promise as a treatment strategy for R/M SCCHN. Clinical Trial Registration NCT01527877.
Databáze: OpenAIRE
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