buparlisib and Squamous-Cell-Carcinoma-of-Head-and-Neck

Five-year overall survival for head and neck squamous cell carcinoma (HNSCC) is relatively poor at around 50-66%, and there has been little improvement over the past several decades.. The authors discuss the PIK3 pathway and the use of PIK3 inhibitors in cancer, with a particular focus on HNSCC. A summary of the safety and efficacy of buparlisib, a class I pan-PI3K inhibitor, from several phase I and phase II HNSCC trials is provided.. With a maximum tolerated dose of 100 mg/day and an acceptable toxicity profile, buparlisib may be effective in HNSCC, irrespective of

Topics: Aminopyridines; Class I Phosphatidylinositol 3-Kinases; Head and Neck Neoplasms; Humans; Maximum Tolerated Dose; Morpholines; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Squamous Cell Carcinoma of Head and Neck

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).. 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.. 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.. The buparlisib/cetuximab combination has significant promise as a treatment strategy for R/M SCCHN.. NCT01527877.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle Checkpoints; Cell Survival; Cetuximab; DNA Copy Number Variations; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Head and Neck Neoplasms; Humans; Male; Mice; Mice, Nude; Mice, SCID; Middle Aged; Morpholines; Mutation; Neoplasm Transplantation; Progression-Free Survival; Reproducibility of Results; Squamous Cell Carcinoma of Head and Neck; Treatment Outcome; Up-Regulation; Whole Genome Sequencing

This study assessed the maximum tolerated dose (MTD) of the PI3K inhibitor buparlisib given concurrently with cetuximab in recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).. Twelve patients with R/M HNSCC were enrolled. Patients were given oral buparlisib starting day 7 and daily thereafter. The dose of buparlisib was escalated in a 3 + 3 design followed by a dose expansion cohort of 6 patients. The MTD of buparlisib per protocol was 100 mg daily with cetuximab given intravenously every 14 days starting day 0.. Ten patients had ≥2 previous treatment regimens (11 with prior cetuximab). There were no dose limiting toxicities observed during dose escalation. One patient achieved a partial response and 4 achieved stable disease.. Based on this pilot study, buparlisib at 100 mg daily plus cetuximab proved to be well-tolerated. Patients previously treated with cetuximab monotherapy showed benefit from this combination.

Topics: Aged; Aminopyridines; Antineoplastic Agents, Immunological; Cetuximab; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Morpholines; Neoplasm Recurrence, Local; Pilot Projects; Squamous Cell Carcinoma of Head and Neck; Treatment Outcome

Hyperactivation of phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in head and neck squamous cell carcinoma (HNSCC). However, clinical outcomes of targeting the PI3K pathway have been underwhelming. In present study, we investigated the resistant mechanisms and potential combination therapeutic strategy to overcome adaptive resistance to PI3K inhibitor in HNSCC. Treatment of NVP-BKM120, a pan-PI3K inhibitor, led to upregulation of interleukin-6 (IL-6) and subsequent activation of either extracellular signal-regulated kinase (ERK) or signal transducers and activators of transcription 3 (STAT3), causing modest antitumor effects on the growth of HNSCC cells. Blockade of autocrine IL-6 signaling with siRNA or neutralizing antibody for IL-6 receptor (IL-6R) completely abolished NVP-BKM120-induced activation of ERK and STAT3 as well as expression of c-Myc oncogene, which resulted in enhanced sensitivity to NVP-BKM120. Moreover, when compared with a pharmacologic inhibitor or silencing of STAT3, trametinib, a MEK inhibitor, in combination with NVP-BKM120 yielded more potent anti-proliferative effects by inhibiting S phase transition, arresting cells at G0/G1 phase, and downregulating IL-6 and c-Myc expression. Furthermore, as compared with either agent alone, combination of NVP-BKM120 with trametinib or tocilizumab, a humanized anti-IL-6R antibody, significantly suppressed tumor growth in NVP-BKM120-resistant patient-derived tumor xenograft (PDTX) models, which was also confirmed in PDTX-derived cell lines. Collectively, these results suggested that IL-6/ERK signaling is closely involved in adaptive resistance of NVP-BKM120 in HNSCC cells, providing a rationale for a novel combination therapy to overcome resistance to PI3K inhibitors.

Topics: Aminopyridines; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Autocrine Communication; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Female; Head and Neck Neoplasms; Humans; Interleukin-6; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Receptors, Interleukin-6; RNA, Small Interfering; Squamous Cell Carcinoma of Head and Neck; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

The purpose of this study was to investigate the effects of combining the phosphotidylinositol-3-kinase (PI3K) inhibitor buparlisib (BKM)120 with the anti-epidermal growth factor receptor (EGFR) agent cetuximab and radiotherapy (RT) on an orthotopic model of head and neck squamous cell carcinoma (HNSCC).. We evaluated the antitumor efficacy of BKM120, cetuximab, and RT, administered alone or in combination, using the human PIK3CA-mutated HNSCC cell line, CAL33, injected into the floor of the mouth of nude mice.. Compared with control, the BKM120-cetuximab and the BKM120-cetuximab-RT combinations led to the highest tumor inhibition (p < .001). The highest inhibitory effect of treatments on cell proliferation, mitogen-activated protein kinase (MAPK) and PI3K/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathways were found with the BKM120-cetuximab association. The association of BKM120 and cetuximab with RT inhibited RT-induced activation of the MAPK pathway.. These results can serve as a preclinical rationale for innovative treatments combining PI3K inhibition with anti-EGFR therapies and irradiation in patients with HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 39: 151-159, 2017.

Topics: Aminopyridines; Animals; Antineoplastic Agents, Immunological; Carcinoma, Squamous Cell; Cetuximab; Combined Modality Therapy; Disease Models, Animal; Female; Head and Neck Neoplasms; Mice; Mice, Nude; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Squamous Cell Carcinoma of Head and Neck; Xenograft Model Antitumor Assays

Topics: Aminopyridines; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemoradiotherapy; Clinical Trials as Topic; Enzyme Inhibitors; Head and Neck Neoplasms; Humans; Molecular Targeted Therapy; Morpholines; Nasopharyngeal Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Programmed Cell Death 1 Receptor; Squamous Cell Carcinoma of Head and Neck

We previously reported that the EGFR-targeted inhibitor erlotinib induces G

Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Cytoprotection; Drug Resistance, Neoplasm; Drug Synergism; Erlotinib Hydrochloride; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Mice; Morpholines; Proto-Oncogene Proteins c-akt; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays