Search results for "Kinase Inhibitors"
showing 10 items of 269 documents
The potential of neurotrophic tyrosine kinase (NTRK) inhibitors for treating lung cancer
2016
Abstract: Introduction: Molecular alterations in neurotrophic tyrosine kinase (NTRK) genes have been identified in several solid tumors including lung cancer. Pre-clinical and clinical evidence suggested their potential role as oncogenic drivers and predictive biomarkers for targeted inhibition, leading to the clinical development of a new class of compounds blocking the NTRK molecular pathway, which are currently undner early clinical investigation. Area covered: This review describes the biology of the NTRK pathway and its molecular alterations in lung cancer. It focuses on the pre-clinical and clinical development of emerging NTRK inhibitors, which have shown very promising activity in e…
Central nervous system involvement in ALK-rearranged NSCLC : promising strategies to overcome crizotinib resistance
2016
ABSTRACT: Introduction: ALK rearranged Non Small Cell Lung Cancers (NSCLCs) represent a distinct subgroup of patients with peculiar clinic-pathological features. These patients exhibit dramatic responses when treated with the ALK tyrosine kinase inhibitor Crizotinib, albeit Central Nervous System (CNS) activity is much less impressive than that observed against extracranial lesions. CNS involvement has become increasingly observed in these patients, given their prolonged survival. Several novel generation ALK inhibitors have been developing to increase CNS penetration and to provide more complete ALK inhibition. Areas covered: The CNS activity of Crizotinib and novel generation ALK inhibito…
CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC
2019
Abstract Although EGFR mutant–selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK–ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI–resistant persister cells. Many patients with non–small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutatio…
PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer
2017
AbstractCombined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoprote…
Targeting Angiogenesis in Biliary Tract Cancers: An Open Option
2017
Abstract: Biliary tract cancers (BTCs) are characterized by a bad prognosis and the armamentarium of drugs for their treatment is very poor. Although the inflammatory status of biliary tract represents the first step in the cancerogenesis, the microenvironment also plays a key role in the pathogenesis of BTCs, promoting tumor angiogenesis, invasion and metastasis. Several molecules, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are involved in the angiogenesis process and their expression on tumor samples has been explored as prognostic marker in both cholangiocarcinoma and gallbladder cancer. Recent studies evaluated the genomic landscape of BTCs and…
Imatinib spares cKit-expressing prostate neuroendocrine tumors, whereas kills seminal vesicle epithelial-stromal tumors by targeting PDGFR-β
2017
Abstract Prostate cancer is a leading cause of cancer-related death in males worldwide. Indeed, advanced and metastatic disease characterized by androgen resistance and often associated with neuroendocrine (NE) differentiation remains incurable. Using the spontaneous prostate cancer TRAMP model, we have shown that mast cells (MCs) support in vivo the growth of prostate adenocarcinoma, whereas their genetic or pharmacologic targeting favors prostate NE cancer arousal. Aiming at simultaneously targeting prostate NE tumor cells and MCs, both expressing the cKit tyrosine kinase receptor, we have tested the therapeutic effect of imatinib in TRAMP mice. Imatinib-treated TRAMP mice experience a pa…
The significance of epidermal growth factor receptor uncommon mutations in non-small cell lung cancer: A systematic review and critical appraisal
2020
Uncommon epidermal growth factor receptor (EGFR) mutations collectively account for 10% of EGFR mutations, harboring heterogeneous molecular alterations within exons 18-21 with clinically variable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced Non-Small Cell Lung Cancer (NSCLC) patients. In addition, with the introduction of different NGS gene approach an improvement of EGFR mutations detection was reported. Today, no specific studies have prospectively evaluated uncommon sensitizing mutations in detail and no firm standard of care has been established in the first-line setting. The aim of this comprehensive review is to critically consider the clinical role of uncommon EGF…
Pazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial
2020
[Background] Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.
mRCC Outcome in the Treatment of Metastatic Renal Cell Carcinoma - A German Single-center Real-world Experience.
2018
Background/Aim: Since the advent of targeted therapeutics, paradigms in metastatic renal cell carcinoma (mRCC) treatment have changed. We investigated if efficacy and safety data from randomized controlled trials can be transferred into real-world settings. Patients and Methods: All patients with mRCC treated from 2006-2015 at the Department of Urology (Marburg-Germany) were retrospectively analyzed. Collected data include: Patient demographics, tumor characteristics, efficacy, safety, and used therapy sequences. Results: In total, 197 patients with mRCC were identified. About one third of patients reached third-line therapy. Median overall survival in real-world amounted to 25.8 months wit…
The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer.
2020
The treatment of metastatic non-small cell lung cancer (NSCLC) has undergone a paradigm shift over the last decade. Better molecular characterization of the disease has led to the rapid improvement of personalized medicine and the prompt delivery of targeted therapies to patients with NSCLC. The discovery of the EML4-ALK fusion gene in a limited subset of patients affected by NSCLC and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research. Unfortunately, acquired resistances regularly develop, hence disease progression occurs. Afterward, modern tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, and lorlat…