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Targeted Therapies
Published in Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke, Radiotherapy and Clinical Radiobiology of Head and Neck Cancer, 2018
Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke
The PI3K/AKT/mTOR pathway plays a major role in different cell processes, including protein synthesis and cell survival. It is a signalling cascade downstream of the EGFR that stimulates cell growth and is often dysregulated in tumour cells. Targeting this pathway is, therefore, one potential method for overcoming resistance to anti-EGFR targeted therapy. The pathway can be activated by the upstream activation of tyrosine kinase receptors such as EGFR and IGF-1R. mTor is a serine/threonine protein kinase that is involved in regulation of cell growth, proliferation of cells, cell motility and protein synthesis and has been shown to be activated in up to 80% of patients with HNC (Williamson et al. 2010). Genetic aberrations of the PI3K pathway are common in HNC cells. One of the isoforms of the 110 kDa catalytic subunit is encoded by the PIK3CA gene, which is mutated in up to 20% of patients with HNC, especially through gene amplification and low-level copy number increase. It has been found to be particularly common in HPV+ patients (Stransky et al. 2011).
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Published in Calver Pang, Ibraz Hussain, John Mayberry, Pre-Clinical Medicine, 2017
Calver Pang, Ibraz Hussain, John Mayberry
Tyrosine kinase receptors are cell surface receptors for growth factors, cytokines and hormones. Examples of tyrosine kinase receptors include epidermal growth factor receptor, fibroblast growth factor receptor, insulin receptor and vascular endothelial growth factor receptor. GABA receptors are either ligand gated ion channel or g protein-coupled receptors, dependent on the subtype.
The Parasite's Way of life
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2015
Eric S. Loker, Bruce V. Hofkin
Of particular interest is the manner in which some parasites co-opt host hormones or immunomodulatory signals to regulate their own development. Insulin, epidermal growth factor, and fibroblast growth factor all have positive impacts on the growth and development of the cestode Echinococcus multilocularis. Certain cytokines (small proteins involved in intercellular communication) stimulate the development of protoscoleces within the hydatid cysts. The involved tyrosine kinase receptors are all structurally analogous to those found in the mammalian host. In schistosomes, it has been shown that activation of host monocytes via cytokines also stimulates parasite development (Figure 3.25).
Tivozanib in relapsed or refractory advanced renal cell carcinoma: a focus on US approval
Published in Expert Review of Anticancer Therapy, 2022
Hollis Viray, David F McDermott, David J Einstein
RCC is characterized by an overexpression of VEGF and an increase in angiogenesis making VEGFR inhibition an attractive targeted therapeutic option in RCC for the systemic treatment of RCC in first-line and subsequent lines of therapy [8]. Moreover, beyond angiogenesis, inhibition of VEGF may also have immunologic effects that complement immune-based therapies, as we have previously reviewed [9]. There are multiple FDA-approved options for VEGFR inhibition including multiple oral tyrosine kinase inhibitors (TKIs) that bind and inhibit the VEGF receptor. As first-generation VEGFR-TKIs, both sorafenib and sunitinib are nonselective inhibitors of VEGFR [10]. As a result, these drugs bind to a broad-spectrum of tyrosine kinase receptors including EGFR, c-KIT, PDGFR-B leading to increased adverse effects such as skin rash, palmar-plantar erythrodysesthesia (PPE), and myelosuppression [11]. In order to more specifically target VEGFR, later generation selective VEGFR TKIs, most notably axitinib and tivozanib, were developed [10].
New and emerging systemic therapy options for well-differentiated gastroenteropancreatic neuroendocrine tumors
Published in Expert Opinion on Pharmacotherapy, 2020
Steven D. Scoville, Jordan M. Cloyd, Timothy M. Pawlik
Tyrosine Kinase receptors are involved in another critical pathway that can be modulated to regulate tumor growth and progression [52]. Specific targets implicated in the tyrosine kinase pathways involved in angiogenesis include VEGFR, PDGFR, c-KIT, Flt-3, and RET. Sunitinib is an orally available tyrosine kinase inhibitor initially approved for renal cell cancer and gastrointestinal stromal tumors [53] that is effective against PNETs. In an international multicenter phase III randomized controlled trial of patients with advanced PNETs, those treated with sunitinib had an improved PFS of 11.4 compared to 5.4 months among patients treated with placebo alone [54]. Similar to everolimus, sunitinib is well tolerated by patients, but can cause diarrhea [55]. Currently, sunitinib is approved only for the treatment of PNETs and is generally avoided in patients with challenging hypertension or cardiovascular disease [34,56].
Frequency of ALK and GD2 Expression in Neuroblastoma
Published in Fetal and Pediatric Pathology, 2019
Zeynep Aygün, Şebnem Batur, Şenol Emre, Tiraje Celkan, Oktay Özman, Nil Comunoglu
Anaplastic lymphoma kinase (ALK) gene mutation has been shown to be the main cause of familial susceptibility in the pathogenesis of neuroblastoma [4]. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor of the insulin receptor superfamily. Tyrosine kinase receptors play an important role in many cellular events such as proliferation, differentiation, survival, motility and malignant transformation [4]. The ALK gene is localized on the chromosome 2p23 in humans and on the distal end of the 17th chromosome in mice. It is a transmembrane protein consisting of 1620 amino acids. The large extracellular area includes the lipophilic transmembrane segment and the cytoplasmic tyrosine kinase region [5]. The ALK gene is normally expressed in the developing nervous system [6]. ALK was first described in 1994 as an oncogenic gene fusion product associated with anaplastic large cell lymphoma (ALCL) [7]. ALK can form different fusion genes with different partners. These fusion proteins have been found in inflammatory myofibroblastic tumor, non-small cell lung carcinoma (NSCLC), squamous cell carcinoma of the esophagus and some of the ALCLs. In another study, ALK expression was detected in 19% of rhabdomyosarcomas, 40% of peripheral nerve sheath tumors, 9% of malignant fibrous histiocytomas and 10% of leiomyosarcomas by immunohistochemistry [8]. In addition, inflammatory breast carcinoma, anaplastic thyroid carcinoma, malignant melanoma, colon carcinoma and Ewing's sarcoma cases have been reported in the literature [9].