Head and Neck Squamous Cell Carcinoma (HNSCC) Protein Profiles Associated with Tumor Response to Treatment

Head and neck squamous cell carcinoma (HNSCC) remains one of the most aggressive malignancies, characterized by limited therapeutic success and poor outcome. Despite continuous development of novel therapeutic strategies, disease-free survival in patients with advanced HNSCC has not been improved during the last 30 years. Evidently, a deeper understanding is needed of the molecular mechanisms underlying both intrinsic and acquired HNSCC cell resistance to currently existing therapeutic approaches. Proteome analysis is a powerful method which can provide deep insight into the molecular basis underlying HNSCC cell survival despite cytotoxic anti-tumor treatment (chemo-, radiotherapy). Evaluation of the protein profiles of cells obtained from locally recurrent or metastatic tumors can allow researchers to identify key protein players which regulate the HNSCC response to therapy. Additionally, subcellular fractionation and isolation of various cell organelles followed by proteomic analysis can provide data about intracellular protein localization, translocation and function following anti-cancer therapy. This review article discusses the protein patterns in HNSCC cells responsible for the radio- and chemo-resistance of these tumors and which result in the carcinoma cell survival and HNSCC recurrence

Inhibition of Ocular Tumor and Endothelial Cell Growth with a TEAD4216 Peptide Fragment

Purpose: Transcriptional enhancer factor 1-related (RTEF-1) also known as TEAD4 is expressed in ocular vascular endothelial cells and plays a role in the control of VEGF expression. Alternative processing of TEAD4 hnRNA results in different proteins able to stimulate or inhibit VEGF gene transcription. The purpose of this study is to test whether short peptide fragments (STY-RMR), representing functional domains of the inhibitory TEAD4216 isoform, can inhibit tumor as well as endothelial cell proliferation.Experimental Design: Cell proliferation was assessed using a colorimetric assay in cell lines incubated with STY-RMR, the amount of secreted VEGF within media was determined both in treated and control cell lines.Results: Significant dose dependent inhibition of cell proliferation was observed. Maximal inhibition of ocular melanoma (Mel 202 and Mel 207) cell proliferation was observed at a dose of 30 mg/100ml of STY-RMR (87% and 60% inhibition, respectively). At the same dose, more than 50% inhibition was observed in retinoblastoma and breast cancer cells (P <0.001). Significant inhibition of primate ocular endothelial cell proliferation (42% at 30 mg/100 ml (p < 0.001), and retinal pigment epithelial cells showed also a 75% inhibition (p = 0.007). Secreted VEGF was decreased in the media of all tested cell lines that had been exposed to STY-RMR.Conclusion: Functional short peptide domains derived from the TEAD4216 isoform may prove to be useful for treatment of ocular tumors and other VEGF dependent neovascular disease.Inhibition of proliferation and VEGF production within ocular endothelial cells indicate the potential of this agent to treat age-related macular degeneration (ARMD) and diabetic retinopathy (DR)

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials

Sentinel lymph node detection by blue dye versus indocyanine green fluorescence imaging in colon cancer

Background/Aim: Nodal staging is used in colorectal cancer (CRC) to determine which patients should receive adjuvant chemotherapy. The aim of this study was to evaluate the role of indocyanine green fluorescence imaging (ICG-FI) in sentinel lymph node (SLN) detection compared to the standard technique. Materials and Methods: Twenty patients with CRC admitted for elective colectomy were included (NCT01995591). Ex vivo SLN detection was performed using patent blue (PB) and free ICG injected around the tumor. Results: Identification rates were 95% (19/20) for both techniques. Sensitivity was 43% for PB and 57% for ICG. Correlation between the techniques was 83%. FI was more sensitive in patients with body mass index (BMI) >25 kg/m2. Serial section analysis did not allow for upstaging of patients. Conclusion: The use of ICG-FI is superior to the blue dye technique in patients with a BMI >25 kg/m2. However, the sensitivity of ICG-FI in SLN detection remains low, with a high rate of false-negative results.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Fluorescence Imaging After Indocyanine Green Injection for Detection of Peritoneal Metastases in Patients Undergoing Cytoreductive Surgery for Peritoneal Carcinomatosis From Colorectal Cancer: A Pilot Study.

The aim of this study was to evaluate the role of fluorescence imaging (FI) using an intraoperative injection of free indocyanine green (ICG) in the detection of peritoneal metastases (PM) due to colorectal cancer (CRC).SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A tailored molecular profiling programme for children with cancer to identify clinically actionable genetic alterations

Background: For children with cancer, the clinical integration of precision medicine to enable predictive biomarkerebased therapeutic stratification is urgently needed. Methods: We have developed a hybrid-capture next-generation sequencing (NGS) panel, specifically designed to detect genetic alterations in paediatric solid tumours, which gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. In this study, we offered an NGS panel, with clinical reporting via a molecular tumour board for children with solid tumours. Furthermore, for a cohort of 12 patients, we used a circulating tumour DNA (ctDNA)especific panel to sequence ctDNA from matched plasma samples and compared plasma and tumour findings. Results: A total of 255 samples were submitted from 223 patients for the NGS panel. Using FFPE tissue, 82% of all submitted samples passed quality control for clinical reporting. At least one genetic alteration was detected in 70% of sequenced samples. The overall detection rate of clinically actionable alterations, defined by modified OncoKB criteria, for all sequenced samples was 51%. A total of 8 patients were sequenced at different stages of treatment. In 6 of these, there were differences in the genetic alterations detected between time points. Sequencing of matched ctDNA in a cohort of extracranial paediatric solid tumours also identified a high detection rate of somatic alterations in plasma. Conclusion: We demonstrate that tailored clinical molecular profiling of both tumour DNA and plasma-derived ctDNA is feasible for children with solid tumours. Furthermore, we show that a targeted NGS panelebased approach can identify actionable genetic alterations in a high proportion of patients.This work was supported by Christopher’s Smile, the National Institute of Health Research (NIHR) Royal Marsden Biomedical Research Centre (BRC), Children With Cancer UK (CWC UK) Cancer Research UK (CRUK), Abbie’s Fund, the Rosetree Trust and the KiCa Fund, managed by the King Baudouin Foundation. Roche provided support for Panel development. T.S.J. is funded by The Brain Tumour Charity, CWC UK, GOSH Children’s Charity (GOSH CC), CRUK, the Olivia Hodson Cancer Fund and the NIHR GOSH BRC. J.A. and D.H. are funded by the GOSH CC and NIHR GOSH BRC. L.V.M. is funded by the Oak Foundation. The authors thank all participants and the CCLG Tissue Bank for access to samples and contributing CCLG Centres, including members of the ECMC Paediatric network. The CCLG Tissue Bank is funded by Cancer Research UK and CCL

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials