Search results for "Kinase inhibitor"

HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion.

2008

The cancer stem cell hypothesis proposes that cancers arise in stem/progenitor cells through disregulation of self-renewal pathways generating tumors, which are driven by a component of 'tumor-initiating cells' retaining stem cell properties. The HER2 gene is amplified in 20-30% of human breast cancers and has been implicated in mammary tumorigenesis as well as in mediating aggressive tumor growth and metastasis. We demonstrate that HER2 overexpression drives mammary carcinogenesis, tumor growth and invasion through its effects on normal and malignant mammary stem cells. HER2 overexpression in normal mammary epithelial cells (NMEC) increases the proportion of stem/progenitor cells as demons…

Refining sorafenib therapy: lessons from clinical practice

2015

ABSTRACT  Understanding the best use of sorafenib is essential in order to maximize clinical benefit in hepatocellular carcinoma. Based on Phase III and noninterventional study data, as well as our extensive experience, we discuss dose modification in order to manage adverse events, disease response evaluation and how to maximize treatment benefit. Sorafenib should be initiated at the approved dose (400 mg twice daily) and reduced/interrupted as appropriate in order to manage adverse events. Dose modification should be considered before discontinuation. Appropriate tumor response assessment is critical. Focusing on radiologic response may result in premature sorafenib discontinuation; symp…

LS104, a non-ATP-competitive small-molecule inhibitor of JAK2, is potently inducing apoptosis in JAK2V617F-positive cells

2008

Abstract The activating JAK2V617F mutation has been described in the majority of patients with BCR-ABL-negative myeloproliferative disorders (MPD). In this report, we characterize the small-molecule LS104 as a novel non-ATP-competitive JAK2 inhibitor: Treatment of JAK2V617F-positive cells with LS104 resulted in dose-dependent induction of apoptosis and inhibition of JAK2 autophosphorylation and of downstream targets. Activation of these targets by JAK2 was confirmed in experiments using small interfering RNA. LS104 inhibited JAK2 kinase activity in vitro. This effect was not reversible using elevated ATP concentrations, whereas variation of the kinase substrate peptide led to modulation of …

Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors.

2011

c-Kit tyrosine kinase receptor and its ligand stem cell factor have multiple functions during development, whereas in adulthood they are mostly needed for stem cell (SC) maintenance and mast cell (MC) biology. c-Kit plays an essential tumor-cell-intrinsic role in many types of cancer, either providing the tumorigenic force when aberrantly activated or conferring stem-like features characterizing the most aggressive variants. A tumor-cell-extrinsic role occurs through c-Kit-dependent accessory cells (such as MCs) that infiltrate tumors and deeply influence their progression. c-Kit-targeted therapy with tyrosine kinase inhibitors (TKIs) may ideally work against both tumor and stromal cells. H…

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.

Analysis of Antiproliferative and Chemosensitizing Effects of Sunitinib on Human Esophagogastric Cancer Cells: Synergistic Interaction With Vandetani…

2009

The receptor tyrosine kinases (RTKs), epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 1-3 (VEGFR1-3), are frequently expressed in gastric cancer and are putative therapeutic targets in this disease. We have investigated the anti-proliferative and chemosensitizing properties of the multitargeted small-molecule RTK inhibitors sunitinib and vandetanib in a panel of 4 human gastric and esophageal cancer cell lines. In the 1st instance, the expression of potential targets of these small-molecule inhibitors was examined by reverse transcriptase-polymerase chain reaction, western blotting, and flow cytometry. EGFR mRNA and protein was detected in all cases, …

Phase 0/1 of Positron Emission Tomography (PET) imaging agent [18F]-ODS2004436 as a marker of EGFR mutation in patients with non-small cell lung canc…

2018

e24184Background: Multiple EGFR tyrosine kinase inhibitors (TKIs) are approved for treatment of NSCLC harboring EGFR activating mutations or secondary TKIs resistant mutation. We evaluate a new PET...

Resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer

2018

ctDNA levels before treatment predict survival in non-small cell lung cancer patients treated with a tyrosine kinase inhibitor.

2020

9542 Background: Currently there is an intense debate concerning therapeutic strategies in EGFR positive NSCLC patients with advance disease. Osimertinib is superior to standard EGFR Tyrosine Kinase Inhibitors (TKIs) as first line treatment. However, it is yet unclear whether this option is superior to sequential treatment of a 1st or 2nd generation TKI followed by osimertinib. In order to clarify this issue it is important to identify which patients are at high risk of progression disease. Methods: This is a prospective, multicentre, cross-sectional study promoted by Spanish Lung Cancer Group. 698 plasma samples from 196 advanced NSCLC patients with tumors harboring an EGFR activating mut…

A phase III study (APROMISS) of AL3818 (Catequentinib, Anlotinib) hydrochloride monotherapy in subjects with metastatic or advanced synovial sarcoma.

2021

11505 Background: AL3818 (Catequentinib, Anlotinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. The primary objective of this Phase 3 study is to evaluate the efficacy of AL3818 monotherapy in patients (pts) with synovial sarcoma (SS) comparing with dacarbazine in randomization setting. Methods: Patients with a diagnosis of synovial sarcoma requiring second line or further line treatment were eligible for enrollment. The regimen was a 21-day cycle with oral AL3818 administered on 14 days on and 7 days off. This phase 3 trial is randomized in 2:1 ratio of AL3818 comparing to dacarbazine with option of crossover after PD of dacarbazine treatment. Progression fr…