Search results for "kinase inhibitor"

Evolutionary dynamics of imatinib-treated leukemic cells by stochastic approach

2008

The evolutionary dynamics of a system of cancerous cells in a model of chronic myeloid leukemia (CML) is investigated by a statistical approach. Cancer progression is explored by applying a Monte Carlo method to simulate the stochastic behavior of cell reproduction and death in a population of blood cells which can experience genetic mutations. In CML front line therapy is represented by the tyrosine kinase inhibitor imatinib which strongly affects the reproduction of leukemic cells only. In this work, we analyze the effects of a targeted therapy on the evolutionary dynamics of normal, first-mutant and cancerous cell populations. Several scenarios of the evolutionary dynamics of imatinib-tr…

PROX1 transcription factor controls rhabdomyosarcoma growth, stemness, myogenic properties and therapeutic targets

2022

Funding Information: ACKNOWLEDGMENTS. We would like to thank Dr. Tuomas Tammela and Dr. Monika Ehnmann for providing RMS cell lines and Dr. Jenny Högström for discussions and comments during the project. Kirsi Mattinen, Jefim Brodkin, Maxime Laird, Manon Gruchet, Ilse Paetau, Tanja Laakkonen, and Tapio Tainola are acknowledged for their excellent technical help. We also thank the Laboratory Animal Center at the University of Helsinki for expert animal care, the Biomedicum Imaging Unit for microscope support, the Biomedicum Functional Genomics Unit for the RNAseq experiments and the FIMM Technology Centre High Throughput Biomedicine for the drug sensitivity and resistance testing. Our first …

SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia

2014

SIRT1 is an important regulator of cellular stress response and genomic integrity. Its role in tumorigenesis is controversial. Whereas sirtuin 1 (SIRT1) can act as a tumor suppressor in some solid tumors, increased expression has been demonstrated in many cancers, including hematologic malignancies. In chronic myeloid leukemia, SIRT1 promoted leukemia development, and targeting SIRT1 sensitized chronic myeloid leukemia progenitors to tyrosine kinase inhibitor treatment. In this study, we investigated the role of SIRT1 in acute myeloid leukemia (AML). We show that SIRT1 protein, but not RNA levels, is overexpressed in AML samples harboring activating mutations in signaling pathways. In FMS-l…

Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition

2020

Abstract The interaction of menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and provides a potential opportunity for treatment of NPM1-mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. In this study, transcriptional profiling after pharmacological inhibition of the menin-MLL complex revealed specific changes in gene expression, with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being the most pronounced. Combining menin-MLL inhibition with specific small-molecule kinase inhibitors…

Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma

2013

Background Tumor models are critical for our understanding of cancer and the development of cancer therapeutics. Here, we present an integrated map of the genome, transcriptome and immunome of an epithelial mouse tumor, the CT26 colon carcinoma cell line. Results We found that Kras is homozygously mutated at p.G12D, Apc and Tp53 are not mutated, and Cdkn2a is homozygously deleted. Proliferation and stem-cell markers, including Top2a, Birc5 (Survivin), Cldn6 and Mki67, are highly expressed while differentiation and top-crypt markers Muc2, Ms4a8a (MS4A8B) and Epcam are not. Myc, Trp53 (tp53), Mdm2, Hif1a, and Nras are highly expressed while Egfr and Flt1 are not. MHC class I but not MHC class…

Extrahepatic spread of hepatocellular carcinoma

2012

Hepatocellular carcinoma (HCC) is a major health problem. The treatment of HCC depends on the tumour stage and on the severity of underlying cirrhosis, however, a majority of HCC patients have advanced disease at presentation. In recent years extra-hepatic spread (ES) of HCC seems to have been observed more frequently than in the past even if few data exist in literature on prevalence, clinical presentation and prognosis of patients with HCC ES. Aim of this brief review is underline the main concerns, pitfalls and warnings in practicing with these patients. ES of HCC are not rare, and the probability of finding ES is higher in patients with advanced intra-hepatic HCC. The more frequent ES s…

Targeted Therapies in Hepatocellular Carcinoma

2014

Abstract: The onset of hepatocellular carcinoma (HCC) is related to the development of non-neoplastic liver disease, such as viral infections and cirrhosis. Even though patients with chronic liver diseases undergo clinical surveillance for early diagnosis of HCC, this cancer is often diagnosed in advanced stage. In this case locoregional treatment is not possible and systemic therapies are the best way to control it. Until now sorafenib, a Raf and multi-kinase inhibitor has been the best, choice to treat HCC systemically. It showed a survival benefit in multicenter phase III trials. However the proper patient setting to treat is not well defined, since the results in Child-Pugh B patients a…

Stereotactic Radiotherapy for the Treatment of Patients With Oligo-progressive Metastatic Renal Cell Carcinoma Receiving Vascular Endothelial Growth …

2020

Aim This retrospective observational study evaluated the role of hypo-fractionated stereotactic radiotherapy (SRT) in patients with oligo-progressive metastatic renal cell carcinoma (mRCC) treated with first-line oral tyrosine kinase inhibitors (TKI). Data on local control, delay of further progression, and safety are reported. Patients and methods Between January 2010 and December 2016, 28 patients with mRCC who showed oligo-progressive disease while receiving first-line pazopanib were treated with hypofractionated SRT to progressive metastatic sites to delay the change of systemic therapy. First and second progression-free survival (PFS-1 and PFS-2) were recorded, as well as objective res…

Low-dose ponatinib is a good option in chronic myeloid leukemia patients intolerant to previous TKIs.

2020

Multi-center observational study on the adherence, quality of life, and adverse events in lung cancer patients treated with tyrosine kinase inhibitor…

2020

Introduction Cancer patients tend to prefer oral instead of parenteral chemotherapy. To date, there is little evidence on the medication adherence in cancer patients. We investigated medication adherence to tyrosine kinase inhibitors in patients suffering from non-small cell lung cancer. Methods Tyrosine kinase inhibitor adherence was measured electronically by MEMS® (medication event monitoring system) over at least six months. Adherence rates were calculated in terms of Dosing Compliance, Timing Compliance, Taking Compliance, and Drug Holidays. Patients were dichotomized as adherent when Dosing Compliance and Timing Compliance were ≥80%, Taking Compliance ranged between 90 and 110%, and &…