Investigational EGFR-targeted therapy in head and neck squamous cell carcinoma

Cassell, Andre; Grandis, Jennifer R.

doi:10.1517/13543781003769844

Cited by 80 publications

(66 citation statements)

References 91 publications

(158 reference statements)

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“…In the setting of SCCHN, it is also useful to interpret our data in the context of similar attempts to define biomarkers for treatment response to anti-EGFR-targeted monoclonal antibodies, such as cetuximab/erbitux, zalutumumab and panitumumab [43]. Despite our ability to design chimeric, humanised or fully human antibodies with exquisite selectivity for a precisely designed target (EGFR) and the clear demonstration that these agents mediate a therapeutic effect in SCCHN, we are apparently no closer to defining biomarkers to predict which patients with this disease will and will not respond to anti-EGFR monoclonal antibody targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway

et al. 2012

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BackgroundReovirus exploits aberrant signalling downstream of Ras to mediate tumor-specific oncolysis. Since ~90% squamous cell carcinomas of the head and neck (SCCHN) over-express EGFR and SCCHN cell lines are sensitive to oncolytic reovirus, we conducted a detailed analysis of the effects of reovirus in 15 head and neck cancer cell lines. Both pre- and post-entry events were studied in an attempt to define biomarkers predictive of sensitivity/resistance to reovirus. In particular, we analysed the role of EGFR/Ras signalling in determining virus-mediated cytotoxicity in SCCHN.MethodsTo test whether EGFR pathway activity was predictive of increased sensitivity to reovirus, correlative analyses between reoviral IC50 by MTT assay and EGFR levels by western blot and FACS were conducted. Inhibition or stimulation of EGFR signalling were analysed for their effect on reoviral oncolysis by MTT assay, and viral growth by TCID50 assay. We next analysed the effects of inhibiting signalling downstream of Ras, by specific inhibitors of p38MAPK, PI3-K or MEK, on reoviral killing examined by MTT assay. The role of PKR in reoviral killing was also determined by blockade of PKR using 2-aminopurine and assaying for cell survival by MTT assay. The apoptotic response of SCCHN to reovirus was examined by western blot analysis of caspase 3 cleavage.ResultsCorrelative analyses between reoviral sensitivity and EGFR levels revealed no association. Intermediate sub-viral and core particles showed the same infectivity/cytotoxicity as intact reovirus. Therefore, sensitivity was not determined by cell entry. In 4 cell lines, oncolysis and viral growth were both unaffected by inhibition or stimulation of EGFR signalling. Inhibition of signalling downstream of Ras did not abrogate reoviral oncolysis and, in addition, modulation of PKR using 2-aminopurine did not alter reovirus sensitivity in resistant cell lines. Caspase 3 cleavage was not detected in infected cells and oncolysis was observed in pan-caspase inhibited cells.ConclusionsIn summary, reovirus is potently oncolytic in a broad panel of SCCHN cell lines. Attempts to define sensitivity/resistance by analysis of the EGFR/Ras/MAPK pathway have failed to provide a clear predictive biomarker of response. Further analysis of material from in vitro and clinical studies is ongoing in an attempt to shed further light on this issue.

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Section: Discussionmentioning

confidence: 99%

Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway

et al. 2012

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“…Thus, mutation screening in HNSCC should not be limited to the NSCLC hotspot regions in exons 19 and 21 of EGFR. Moreover, given that the overall prevalence of EGFR TKD mutations in HNSCC is 2.8%, it is challenging to identify specific EGFR mutations related to response or resistance to anti-EGFR therapy or other targeted therapies (31).…”

Section: Distribution Of Mutations In the Egfr Kinase Domain Categorimentioning

confidence: 99%

Prevalence of EGFR Tyrosine Kinase Domain Mutations in Head and Neck Squamous Cell Carcinoma: Cohort Study and Systematic Review

Perisanidis

2017

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Abstract. Background: Mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain (TKDHead and neck squamous cell carcinoma (HNSCC) remains a challenging disease despite intensive clinical and translational research (1-3). A subset of head and neck cancer is caused by human papillomavirus (HPV) and represents a biologically distinct entity (4). In the past decades, several treatment strategies have been applied to treat HNSCC, however, survival outcomes have not substantially changed, emphasizing the need for more personalized medicine (5-8). Many efforts have, therefore, been made to identify predictive biomarkers and tailor treatment to the individual patient based on their own genetic and molecular profile.The epidermal growth factor receptor (EGFR) is a transmembrane cell surface receptor belonging to the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. EGFR overexpression occurs in more than 90% of HNSCCs and has been correlated with poor outcome (9). Robust preclinical evidence underlines the role of EGFR in the development of HNSCC, showing that EGFR activation triggers several downstream signaling pathways that play a crucial role in cancer pathogenesis (3,10,11). In this context, strategies for inhibition of EGFR signaling using monoclonal antibodies and tyrosine kinase inhibitors (TKIs) have been investigated intensively in clinical trials. De novo or acquired resistance to EGFR-targeted therapy, however, has led to a modest survival benefit for patients with HNSCC, while up-to-date predictive biomarkers of treatment response remain elusive (8,12,13).In non-small cell lung carcinoma (NSCLC), patients with activating mutations in the EGFR tyrosine kinase domain (TKD) are sensitive to small-molecule EGFR TKIs such as gefitinib, erlotinib, and afatinib (14-17). Given that mutations in the EGFR TKD may help in the selection of patients for EGFR TKIs or other targeted therapies, the EGFR mutation status in treatment-naïve patients with locally advanced oral and oropharyngeal squamous cell carcinoma (OOSCC) was retrospectively evaluated. In addition, a systematic literature review was undertaken to 23 This article is freely accessible online.

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“…Other monoclonal antibodies, including nimotuzumab, panitumumab and zalitumumab are being evaluated for enhanced properties like antibody-dependent cell-mediated cytotoxicity and unique binding sites [15]. Alternatively, tyrosine kinase inhibitors do not induce antibody-dependent cell-mediated cytotoxicity and may be less efficacious than monoclonal antibodies due to the lack of tyrosine kinase mutations in this cancer [16].…”

Section: Discussionmentioning

confidence: 99%

Nimotuzumab with Concurrent Chemo-Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of Head and Neck (LASCCHN)

Somani¹

2015

JCT

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Background: Head and neck cancers (HNCs) constitute 5% of all cancers globally and are the most common cancers in India. Chemotherapy and radiotherapy have not been proved to be effective in advanced cases and the prognosis remains dismal. This underscores the need for newer treatment options in these cases. Nimotuzumab, an anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, was safer when combined with chemo-or radio-therapy. Aim: To evaluate the safety and efficacy of concurrently administered nimotuzumab with chemo-radiotherapy in patients with advanced inoperable squamous cell carcinomas of head and neck (LASCCHN).

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Investigational EGFR-targeted therapy in head and neck squamous cell carcinoma

Cited by 80 publications

References 91 publications

Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway

Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway

Prevalence of EGFR Tyrosine Kinase Domain Mutations in Head and Neck Squamous Cell Carcinoma: Cohort Study and Systematic Review

Nimotuzumab with Concurrent Chemo-Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of Head and Neck (LASCCHN)

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