Selective MET Kinase Inhibition in MET-Dependent Glioma Models Alters Gene Expression and Induces Tumor Plasticity

The receptor tyrosine kinase (RTK) MET represents a promising tumor target in a subset of glioblastomas. Most RTK inhibitors available in the clinic today, including those inhibiting MET, affect multiple targets simultaneously. Previously, it was demonstrated that treatment with cabozantinib (MET/VEGFR2/RET inhibitor) prolonged survival of mice carrying orthotopic patient-derived xenografts (PDX) of the MET-addicted glioblastoma model E98, yet did not prevent development of recurrent and cabozantinib-resistant tumors. To exclude VEGFR2 inhibition-inflicted blood–brain barrier normalization and diminished tumor distribution of the drug, we have now investigated the effects of the novel MET-selective inhibitor Compound A in the orthotopic E98 xenograft model. In vitro, Compound A proved a highly potent inhibitor of proliferation of MET-addicted cell lines. In line with its target selectivity, Compound A did not restore the leaky blood–brain barrier and was more effective than cabozantinib in inhibiting MET phosphorylation in vivo. Compound A treatment significantly prolonged survival of mice carrying E98 tumor xenografts, but did not prevent eventual progression. Contrasting in vitro results, the Compound A–treated xenografts displayed high levels of AKT phosphorylation despite the absence of phosphorylated MET. Profiling by RNA sequencing showed that in vivo transcriptomes differed significantly from those in control xenografts. Implications: Collectively, th...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Oncogenes and Tumor Suppressors Source Type: research

Related Links:

We present a case where nocardial abscesses of lung and brain were initially suspected as lung cancer with brain metastases. The patient was treated with a combination of surgical resection and antimicrobial therapy with good outcome. PMID: 31969769 [PubMed - in process]
Source: Acta Clinica Croatica - Category: General Medicine Tags: Acta Clin Croat Source Type: research
PROGNOSTIC ROLE OF CD44 EXPRESSION AND NEOVASCULARIZATION DETERMINED BY ENDOGLIN (CD105) IN GLIOBLASTOMA PATIENTS. Acta Clin Croat. 2019 Sep;58(3):455-462 Authors: Mihić J, Rotim K, Vučić M, Hude Dragičević I, Borić M, Lugović-Mihić L Abstract Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. Clinically useful molecular markers that help predict response to therapy and prognosis are still rare. The research was conducted in 55 patients with GBM, 26 (47.3%) women and 29 (52.7%) men, mean age 62.58 years. On immunohistochemical analysis,...
Source: Acta Clinica Croatica - Category: General Medicine Tags: Acta Clin Croat Source Type: research
MEAN PLATELET VOLUME: AN OVERLOOKED HERALD OF MALIGNANT THYROID NODULES. Acta Clin Croat. 2019 Sep;58(3):417-420 Authors: Sit M, Aktas G, Ozer B, Kocak MZ, Erkus E, Erkol H, Yaman S, Savli H Abstract Physicians and surgeons pay much attention to evaluating thyroid nodules due to the malignant potential of these growths. Inflammation has a crucial role in the development of cancer. Increase in the mean platelet volume (MPV) has been described in various inflammatory conditions. Since some of thyroid nodules are malignant, we aimed to compare MPV values between patients with malignant and benign thyroid ...
Source: Acta Clinica Croatica - Category: General Medicine Tags: Acta Clin Croat Source Type: research
Publication date: Available online 23 January 2020Source: LWTAuthor(s): Xin-Yun Wang, Jing XieAbstractAcinetobacter johnsonii and Pseudomonas fluorescens are specific spoilage microorganisms (SSO) of aquatic products, and their metabolites are effective indicators for analyzing these two SSOs. However, the metabolome of a coculture of A. johnsonii and P. fluorescens is still unclear. The aim of this study was to investigate the metabolomic changes in A. johnsonii, P. fluorescens, and their co-culture by screening for metabolic markers. PCA and PLS-DA revealed that A, P, and AP groups were different from each other, indicat...
Source: LWT Food Science and Technology - Category: Food Science Source Type: research
Antonio Lucena-Cacace1, Masayuki Umeda1, Lola E. Navas2,3 and Amancio Carnero2,3* 1Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan 2CIBERONC, ISCIII, Madrid, Spain 3Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), CSIC, Universidad de Sevilla, Sevilla, Spain Glioma Cancer Stem-Like Cells (GSCs) are a small subset of CD133+ cells with self-renewal properties and capable of initiating new tumors contributing to Glioma progression, maintenance, hierarchy, and complexity. GSCs are highly res...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusion Several TISC-based immunotherapeutic approaches are under development in various stages of preclinical studies. As outlined in this review article, a careful and more exhaustive genetic and metabolic understanding of TISC-associated phenotypes is critical to develop novel TISC based immunotherapies. Various components within the tumor microenvironment such as tumor cells, infiltrating immune cells, and supporting stromal cells impact the TISC metabolism. This unique metabolic profile leads to upregulation of certain enzymes and proteins such as ALDH1, CEP55, IDO COA1 etc., which can be utilized for development ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusion The expression of the components of the PTN-MK-RPTPβ/ζ axis in immune cells and in inflammatory diseases suggests important roles for this axis in inflammation. Pleiotrophin has been recently identified as a limiting factor of metainflammation, a chronic pathological state that contributes to neuroinflammation and neurodegeneration. Pleiotrophin also seems to potentiate acute neuroinflammation independently of the inflammatory stimulus while MK seems to play different -even opposite- roles in acute neuroinflammation depending on the stimulus. Which are the functions of MK and PTN in chronic neuroinfla...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
n M, Campos-Sandoval JA Abstract Cancer cells develop and succeed by shifting to different metabolic programs compared with their normal cell counterparts. One of the classical hallmarks of cancer cells is their higher glycolysis rate and lactate production even in the presence of abundant O2 (Warburg effect). Another common metabolic feature of cancer cells is a high rate of glutamine (Gln) consumption normally exceeding their biosynthetic and energetic needs. The term Gln addiction is now widely used to reflect the strong dependence shown by most cancer cells for this essential nitrogen substrate after metabolic...
Source: Neurochemical Research - Category: Neuroscience Authors: Tags: Neurochem Res Source Type: research
A remarkably rapidly expanding body of literature points to the epigenome as a new previously unsuspected mechanism of oncogenesis and another “hallmark of cancer.” Indeed, in a large number of cancers, aberrant epigenetic states occur through different mechanisms including altered DNA methylation, covalent histone modification, the reading of these histone modifications by protein regulation modules, histone exchange, chromatin remodelers, or via the effects of non-coding RNAs. Although mutations are also found in canonical signaling pathway genes, we and others identified chromatin-associated proteins to be m...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Mutational Landscape in Brain Tumors Source Type: research
Conclusions] Inhibition of RTK and its downstream molecule induced synergistic antitumor effects but sensitivity of GSC lines to therapies was diverse. Examining colonies initiated by GSCs obtained from individual patients may be useful for drug sensitivity testing in personalized cancer therapy.Citation Format: Takashi Shingu, Lindsay Holmes, Verlene Henry, Khatri Latha, Anupama E. Gururaj, Laura A. Gibson, Tiffany Doucette, Frederick F. Lang, Ganesh Rao, Liang Yuan, Erik P. Sulman, Nicholas P. Farrell, Waldemar Priebe, Kenneth R. Hess, Yaoqi A. Wang, Jian Hu, Oliver Bogler. Synergistic combination therapy with molecular ...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Experimental and Molecular Therapeutics Source Type: research
More News: Addiction | Brain | Brain Cancers | Brain Tumor | Cancer | Cancer & Oncology | Genetics | Glioma | Neurology