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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Familial adenomatous polyposis (FAP) is a hereditary condition that occurs in approximately 1:10,000 individuals worldwide, and is caused by mutations in the Adenomatous Polyposis Coli (APC) gene. As a result of these mutations, epithelial cells lining the intestinal tract have increased levels of the protein beta-catenin, which, in turn, results in uncontrolled cell growth. Proliferation of the epithelial cells results in the formation of numerous (hundreds to thousands) noncancerous growths (polyps) throughout the large intestine. CEQ508 is the first drug candidate in a novel class of therapeutic agents utilizing the “transkingdom” RNA interference (tkRNAi) platform developed by Marina Biotech Inc and which is an expressed RNA in a bacterial delivery system. The agent CEQ508 comprises attenuated bacteria that are engineered to enter dysplastic tissue and release a payload of short-hairpin RNA (shRNA) targeting the mRNA of beta-catenin, which is known to be dysregulated in classical FAP. CEQ508 was being developed by Marina as an orally administered treatment to reduce the levels of beta-catenin protein in the epithelial cells of the small and large intestine. In 2012 the company announced positive results for CEQ508 in safety Phase I trials, and the FDA granted fast track designation in 2015.
Soft Tissue Sarcomas
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Thomas F. DeLaney, David C. Harmon, Karol Sikora, Francis J. Hornicek
In contrast, APC mutations are uncommon in sporadic desmoids, which usually arise from mutations in the gene for beta-catenin, CTNNB1. Mutations in CTNNB1 have been found in sporadic desmoid tumors with variable prevalence (39%–87%); however, larger and more recent studies place the prevalence estimate at approximately 85%. CTNNB1 gene mutations are therefore the most common route of Wnt pathway activation in desmoids. Phosphorylation of beta-catenin is mediated by a portion of the protein encoded by exon 3 of CTNNB1 gene. Three specific mutations are encountered in desmoid tumors: T41A, S45F, and S45P. At least some data suggest that S45F mutations are associated with a higher rate of recurrence after surgical resection of a primary desmoid tumor.52 It is hoped that the elucidation of the central role of beta-catenin in the pathogenesis of desmoid tumors will lead to future therapeutic advances targeting this molecule.
Craniopharyngioma
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Hermann L. Müller, Claire Alapetite, Jeffrey Wisoff
The WNT signaling pathway is strongly implicated in the pathogenesis of adamantinomatous craniopharyngioma. Genetic analyses have confirmed that as many as 95% of the tumors show mutations in exon 3 of the beta-catenin gene (CTNNB1).38–41 These mutations within the degradation targeting box of beta-catenin lead to activation of the WNT signaling pathway, indicated by aberrant cytoplasmic and nuclear accumulation of beta-catenin protein and respective target gene activation.42 Mouse models confirm the tumor-initiating strength of these alterations.43 In contrast, papillary craniopharyngioma harbor the BRAF V600E mutation in nearly all cases.38,44 The apparent mutual exclusivity of CTNNB1 and BRAF V600E mutations in both craniopharyngioma variants demonstrates that these histological categories can be defined by their underlying molecular genetics (Figure 18.1b).
Interplay between EGFR, E-cadherin, and PTP1B in epidermal homeostasis
Published in Tissue Barriers, 2023
Tessa Arnaud, Fernando Rodrigues-Lima, Mireille Viguier, Frédérique Deshayes
The crosstalk between both molecules has firstly been described through interactions via intracellular partners belonging to the AJ complex. As early as the 1990s, it was demonstrated using recombinant proteins that beta-catenin directly interacts with EGFR. This interaction seems to be mediated by the central region of beta-catenin. This region having about 80% identity at the amino acid level with plakoglobin and armadillo protein suggests possible interactions of EGFR with these molecules.42 More recently, it has been shown that EGFR also interacts with another catenin of the AJ complex: δ-catenin. This direct interaction has been demonstrated in bosc23 (human kidney cell line) and CWR22Rv-1 cells (Human Prostate cancer cell line) cells. Moreover, the authors noted that this interaction was decreased in the presence of EGF without affecting the localization of δ-catenin.
Targeted therapy of tumour microenvironment by gold nanoparticles as a new therapeutic approach
Published in Journal of Drug Targeting, 2022
Negah Mahhengam, Kimia Kazemnezhad, Hendrik Setia Budi, Mohammad Javed Ansari, Dmitry Olegovich Bokov, Wanich Suksatan, Lakshmi Thangavelu, Homayoon Siahmansouri
Beta-catenin (β-catenin) is a dual function protein with a coordination task in physiological homeostasis. Its unusual expression results in severe diseases, including cancer. Naturally, beta-catenin helps maintain the integrated structure of epithelial tissue and controls the transcription of various genes through extracellular agents. β-catenin operates as a part of the cadherin protein complex in the epithelial tissues and adjusts intracellular adhesion and epithelial cell development. In Wnt signalling, beta-catenin is the primary transcriptional regulator and plays a pivotal role in stem cell renewal, embryogenesis, and organ repair. What is more, the Improper expression of beta-catenin leads normal cells to become malignant. As mentioned earlier, this protein can act as a transcription modifier and oncogene to induce cancer, development of malignant cells, survival, and relapse. For these reasons, researchers have considered beta-catenin as one of the ideal targets for drug delivery [151].
Novel mutation in CTNNB1 causes familial exudative vitreoretinopathy (FEVR) and microcephaly: case report and review of the literature
Published in Ophthalmic Genetics, 2020
Razek Georges Coussa, Yue Zhao, Meghan J. DeBenedictis, Allison Babiuch, Jonathan Sears, Elias I. Traboulsi
The CTNNB1 (cadherin-associated protein beta 1, OMIM# 116806) gene is located at 3p22.1 and contains 16 exons (13). It is inherited in an autosomal dominant fashion. Beta-catenin 1 protein is the gene product of CTNNB1. Beta-catenin 1 protein is an adherens junction protein essential for E-cadherin-mediated cell-to-cell adhesion. As most of the genes whose mutations cause FEVR (Table 1), CTNNB1 is involved in the Wnt-signaling pathway and functions as a co-factor to the T cell-factor/lymphoid-enhancer-factor (Tcf/Lef) complex, which proved to be vital for ocular morphogenesis and retinal angiogenesis (13–15). The inherent relation between beta-catenin and the Wnt pathway was demonstrated in a knockout mouse model that showed CNS and retinal angiogenesis abnormalities (16,17). Interestingly, recent studies have reported an association between autism spectrum disorder and cerebral angiogenesis abnormalities (18). In fact, about 93% of patients carrying CTNNB1 mutations are also diagnosed with autism spectrum disorder (19). This high prevalence consolidates the association between CTNNB1 and cerebral angiogenesis. There is also evidence of angiogenic defects associated with not only autism spectrum disorder (18) but also developmental delay (20). These findings could explain the various syndromic features, including developmental/motor/speech delays and retinal avascularity, associated with a gene involved in angiogenesis.