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Familial Chordoma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Alexandra Suttman, Sydney T. Grob, Jean M. Mulcahy Levy
Chordoma lesions often display resistance to chemotherapy agents, making this treatment option of low efficacy. Chemotherapy may be used as a last resort option when surgical resection and radiation have both failed [37]. Improved technology has become available which has made understanding the molecular underpinnings and genetic aberrations of tumors much more apparent [38]. This has resulted in the more recent development of targeted therapies. For instance, the activation of phosphorylated forms of platelet-derived growth factor hormone (PDGFR)-b and of KIT receptors have been targeted with drugs such as imatinib, which has shown success in clinical trial when used by themselves or with sirolimus. Another example of using targeted therapies in pediatric chordoma include using inhibitory drugs linked to EGFR like cetuximab, gefitinib, and erlotinib [31]. The further development of targeted therapy and its use in patients with chordoma remains an area of evolving research.
The gastrointestinal system
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Sharon J. White, Francis A. Carey
It has been shown that approximately 75% of GISTs show a mutation of the c-kit oncogene, and overexpress the gene product CD117 on the cell membrane. Mutations of the platelet-derived growth factor receptor a (PDGFRA) gene are seen in a further 10% of GISTs. Detection of these mutations in tumour tissue is useful in diagnosing these neoplasms. It is also of great therapeutic importance, because the tyrosine kinase-inhibiting drug imatinib acts directly to inhibit the effect of the c-kit oncogene mutation. This drug can be remarkably effective in controlling inoperable and metastatic GISTs. However, efficacy is most marked in the presence of some specific mutations (e.g. in codon 11 of c-kit) whereas other mutations in c-kit and PDGFRA are markers of drug resistance. This story is an excellent example of how understanding tumour biology can lead to the development of specific, effective, non-toxic therapy.
GIST of the Lower Gastrointestinal Tract
Published in Peter Sagar, Andrew G. Hill, Charles H. Knowles, Stefan Post, Willem A. Bemelman, Patricia L. Roberts, Susan Galandiuk, John R.T. Monson, Michael R.B. Keighley, Norman S. Williams, Keighley & Williams’ Surgery of the Anus, Rectum and Colon, 2019
Rohin Mittal, Benjamin Perakath
About 5% of all GISTs are CD117 (c-kit) negative. This number is as high as 17% in colonic GISTs and 9% in rectal GISTs.24,25 Many of these have mutations in another tyrosine receptor kinase, the platelet derived growth factor receptor alpha (PDGFRA).26,27 The mechanism of tumourogenesis in these is similar to Kit gene mutations. Again, sensitivity to treatment with Imatinib depends on the specific mutation, and has a variable spectrum from being very sensitive to very resistant.28 Specific mutational analysis is not recommended in routine clinical practice,23 and all patient are given a trial of Imatinib, if indicated.
Novel therapeutic perspectives for crescentic glomerulonephritis through targeting parietal epithelial cell activation and proliferation
Published in Expert Opinion on Therapeutic Targets, 2023
Yanjie Huang, Xueru Zhao, Qiushuang Zhang, Xiaoqing Yang, Gailing Hou, Chaoqun Peng, Mengzhen Jia, Li Zhou, Tatsuo Yamamoto, Jian Zheng
Platelet-derived growth factor (PDGF) is a family of growth regulator molecules composed of a sulfide-bonded dimeric structure [76]. The PDGF family consists of four isoforms (PDGF-A, -B, -C, and -D) and two receptor chains (PDGFR-α and -β), which play essential roles in multiple biological processes, such as wound healing, fibrosis, and malignancy. PDGF-mediated cell migration is involved in signal transduction through the phosphorylation of platelet-derived growth factor receptor (PDGFR). PDGFR has tyrosine kinase activity. It can autophosphorylate after binding to its ligand and activate the Ras/MAPK signaling system that contains the Src homology 2 domain. p-ERK1/2 then catalyzes the nuclear transcription factor, cyclin D1, to initiate the transcription of targeted genes and promote cell proliferation (Figure 2) [77–80]. Immunohistochemical experiments confirmed that PDGF-D was expressed in podocytes of normal human kidneys [81]. Parietal epithelial cells have been reported to express PDGFR-β in humans, and PDGFR-β has been detected in glomerular crescents. Overexpression of PDGF-D in podocytes can induce CrGN and glomerulosclerosis [7]. Thus, it was speculated that PEC proliferation might be caused by the activation of PDGFR through podocyte-derived PDGF-D (Table 1) [76].
An updated safety review of the drug treatments for idiopathic pulmonary fibrosis
Published in Expert Opinion on Drug Safety, 2021
Giacomo Sgalla, Alessia Comes, Luca Richeldi
Nintedanib, formerly known as BIBF 1120, is a small molecule that was originally designed as an anti-angiogenic drug for cancer indications. As nintedanib competitively binds to the kinase domains of platelet-derived growth factor receptor (PDGFR)-a and ß, fibroblast growth factor receptor (FGFR)-1 and vascular endothelial growth factor receptor (VEGFR)-2, inhibiting the fibroblast proliferation, migration and differentiation, and the secretion and deposition of extracellular matrix which are considered involved in the progression of fibrosis, it was selected as a potential treatment for IPF [10]. Nintedanib has been shown to slow disease progression, reducing the FVC decline, shorten the time to first acute exacerbation and improve quality of life at 1 year [11]. Nintedanib was approved, simultaneously with pirfenidone, as a treatment for IPF by the Food and Drug Administration (FDA) in the USA in October 2014 and by EMA (European Medicines Agency) in Europe since January 2015.
Targeting platelet-derived growth factor receptor β inhibits the proliferation and motility of human pterygial fibroblasts
Published in Expert Opinion on Therapeutic Targets, 2019
Weiqian Mai, Minfeng Chen, Maohua Huang, Jincheng Zhong, Jian Chen, Xiaoyong Liu, Juan Deng, Xiaoxi Yang, Wencai Ye, Rijia Zhang, Qing Zhou, Dongmei Zhang
Platelet-derived growth factor receptor-β (PDGFR-β) is a class III receptor tyrosine kinase that is mainly expressed in fibroblasts [21]. PDGF-BB-stimulated phosphorylation of PDGFR-β in fibroblasts induces the activation of multiple downstream signaling pathways, such as extracellular signal-regulated kinase (ERK) [22], Akt [23] and signal transducer and activator of transcription 3 (STAT3) [24]. These effects are responsible for a myriad of cellular functions, such as proliferation, differentiation, migration and invasion [25,26]. Therefore, targeting PDGFR-β holds therapeutic potential for fibrotic diseases [27]. Previous reports have demonstrated that PDGF, the ligand of PDGFR-β, is highly expressed in pterygia [28]. However, the expression profile of PDGFR-β and its functional role in pterygium have yet to be explored.