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Scutellaria Species and Cancer Research
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Samantha H. Sherman, Lani Irvin, Prahlad Parajuli, Nirmal Joshee
Cancer starts with an accumulation of multiple mutations in oncogenes, tumor suppressor genes and apoptosis/cell death regulating genes, which provide the neoplastic cell with a capacity of uninhibited continuous proliferation (Hanahan and Weinberg, 2011). As the tumor progresses, the cancer cells acquire continuous growth signaling capability via overexpression or mutation of various growth factor receptors. This is supplemented by the induction of new blood vessels (angiogenesis) for nutrient supply, as well as for recruitment of pro-tumor inflammatory immune cells. There is a complex interaction among tumor cells and stromal components, mostly fibroblasts and immune cells, that drives a malignant phenotype (Hanahan and Weinberg, 2011).
Fibroblast Growth Factors
Published in Jason Kelley, Cytokines of the Lung, 2022
Since all of the members of this FGF receptor family have tyrosine kinase-like domains, it is likely that initial FGF signal transduction occurs through activation of the receptor tyrosine kinase. Many growth factor receptors transmit their signal through an intrinsic tyrosine kinase activity. Interaction of the growth factor with these receptors results in autophosphorylation of the receptor and phosphorylation of specific cellular substrates. It has been shown that interaction of aFGF, bFGF, K-FGF, or keratinocyte growth factor with cloned or purified FGF receptors results in receptor autophosphorylation on tyrosine residues, demonstrating that these receptors do contain an active tyrosine kinase (Kuo et al., 1990; Mansukhani et al., 1990; Miki et al., 1991; Ruta et al., 1989). It addition, in cells stimulated by aFGF, bFGF, or keratinocyte growth factor the phosphorylation of several other cellular proteins is induced (Bottaro et al., 1990; Coughlin et al., 1988; Friesel et al., 1989; Pasquale et al., 1988). One of these proteins has been identified as phospholipase Cγ (Burgess et al., 1990a), suggesting that activation of phospholipid metabolism may be part of the FGF signaling pathway.
Fetal Growth Factors*
Published in Emilio Herrera, Robert H. Knopp, Perinatal Biochemistry, 2020
Philip A. Gruppuso, Thomas R. Curran, Roderick I. Bahner
An examination of the role of protein phosphorylation can begin with the structure and function of growth factor receptors. The receptors for insulin, EGF and PDGF represent three distinct classes of growth factor receptors which can be distinguished based on structure.25 All may be viewed as allosteric enzymes (tyrosine kinases) which are subject to multiple regulatory influences. The primary allosteric activators for these receptors/enzymes are their ligands. Binding of the ligand to the extracellular domain promotes a conformational change in the intracellular domain which leads to autophosphorylation of tyrosine residues. Autophosphorylation has been shown to enhance the ability of the insulin receptor tyrosine kinase to phosphorylate exogenous substrates. In the case of the EGF receptor, recent studies by Hsu et al.57 have shown that autophosphorylation leads to activation of kinase activity with a physiologic substrate, phospholipase C-γ-1. The general phenomenon of receptor autoactivation via autophosphorylation represents the first site of control in growth factor signal transmission. As described above, a change in receptor specific kinase activity (as measured by autophosphorylation) may be physiologically regulated in fetal liver.
New insights into ErbB3 function and therapeutic targeting in cancer
Published in Expert Review of Anticancer Therapy, 2020
Umbreen Hafeez, Adam C Parslow, Hui K Gan, Andrew M Scott
ErbB3 mutations, overexpression, and amplification are not routinely tested in clinical practice, however ErB3 has an important role in tumor growth, and in the development of resistance to many cancer therapies. ErbB3 has also emerged as an important target for new therapeutic approaches. Despite numerous clinical trials being conducted with anti-ErbB3 therapies, no approved ErbB3 therapeutic has been developed to date. This may in part be due to the complex interplay of signaling of growth factor receptors resulting in compensatory pathways when receptor inhibition or downregulation occurs. Most of the clinically evaluated anti-ErbB3 antibodies inhibit ligand binding and can only prevent neuregulin driven tumor growth. This approach may be be ineffective against those tumors where ErbB3 is activated in a ligand-independent fashion. Hence, it is imperative to develop innovative strategies to target ligand-dependent and ligand-independent ErbB3 activation simultaneously. In addition, targeting ErbB3 in isolation may not be sufficient to fully inhibit cancer cell signaling, and combination therapy targeting ErbB3 and other anti-ErbB receptors or growth factor receptors, or with hormonal therapy, chemotherapy, immunotherapy, or radiotherapy may also enhance therapeutic effect. The delivery of therapeutics (e.g. drugs) to ErbB3 expressing cancer cells with anti-ErbB3 ADCs is an additional promising area for clinical trials. Identification of tumor specific ErbB3 therapeutics may also be a strategy for future development, aiming to enhance therapeutic effect and reduce potential toxicity.
Changing paradigms for targeted therapies against diffuse infiltrative gliomas: tackling a moving target
Published in Expert Review of Neurotherapeutics, 2019
Candice D. Carpenter, Iyad Alnahhas, Javier Gonzalez, Pierre Giglio, Vinay K. Puduvalli
Activation of growth factor receptor pathways is thought to play a role in carcinogenesis via inducing cell proliferation, angiogenesis, and survival of cancer cells. Receptor tyrosine kinases (RTKs) regulate growth factor signaling. Gene expression profiling of GBM through the Cancer Genome Atlas project demonstrated a high degree of heterogeneity as a result of several genetic and epigenetic alterations including amplification, gain-of-function mutations, copy number loss or gain and methylation that promote growth factor receptor signaling, and loss-of-function mutations in tumor suppressor genes (e.g. PTEN and P53) [57,59,60]. As discussed above, EGFR is among the most commonly mutated genes; approximately 50% of GBMs have amplification of EGFR [66,91]. EGFRvIII is the most common EGFR gain-of-function mutation and hence the most common mutation in GBM [92]. Other mutated RTKs include platelet-derived growth factor receptor alpha polypeptide (PDGFRA), c-MET and fibroblast growth factor receptor (FGFR) [91,92].
Characterization of zolbetuximab in pancreatic cancer models
Published in OncoImmunology, 2019
Ӧzlem Türeci, Rita Mitnacht-Kraus, Stefan Wöll, Tomohiro Yamada, Ugur Sahin
Therapeutic antibodies initially developed for solid tumors acted by inhibiting tumor growth-promoting molecules (eg, growth factor receptors, angiogenic agents). A second class of mAbs for solid tumors, the immune checkpoint inhibitors that enhance T-cell-mediated cytolysis, were developed more recently and include drugs such as pembrolizumab and nivolumab. Some mAbs, such as the anti-HER2 trastuzumab, also stimulate immune effector pathways such as ADCC, although not as their primary cytolytic mechanism. A targeted, high efficacy treatment for PC remains an unmet medical need; drugs that have failed include growth factor-inhibiting mAbs and small-molecule tyrosine kinase inhibitors.18–23 In these nonclinical studies, we demonstrate that zolbetuximab, a mAb that acts through a novel target and mechanism, has antitumor activity in animal PC models utilizing human PC cell lines.