Search results for "MUTATION"

Absence of mutations in the activation loop and juxtamembrane domains of VEGFR-1 and VEGFR-2 gene in chronic myelomonocytic leukemia (CMML)

2012

In the literature: December 2019

2020

The introduction of new high-throughput technologies in oncology and the need to apply precision medicine for cancer patients has led to the detection of several molecular alterations. Among them, activating mutations of ERBB2 have been reported in many solid tumours. In the last years, several clinical trials with covalent tyrosine kinase inhibitors (TKIs) for ERBB2 mutant cancers have been conducted, with different results among several cancer types. In the SUMMIT trial, neratinib was most effective in breast cancer patients, with the majority of responders having tumours with L755S, V777L, or L869R ERBB2 mutations.1 In an elegant article published in C ancer C ell by Robichaux et al ,2 d…

Translation of genomics-guided RNA-based personalised cancer vaccines: towards the bedside

2014

Cancer is a disease caused by DNA mutations. Cancer therapies targeting defined functional mutations have shown clinical benefit. However, as 95% of the mutations in a tumour are unique to that single patient and only a small number of mutations are shared between patients, the addressed medical need is modest. A rapidly determined patient-specific tumour mutation pattern combined with a flexible mutation-targeting drug platform could generate a mutation-targeting individualised therapy, which would benefit each single patient. Next-generation sequencing enables the rapid identification of somatic mutations in individual tumours (the mutanome). Immunoinformatics enables predictions of mutat…

Clinical use of RNA sequencing and oncobox analytics to predict personalized targeted therapeutic efficacy.

2020

e13676 Background: Analysis of mutation profiles in cancer patients does not provide clinical benefits in 80-90% of cases in the US (Marquart et al., 2018). Gene expression analysis potentially complements standard detection of clinically relevant mutations. Methods: 239 adult late-stage cancer patients. RNA gene expression sequencing completed on solid tumor samples using FFPE blocks. Patient mRNA profiles were analyzed using Oncobox bioinformatics, prioritizing target drugs according to their personalized predicted efficacy. Summary reports were provided to oncologists and resulting treatment selection and outcomes were assessed. Results: As of February 2020, feedback was received from p…

Transforming Growth Factor-β–Mediated Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Expression and Apoptosis in Hepatoma Cells Requires Fun…

2008

Abstract Transforming growth factor-β (TGF-β) has been shown to induce apoptotic cell death in normal and transformed hepatocytes. We recently identified tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as an important mediator of TGF-β–induced apoptosis in hepatoma cells. In this study, we have further explored the mechanism by which TGF-β up-regulates TRAIL expression. The 5′-flanking region of the TRAIL gene was isolated and characterized. Deletion mutants of the 5′-untranslated region of the TRAIL gene revealed a region comprising nucleotides −1950 to −1100 responsible for TRAIL induction following treatment with TGF-β. Within this region, we have identified an activator …

Smac induces cytochrome c release and apoptosis independently from Bax/Bcl-xL in a strictly caspase-3-dependent manner in human carcinoma cells

2004

The mitochondrial apoptosis pathway mediates cell death through the release of various pro-apoptotic factors including cytochrome c and Smac, the second mitochondrial activator of caspases, into the cytosol. Smac was shown previously to inhibit IAP proteins and to facilitate initiation of the caspase cascade upon cytochrome c release. To investigate Smac function during apoptosis and to explore Smac as an experimental cancer therapeutic, we constructed an expression system based on a single adenoviral vector containing Smac under control of the Tet-off system supplied in cis. Conditional expression of Smac induced apoptosis in human HCT116 and DU145 carcinoma cells regardless of the loss of…

Topotecan-triggered degradation of topoisomerase I is p53-dependent and impacts cell survival.

2005

Abstract The anticancer drug topotecan belongs to the group of topoisomerase I (topo I) inhibitors. In the presence of topotecan, topo I cleaves the DNA but is unable to religate the single-strand break. This leads to stabilization of topo I-DNA–bound complexes and the accumulation of DNA strand breaks that may interfere with DNA replication. The molecular mechanism of controlling the repair of topo I-DNA covalent complexes and its impact on sensitivity of cells to topotecan is largely unknown. Here, we used mouse embryonic fibroblasts expressing wild-type p53 and deficient in p53, in order to elucidate the role of p53 in topotecan-induced cell death. We show that p53-deficient mouse embryo…

Evaluation of genetic melanoma vaccines in cdk4-mutant mice provides evidence for immunological tolerance against authochthonous melanomas in the skin

2005

We evaluated the efficacy of a candidate melanoma vaccine approach in mice genetically prone to develop melanoma due to the introduction of an oncogenic mutation (R24C) in the germline sequence of the cyclin-dependent kinase 4 (cdk4), a protein critically involved in cell cycle regulation. Melanomas were induced in cdk4-mutant mice by chemical carcinogenesis and UVB irradiation. A genetic prime-boost strategy targeting the clinically relevant differentiation antigen tyrosinase-related protein 2 (TRP2) was performed which was able to stimulate a melanocyte-specific cellular immune response associated with localized autoimmune vitiligo-like depigmentation. However, significant destruction of …

Role of adjuvant imatinib dose in radically resected GIST harboring KIT exon 9 mutations

2020

11533 Background: Gastrointestinal stromal tumors (GIST) with a driver mutation in KIT exon 9 (Ex9) represent about 10% of all newly diagnosed cases. In the metastatic setting, Ex9-mutated GIST patients benefit from higher doses of imatinib (800 mg/day vs standard 400 mg/day). The additional therapeutic benefit from a higher dose of imatinib in the adjuvant setting in this molecular subgroup has not been confirmed. Methods: We retrospectively identified 105 patients (pts) with resected Ex9-mutated GIST treated with adjuvant imatinib (800 mg/day or 400 mg/day) in 15 different European centers. Disease-Free Survival (DFS) and Imatinib Failure-Free Survival (IFFS) were calculated and analyzed…

Bmi1 and Cell of Origin Determinants of Brain Tumor Phenotype

2007

Glioblastomas frequently express oncogenic EGFR and loss of the Ink4a/Arf locus. Bmi1, a positive regulator of stem cell self renewal, may be critical to drive brain tumor growth. In this issue of Cancer Cell, Bruggeman and colleagues suggest that brain tumors with these molecular alterations can be initiated in both neural precursor and differentiated cell compartments in the absence of Bmi1; however, tumorigenicity is reduced, and tumors contain fewer precursor cells. Surprisingly, tumors appear less malignant when initiated in precursor cells. Bmi1-deficient tumors also had fewer neuronal lineage cells, suggesting a role for Bmi1 in determination of cell lineage and tumor phenotype.