Stathmin as a surrogate marker of phosphatidylinositol-3-kinase pathway activity: Towards precision medicine in HPV-negative head & neck squamous cell carcinoma.
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SUBMITTER: Turk AT
PROVIDER: S-EPMC9243320 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective:To provide a review of emerging knowledge from genomics and related basic science, preclinical, and clinical precision medicine studies in head and neck squamous cell carcinoma (HNSCC). Data Sources:The Cancer Genome Atlas Network (TCGA) publications, PubMed-based literature review, and ClinicalTrials.gov. Review Methods:TCGA publications, PubMed, and ClinicalTrials.gov were queried for genomics and related basic science, preclinical, and developmental clinical precision medicine studies in HNSCC. Results:TCGA reported comprehensive genomic analyses of 279 HNSCC, defining the landscape and frequency of chromosomal copy number alterations, mutations, and expressed genes that contribute to pathogenesis, prognosis, and resistance to therapy. This provides a road map for basic science and preclinical studies to identify key pathways in cancer and cells of the tumor microenvironment affected by these alterations, and candidate targets for new small molecule and biologic therapies. Conclusion:Recurrent chromosomal abnormalities, mutations, and expression of genes affecting HNSCC subsets are associated with differences in prognosis, and define molecules, pathways, and deregulated immune responses as candidates for therapy. Activity of molecularly targeted agents appears to be enhanced by rational combinations of these agents and standard therapies targeting the complex alterations that affect multiple pathways and mechanisms in HNSCC. Level of Evidence:NA.
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Project description:Standard treatment in head and neck squamous cell carcinoma (HNSCC) is limited currently with decisions being made primarily based on tumor location, histology, and stage. The role of the human papillomavirus in risk stratification is actively under clinical trial evaluations. The molecular complexity and intratumoral heterogeneity of the disease are not actively integrated into management decisions of HNSCC, despite a growing body of knowledge in these areas. The advent of the genomic era has delivered vast amounts of information regarding different cancer subtypes and is providing new therapeutic targets, which can potentially be elucidated using next-generation sequencing and other modern technologies. The task ahead is to expand beyond the existent armamentarium by exploiting beyond the genome and perform integrative analysis using innovative systems biology methods, with the goal to deliver effective precision medicine-based theragnostic options in HNSCC.
| S-EPMC5989049 | biostudies-other
Project description:Head and neck cancers (HNCs) represent the sixth most widespread malignancy worldwide. Surgery, radiotherapy, chemotherapeutic and immunotherapeutic drugs represent the main clinical approaches for HNC patients. Moreover, HNCs are characterised by an elevated mutational load; however, specific genetic mutations or biomarkers have not yet been found. In this scenario, personalised medicine is showing its efficacy. To study the reliability and the effects of personalised treatments, preclinical research can take advantage of next-generation sequencing and innovative technologies that have been developed to obtain genomic and multi-omic profiles to drive personalised treatments. The crosstalk between malignant and healthy components, as well as interactions with extracellular matrices, are important features which are responsible for treatment failure. Preclinical research has constantly implemented in vitro and in vivo models to mimic the natural tumour microenvironment. Among them, 3D systems have been developed to reproduce the tumour mass architecture, such as biomimetic scaffolds and organoids. In addition, in vivo models have been changed over the last decades to overcome problems such as animal management complexity and time-consuming experiments. In this review, we will explore the new approaches aimed to improve preclinical tools to study and apply precision medicine as a therapeutic option for patients affected by HNCs.
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Project description:Head and neck squamous cell carcinoma (HNSCC) is the sixth most incident cancer worldwide. More than half of HNSCC patients experience locoregional or distant relapse to treatment despite aggressive multimodal therapeutic approaches that include surgical resection, radiation therapy, and adjuvant chemotherapy. Before the arrival of immunotherapy, systemic chemotherapy was previously employed as the standard first-line protocol with an association of cisplatin or carboplatin plus 5-fluorouracil plus cetuximab (anti-EFGR antibody). Unfortunately, acquisition of therapy resistance is common in patients with HNSCC and often results in local and distant failure. Despite our better understanding of HNSCC biology, no other molecular-targeted agent has been approved for HNSCC. In this review, we outline the mechanisms of resistance to the therapeutic strategies currently used in HNSCC, discuss combination treatment strategies to overcome them, and summarize the therapeutic regimens that are presently being evaluated in early- and late-phase clinical trials.
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Project description:The pathogenesis of Cushing's disease is poorly understood; two recent reports identifying somatic mutations in USP8 in pituitary corticotroph tumors provide exciting advances in this field. These mutations alter EGFR trafficking and signaling, raising the prospect that EGFR inhibitors may move the treatment of this disease into the era of precision medicine.
| S-EPMC4456621 | biostudies-other
Project description:Epithelial to mesenchymal transition (EMT) promotes therapy resistance in head and neck cancer (HNC) cells. In this study, EMT was quantified in HNC tumor samples by the cellular co-localization of cytokeratin/vimentin, E‑cadherin/β‑catenin and by Slug expression. Tissue samples from HNC patients were stained with antibody pairs against cytokeratin/vimentin and E-cadherin/β-catenin. Epithelial-mesenchymal co-localization was quantified using immunofluorescence multichannel image cytometry. Double positivity was confirmed using confocal microscopy. Slug was semi-quantified by 2 specialists and quantified by bright field image cytometry. Tumor samples of 102 patients were investigated. A loss of E-cadherin positive cells (56.9 ± 2.6% vs. 97.9 ± 1.0%; p < 0.0001) and E-cadherin/β-catenin double positive cells (15.4 ± 5.7% vs. 85.4 ± 1.2%; p < 0.0001) was observed in tumor samples. The percentage of Slug positive cells was increased in tumor samples (12.1 ± 3.6% vs. 3.2 ± 2.6%; p = 0.001). Ordinal Slug scores judged by two specialists closely correlated with percentage of Slug-positive cells (Spearman's rho = 0.81; p < 0.001). Slug score correlated negatively with the percentage of E-cadherin positive cells (r = 0.4; p = 0.006), the percentage of E-cadherin/β-catenin positive cells (r = 0.5; p = 0.001) and positively with cytokeratin/vimentin positive cells (r = 0.4, p = 0.003). EMT can be assessed in HNC tumor probes by cytokeratin/vimentin co-expression and loss of E-cadherin/β-catenin co-expression. Slug score provides a convenient surrogate marker for EMT.
| S-EPMC7408865 | biostudies-literature
Project description:Opinion statementAs the field of oncology enters the era of precision medicine and targeted therapies, we have come to realize that there may be no single "magic bullet" for patients with head and neck cancer. While immune check point inhibitors and some targeted therapeutics have shown great promise in improving oncologic outcomes, the current standard of care in most patients with head and neck squamous cell carcinoma (HNSCC) remains a combination of surgery, radiation, and/or cytotoxic chemotherapy. Nevertheless, advances in precision medicine, next-generation sequencing (NGS), and targeted therapies have a potential future in the treatment of HNSCC. These roles include increased patient treatment stratification based on predictive biomarkers or targetable mutations and novel combinatorial regimens with existing HNSCC treatments. There remain challenges to precision medicine and NGS in HNSCC, including intertumor and intratumor heterogeneity, challenging targets, and need for further trials validating the utility of NGS and precision medicine. Additionally, there is a need for evidence-based practice guidelines to assist clinicians on how to appropriately incorporate NGS in care for HNSCC. In this review, we describe the current state of precision medicine and NGS in HNSCC and opportunities for future advances in this challenging but important field.
| S-EPMC9196261 | biostudies-literature
Project description:Head and neck cancers (HNCs) are a highly heterogeneous group of tumours that are associated with diverse clinical outcomes. Recent evidence has demonstrated that human papillomavirus (HPV) is involved in up to 25% of HNCs; particularly in the oropharyngeal carcinoma (OPC) subtype where it can account for up to 60% of such cases. HPVs are double-stranded DNA viruses that infect epithelial cells; numerous HPV subtypes, including 16, 18, 31, 33, and 35, drive epithelial cell transformation and tumourigenesis. HPV positive (HPV+) HNC represents a distinct molecular and clinical entity from HPV negative (HPV-) disease; the biological basis for which remains to be fully elucidated. HPV positivity is strongly correlated with a significantly superior outcome; indicating that such tumours should have a distinct management approach. This review focuses on the recent scientific and clinical investigation of HPV+ HNC. In particular, we discuss the importance of molecular and clinical evidence for defining the role of HPV in HNC, and the clinical impact of HPV status as a biomarker for HNC.
| S-EPMC4999784 | biostudies-literature
Project description:Tumor biomarkers play important roles in tumor growth, invasion, and metastasis. Imaging of specific biomarkers will help to understand different biological activities, thereby achieving precise medicine for each head and neck squamous cell carcinoma (HNSCC) patient. Here, we describe various molecular targets and molecular imaging modalities for HNSCC imaging. An extensive search was undertaken in the PubMed database with the keywords including "HNSCC," "molecular imaging," "biomarker," and "multimodal imaging." Imaging targets in HNSCC consist of the epidermal growth factor receptor, cluster of differentiation 44 variant 6 (CD44v6), and mesenchymal-epithelial transition factor and integrins. Targeted molecular imaging modalities in HNSCC include optical imaging, ultrasound, magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography. Making the most of each single imaging method, targeted multimodal imaging has a great potential in the accurate diagnosis and therapy of HNSCC. By visualizing tumor biomarkers at cellular and molecular levels in vivo, targeted molecular imaging can be used to identify specific genetic and metabolic aberrations, thereby accelerating personalized treatment development for HNSCC patients.
| S-EPMC7289307 | biostudies-literature
Project description:Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with high mortality and a lack of targeted therapies. To identify and prioritize druggable targets, we performed genome analysis together with genome-scale siRNA and oncology drug profiling using low-passage tumor cells derived from a patient with treatment-resistant HPV-negative HNSCC.Experimental Design: A tumor cell culture was established and subjected to whole-exome sequencing, RNA sequencing, comparative genome hybridization, and high-throughput phenotyping with a siRNA library covering the druggable genome and an oncology drug library. Secondary screens of candidate target genes were performed on the primary tumor cells and two nontumorigenic keratinocyte cell cultures for validation and to assess cancer specificity. siRNA screens of the kinome on two isogenic pairs of p53-mutated HNSCC cell lines were used to determine generalizability. Clinical utility was addressed by performing drug screens on two additional HNSCC cell cultures derived from patients enrolled in a clinical trial.Results: Many of the identified copy number aberrations and somatic mutations in the primary tumor were typical of HPV(-) HNSCC, but none pointed to obvious therapeutic choices. In contrast, siRNA profiling identified 391 candidate target genes, 35 of which were preferentially lethal to cancer cells, most of which were not genomically altered. Chemotherapies and targeted agents with strong tumor-specific activities corroborated the siRNA profiling results and included drugs that targeted the mitotic spindle, the proteasome, and G2-M kinases WEE1 and CHK1 We also show the feasibility of ex vivo drug profiling for patients enrolled in a clinical trial.Conclusions: High-throughput phenotyping with siRNA and drug libraries using patient-derived tumor cells prioritizes mutated driver genes and identifies novel drug targets not revealed by genomic profiling. Functional profiling is a promising adjunct to DNA sequencing for precision oncology. Clin Cancer Res; 24(12); 2828-43. ©2018 AACR.
| S-EPMC6004257 | biostudies-literature