Genomics-driven cancer therapeutics has gained prominence in personalized cancer treatment. However, its utility in indications lacking biomarker-driven treatment strategies remains limited. Here we present a “phenotype-driven precision-oncology” approach, based on the notion that biological response to perturbations, chemical or genetic, in ex vivo patient-individualized models can serve as predictive biomarkers for therapeutic response in the clinic. We generated a library of “screenable” patient-derived primary cultures (PDCs) for head and neck squamous cell carcinomas that reproducibly predicted treatment response in matched patient-derived-xenograft models. Importantly, PDCs could guide clinical practice and predict tumour progression in two n = 1 co-clinical trials. Comprehensive “-omics” interrogation of PDCs derived from one of these models revealed YAP1 as a putative biomarker for treatment response and survival in ~24% of oral squamous cell carcinoma. We envision that scaling of the proposed PDC approach could uncover biomarkers for therapeutic stratification and guide real-time therapeutic decisions in the future.
BackgroundCarcinoma of the oral tongue (OTSCC) is the most common malignancy of the oral cavity, characterized by frequent recurrence and poor survival. The last three decades has witnessed a change in the OTSCC epidemiological profile, with increasing incidence in younger patients, females and never-smokers. Here, we sought to characterize the OTSCC genomic landscape and to determine factors that may delineate the genetic basis of this disease, inform prognosis and identify targets for therapeutic intervention.MethodsSeventy-eight cases were subjected to whole-exome (n = 18) and targeted deep sequencing (n = 60).ResultsWhile the most common mutation was in TP53, the OTSCC genetic landscape differed from previously described cohorts of patients with head and neck tumors: OTSCCs demonstrated frequent mutations in DST and RNF213, while alterations in CDKN2A and NOTCH1 were significantly less frequent. Despite a lack of previously reported NOTCH1 mutations, integrated analysis showed enrichments of alterations affecting Notch signaling in OTSCC. Importantly, these Notch pathway alterations were prognostic on multivariate analyses. A high proportion of OTSCCs also presented with alterations in drug targetable and chromatin remodeling genes. Patients harboring mutations in actionable pathways were more likely to succumb from recurrent disease compared with those who did not, suggesting that the former should be considered for treatment with targeted compounds in future trials.ConclusionsOur study defines the Asian OTSCC mutational landscape, highlighting the key role of Notch signaling in oral tongue tumorigenesis. We also observed somatic mutations in multiple therapeutically relevant genes, which may represent candidate drug targets in this highly lethal tumor type.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0219-2) contains supplementary material, which is available to authorized users.
Treatment failure in solid tumors occurs due to the survival of specific subpopulations of cells that possess tumor-initiating (TIC) phenotypes. Studies have implicated G protein-coupled-receptors (GPCRs) in cancer progression and the acquisition of TIC phenotypes. Many of the implicated GPCRs signal through the G protein GNA13. In this study, we demonstrate that GNA13 is upregulated in many solid tumors and impacts survival and metastases in patients. GNA13 levels modulate drug resistance and TIC-like phenotypes in patient-derived head and neck squamous cell carcinoma (HNSCC) cells in vitro and in vivo. Blockade of GNA13 expression, or of select downstream pathways, using small-molecule inhibitors abrogates GNA13-induced TIC phenotypes, rendering cells vulnerable to standard-of-care cytotoxic therapies. Taken together, these data indicate that GNA13 expression is a potential prognostic biomarker for tumor progression, and that interfering with GNA13-induced signaling provides a novel strategy to block TICs and drug resistance in HNSCCs.
ObjectiveOrocutaneous and pharyngocutaneous fistula (OPCF) is a debilitating complication of head and neck surgery for squamous cell carcinoma (SCC), resulting in delayed adjuvant treatment and prolonged hospitalization. As yet, there is no established test that can help in prompt and accurate diagnosis of OPCF. This study aims to determine the accuracy of bedside blue dye testing and its role as part of an algorithm for early diagnosis. We also analyze the risk factors predisposing to OPCF.Study DesignRetrospective cohort study from 2012 to 2014.MethodsPatients with head and neck SCC who underwent major resection and reconstruction, at risk of OPCF, were included. Results of blue‐dye and video‐fluoroscopic swallow‐studies (VFSS) testing for OPCF were recorded. For the patients that were noted to develop OPCF, the length of time to diagnosis of fistula and subsequent mode of management were examined.ResultsOf the 93 patients in this study, 25 (26.9%) developed OPCF. Advanced T‐classification (T3/T4) was the only significant predisposing risk factor (p = 0.013). The sensitivity and specificity of the bedside blue dye testing was found to be 36.4% and 100%, respectively. The test positive patients were diagnosed with OPCF at a median of postoperative day (POD) 9.5 as compared to POD 13 for the test negative patients (p = 0.001). Early diagnosis was associated with faster fistula resolution with treatment.ConclusionBlue dye testing is a simple bedside test that can assist in the early diagnosis of OPCF in patients, allowing treatment to be instituted earlier with improved outcomes.Level of Evidence3
Patients with HNSCC living in smaller, higher-subsidy apartments have poorer survival despite no apparent delays in presentation. Cancer 2017;123:1998-2005. © 2017 American Cancer Society.
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