Exploiting High-Throughput Cell Line Drug Screening Studies to Identify Candidate Therapeutic Agents in Head and Neck Cancer

BACKGROUND: There is an urgent need for better therapeutics in head and neck squamous cell cancer (HNSCC) to improve survival and decrease treatment morbidity. Recent advances in high-throughput drug screening techniques and next-generation sequencing have identified new therapeutic targets in other cancer types, but an HNSCC-specific study has not yet been carried out. We have exploited data from two large-scale cell line projects to clearly describe the mutational and copy number status of HNSCC cell lines and identify candidate drugs with elevated efficacy in HNSCC. METHODS: The genetic landscape of 42 HNSCC cell lines including mutational and copy number data from studies by Garnett et al., and Barretina et al., were analyzed. Data from Garnett et al. was interrogated for relationships between HNSCC cells versus the entire cell line pool using one- and two-way analyses of variance (ANOVAs). As only seven HNSCC cell lines were tested with drugs by Barretina et al., a similar analysis was not carried out. RESULTS: Recurrent mutations in human papillomavirus (HPV)-negative patient tumors were confirmed in HNSCC cell lines, however additional, recurrent, cell line-specific mutations were identified. Four drugs, Bosutinib, Docetaxel, BIBW2992, and Gefitinib, were found via multiple-test corrected ANOVA to have lower IC50 values, suggesting higher drug sensitivity, in HNSCC lines versus non-HNSCC lines. Furthermore, the PI3K inhibitor AZD6482 demonstrated significantly higher activity (as measured by the IC50) in HNSCC cell lines harbouring PIK3CA mutations versus those that did not. CONCLUSION: HNSCC-specific reanalysis of large-scale drug screening studies has identified candidate drugs that may be of therapeutic benefit and provided insights into strategies to target PIK3CA mutant tumors. PIK3CA mutations may represent a predictive biomarker for response to PI3K inhibitors. A large-scale study focused on HNSCC cell lines and including HPV-positive lines is necessary and has the potential to accelerate the development of improved therapeutics for patients suffering with head and neck cancer. This strategy can potentially be used as a template for drug discovery in any cancer type

Functional outcomes in early (T1/T2) supraglottic cancer: a systematic review

ObjectivesOrgan preserving surgery (OPS) and radiotherapy (RT) are both accepted treatment options for early stage supraglottic cancer (SGC). Radiation has supplanted surgery in most cases, because of the perception that surgery results in poorer functional outcomes. However, evidence suggests that OPS with a neck dissection may be associated with improved survival. Our objective was to conduct a systematic review of the literature to compare functional outcomes of OPS and RT for early SGC.MethodsWe searched Medline, EMBASE and Cochrane Central Register of Controlled Trials to identify studies. Studies were included if they reported functional outcomes on 10 or more patients with early stage SGC treated with radiation or OPS, including open partial laryngectomy, transoral laser microsurgery (TLM) or transoral robotic surgery (TORS). Two reviewers independently screened articles for relevance using pre-determined criteria.ResultsFrom 7720 references, we included 10 articles (n=640 patients). 50% (n=320) of patients were treated with surgery. Three head-to-head RT versus OPS papers were included, however different outcome measures were used for each group. Intractable aspiration management (including total laryngectomy or permanent tracheostomy) following OPS was reported in five papers representing 186 patients; the definitive intractable aspiration management rate was 2.6% (95% CI 1.0-6.8%). Four papers reported permanent G-tube rate for the surgical group (n=198), calculating a rate of 5.3% (95% CI 2.6-10.5%), this was not reported for the RT group in any papers. One study reported quality of life. Two studies reported objective voice measures.ConclusionsThis systematic review revealed a paucity of objective measures and significant data heterogeneity, rendering the comparison of functional outcomes following OPS versus RT for early SGC limited. Future research should include objective measures of functional outcomes including laryngectomy rate, g-tube rate, tracheostomy dependence, quality of life, and voice quality measures

Assessing the Risk of SARS-CoV-2 Transmission via Surgical Electrocautery Plume

This quality improvement study used a nonhuman subject research approach to examine whether SARS-CoV-2 from aerosolized virus is present in and potentially transmissible from a electrocautery plume in surgery

High-throughput testing in head and neck squamous cell carcinoma identifies agents with preferential activity in human papillomavirus-positive or negative cell lines.

Head and neck squamous cell carcinoma (HNSCC) is a common cancer diagnosis worldwide. Despite advances in treatment, HNSCC has very poor survival outcomes, emphasizing an ongoing need for development of improved therapeutic options. The distinct tumor characteristics of human papillomavirus (HPV)-positive vs. HPV-negative disease necessitate development of treatment strategies tailored to tumor HPV-status. High-throughput robotic screening of 1,433 biologically and pharmacologically relevant compounds at a single dose (4 μM) was carried out against 6 HPV-positive and 20 HPV-negative HNSCC cell lines for preliminary identification of therapeutically relevant compounds. Statistical analysis was further carried out to differentiate compounds with preferential activity against cell lines stratified by the HPV-status. These analyses yielded 57 compounds with higher activity in HPV-negative cell lines, and 34 with higher-activity in HPV-positive ones. Multi-point dose-response curves were generated for six of these compounds (Ryuvidine, MK-1775, SNS-032, Flavopiridol, AZD-7762 and ARP-101), confirming Ryuvidine to have preferential potency against HPV-negative cell lines, and MK-1775 to have preferential potency against HPV-positive cell lines. These data comprise a valuable resource for further investigation of compounds with therapeutic potential in the HNSCC

Repurposing Albendazole: new potential as a chemotherapeutic agent with preferential activity against HPV-negative head and neck squamous cell cancer.

Albendazole is an anti-helminthic drug that has been shown to exhibit anti-cancer properties, however its activity in head and neck squamous cell cancer (HNSCC) was unknown. Using a series of in vitro assays, we assessed the ability of albendazole to inhibit proliferation in 20 HNSCC cell lines across a range of albendazole doses (1 nM-10 μM). Cell lines that responded to treatment were further examined for cell death, inhibition of migration and cell cycle arrest. Thirteen of fourteen human papillomavirus-negative HNSCC cell lines responded to albendazole, with an average IC50 of 152 nM. In contrast, only 3 of 6 human papillomavirus-positive HNSCC cell lines responded. Albendazole treatment resulted in apoptosis, inhibition of cell migration, cell cycle arrest in the G2/M phase and altered tubulin distribution. Normal control cells were not measurably affected by any dose tested. This study indicates that albendazole acts to inhibit the proliferation of human papillomavirus-negative HNSCC cell lines and thus warrants further study as a potential chemotherapeutic agent for patients suffering from head and neck cancer

A case report and genetic characterization of a massive acinic cell carcinoma of the parotid with delayed distant metastases.

We describe the presentation, management, and clinical outcome of a massive acinic cell carcinoma of the parotid gland. The primary tumor and blood underwent exome sequencing which revealed deletions in CDKN2A as well as PPP1R13B, which induces p53. A damaging nonsynonymous mutation was noted in EP300, a histone acetylase which plays a role in cellular proliferation. This study provides the first insights into the genetic underpinnings of this cancer. Future large-scale efforts will be necessary to define the mutational landscape of salivary gland malignancies to identify therapeutic targets and biomarkers of treatment failure

Strengthening Links Between Waterfowl Research and Management

Waterfowl monitoring, research, regulation, and adaptive planning are leading the way in supporting science-informed wildlife management. However, increasing societal demands on natural resources have created a greater need for adaptable and successful linkages between waterfowl science and management. We presented a special session at the 2016 North American Duck Symposium, Annapolis, Maryland, USA on the successes and challenges of linking research and management in waterfowl conservation, and we summarize those thoughts in this commentary. North American waterfowl management includes a diversity of actions including management of harvest and habitat. Decisions for waterfowl management are structured using decision analysis by incorporating stakeholder values into formal objectives, identifying research relevant to objectives, integrating scientific knowledge, and choosing an optimal strategy with respect to objectives. Recently, the consideration of the value of information has been proposed as a means to evaluate the utility of research designed to meet objectives. Despite these advances, the ability to conduct waterfowl research with direct management application may be increasingly difficult in research institutions for several reasons including reduced funding for applied research and the lower perceived value of applied versus theoretical research by some university academics. In addition, coordination between researchers and managers may be logistically constrained, and communication may be ineffective between the 2 groups. Strengthening these links would help develop stronger and more coordinated approaches for the conservation of waterfowl and the wetlands upon which they depend

Strengthening Links Between Waterfowl Research and Management

Waterfowl monitoring, research, regulation, and adaptive planning are leading the way in supporting science-informed wildlife management. However, increasing societal demands on natural resources have created a greater need for adaptable and successful linkages between waterfowl science and management. We presented a special session at the 2016 North American Duck Symposium, Annapolis, Maryland, USA on the successes and challenges of linking research and management in waterfowl conservation, and we summarize those thoughts in this commentary. North American waterfowl management includes a diversity of actions including management of harvest and habitat. Decisions for waterfowl management are structured using decision analysis by incorporating stakeholder values into formal objectives, identifying research relevant to objectives, integrating scientific knowledge, and choosing an optimal strategy with respect to objectives. Recently, the consideration of the value of information has been proposed as a means to evaluate the utility of research designed to meet objectives. Despite these advances, the ability to conduct waterfowl research with direct management application may be increasingly difficult in research institutions for several reasons including reduced funding for applied research and the lower perceived value of applied versus theoretical research by some university academics. In addition, coordination between researchers and managers may be logistically constrained, and communication may be ineffective between the 2 groups. Strengthening these links would help develop stronger and more coordinated approaches for the conservation of waterfowl and the wetlands upon which they depend

A Pilot Study Comparing HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinomas by Whole Exome Sequencing.

Background. Next-generation sequencing of cancers has identified important therapeutic targets and biomarkers. The goal of this pilot study was to compare the genetic changes in a human papillomavirus- (HPV-)positive and an HPV-negative head and neck tumor. Methods. DNA was extracted from the blood and primary tumor of a patient with an HPV-positive tonsillar cancer and those of a patient with an HPV-negative oral tongue tumor. Exome enrichment was performed using the Agilent SureSelect All Exon Kit, followed by sequencing on the ABI SOLiD platform. Results. Exome sequencing revealed slightly more mutations in the HPV-negative tumor (73) in contrast to the HPV-positive tumor (58). Multiple mutations were noted in zinc finger genes (ZNF3, 10, 229, 470, 543, 616, 664, 638, 716, and 799) and mucin genes (MUC4, 6, 12, and 16). Mutations were noted in MUC12 in both tumors. Conclusions. HPV-positive HNSCC is distinct from HPV-negative disease in terms of evidence of viral infection, p16 status, and frequency of mutations. Next-generation sequencing has the potential to identify novel therapeutic targets and biomarkers in HNSCC