3288 results for "ovarian cancer"

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• Treatment stratification and biomarker validation using patient-derived head and neck cancer organoids

  Background Organoids are three-dimensional structures that can be grown from patient-derived material including carcinomas. These in vitro models can be cryopreserved to generate “living” biobanks that reflect patient heterogeneity. Head and neck cancer (HNC) is a collective term used for tumors arising in the head and neck area, including squamous cell carcinomas (HNSCC) and adenocarcinoma of the salivary gland. Methods to culture patient-derived HNC organoids have previously been described. Methods Organoids were derived from resection or biopsy material of patients included between 2016 and 2022. Organoids were characterised with immunohistochemistry and whole exome sequencing (WES) and exposed to chemo-, radio- and targeted-therapies. CRISPR/Cas9-based gene editing was applied to validate proposed biomarkers. Results We have extended our previously published organoid biobank to a total of 110 organoid models, some of which were characterised by histology and WES. Organoids recapitulated both single nucleotide variants and copy number alterations as found in patient HNSCC samples. Organoid and patient response to radiotherapy (RT; primary (n=6) and adjuvant (n=15)) could be compared in 21 HNC cases. In the adjuvant RT group, organoids derived from patients that relapsed were more resistant to RT in vitro, showing potential for guiding treatment options in this subset of patients. Conclusion Taken together, these results indicate illustrate the potential of organoids as a diagnostic tool in personalised medicine for HNC and indicate the potential of this technology for biomarker discovery and validation within the context of relevant patient heterogeneity.

  Study EGAS00001007076

• RB Loss in Resistant EGFR Mutant Lung Adenocarcinomas that Transform to Small Cell Lung Cancer

  Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs typically occurs afterafter an average of one year of continuous treatment. In a subset of patients, aA fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in resistant EGFR mutant cancers that transformed to SCLC. Consistent Further, with their similarities to classical SCLC at the genetic and gene expression levelincreased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared to resistant NSCLCs. , cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to Bcl-2 family inhibition with ABT-263 compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.

  Study EGAS00001001102

• MYO5B mutations in Pheochromocytoma/Paraganglioma promote cancer progression

  Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status.Immunohistochemistry and mRNA expression analysis in 30 primary PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic tumor cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmatic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a PGL case harboring a MYO5B:p.G1611S mutation. Mutation analysis of additional PPGL tumors revealed additional, and hence recurrent, mutations in the paralog MYO5A. Three missense mutations in MYO5B were functionally studied using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293 cell line). Functional analysis of the mutants verified a significant increased proliferation rate in all MYO5B mutated clones (p.L587P, p.G1611S, and p.R1641C). The two somatically derived mutations p.L587P and p.G1611S were also found to increase the migration rate, and all three mutants affected intracellular transport by increased transferrin uptake. Downstream expression analysis of MYO5B mutants demonstrated a transcriptional activation of genes involved in glucose metabolism, proliferation, homeostasis, and migration. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved the malignant progression of PPGL tumors.

  Study EGAS00001003991

• A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer

  Background Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. Methods We combined immunohistochemistry (IHC) with RNA-sequencing and whole genome sequencing across a diverse spectrum of high-risk paediatric cancers to develop an alternative, expression-based signature associated with CD8+ T-cell infiltration of the TIME. Further, we explored transcriptional features of immune archetypes, T-cell receptor sequencing diversity, assessed the relationship between CD8+ and CD4+ abundance by IHC and deconvolution predictions, and assessed common adult biomarkers such as neoantigen load and TMB. Results A novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), was identified. Using this signature, we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. In addition, we showed that PD-L1 protein expression is poorly correlated with PD-L1 RNA expression and TMB and neoantigen load are not predictive of T-cell infiltration in paediatrics. Furthermore, deconvolution algorithms are only weakly correlated with IHC measurements of T-cells. Conclusions Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.

  Study EGAS00001007029

• CALGB/SWOG 80405: Genome-Wide Association Study of Patients with Advanced or Metastatic Colorectal Cancer Treated with First-Line Chemotherapy Combined with Cetuximab and/or Bevacizumab

  CALGB/SWOG 80405 (NCT00265850) was a randomized phase III study of bevacizumab, cetuximab, or the combination of these two monoclonal antibodies, in addition to systemic chemotherapy for patients with untreated metastatic adenocarcinoma of the colon or rectum. We prospectively collected germline DNA and conducted genome-wide association studies using clinical outcomes and molecular features.

  Study phs003428

• Human Cancer-Targeted Immunity via Transgenic Hematopoietic Stem Cell Progeny

  Analysis of a patient biopsy from the clinical trial (NCT03240861), a first-in-human study of transgenic NY-ESO-1 TCR- T cells and NY-ESO-1 TCR+ sr39tk autologous hematopoietic stem cells tandem therapy for solid tumors after myeloablative conditioning chemotherapy with busulfan and fludarabine. Single-cell RNAseq and single-cell ATACseq analysis from peripheral blood mononuclear cells obtained from subject NYSCT-03.

  Study phs003898

• Single cell atlas of relapsed/refractory large B-cell lymphoma

  Relapsed/refractory large B-cell lymphomas (rrLBCL) are clinically and biologically diverse lymphoid malignancies with intricate microenvironments that play a key role in disease development. In this study, we used single-nucleus multiome profiling along with bulk DNA and RNA sequencing on 120 tumor and control biopsies to comprehensively characterize the various cell types and subsets found in rrLBCL tumors.

  Study EGAS50000001293

• Excised DNA Circles from V(D)J Recombination Promote Relapsed Leukaemia

  In this study, we show that ESCs replicate and persist through many cell generations. High ESC copies at diagnosis of BCP-ALL strongly correlate with subsequent relapse. These data provide the first demonstration that the V(D)J recombination by-product, when replicated to elevated levels, potently associates with the V(D)J recombinase to cause adverse disease outcomes.

  Study EGAS50000000407

• Bevacizumab plus erlotinib in advanced solid cancers with Krebs cycle gene mutations: A multicenter phase II study

  Targeting aberrant metabolism in tumors with alterations in genes encoding Krebs cycle enzymes, a central component of glucose metabolism, is a promising therapeutic strategy. These tumors rely on aerobic glycolysis and promote VEGF-dependent angiogenesis; furthermore, EGFR signaling enhances aerobic glycolysis. This phase 2 trial evaluated bevacizumab and erlotinib in patients with solid tumors harboring Krebs cycle gene mutations.

  Study EGAS50000001243

• EXPRESSION OF ANTIBODY-DRUG CONJUGATE TARGETS IN BREAST CANCER METASTASES AND NORMAL TISSUE

  Using bulk mRNA sequencing, we investigated the expression of 72 ADC targets, which are clinically approved or under investigation, in 909 samples (64 primary untreated, 749 metastatic, 96 normal) from 30 female patients from our post-mortem tissue donation program UPTIDER (NCT04531696). The study explores changes in target expression across multiple samples to identify novel targets of clinical interest and validation

  Study EGAS50000001334