China
Africa
Explore chapters and articles related to this topic
Identifying Breast Cancer Treatment Biomarkers Using Transcriptomics
Published in Shazia Rashid, Ankur Saxena, Sabia Rashid, Latest Advances in Diagnosis and Treatment of Women-Associated Cancers, 2022
The receptor tyrosine kinase c-MET gene is a very well-known proto-oncogene that has been found to be involved in multiple cancers including breast cancer. The HGF/c-Met pathway has been shown to be associated with breast cancer. This gene controls many cellular functions important for organ development and cancer progression. A variety of cancers have reported anomalous transcriptional signalling in this gene. Aberrant transcription in this gene has been reported extensively (Miglio et al., 2018). Demethylation of the antisense promoter of the LINE-1 in the second intron of this gene produces antisense transcripts which were found to be enriched in triple-negative breast cancer (TNBC) and high-grade carcinomas. Higher levels of the aberrant transcript have been strongly correlated with aggressive cancers. Interestingly, cell lines expressing the aberrant transcript were initially identified in silico. This highlights the importance of transcriptomics-based analysis using RNA-Seq for proto-oncogene biomarker detection and its usefulness. There are many public resources like euL1db (Mir et al., 2014) (http://eul1db.ircan.org/), which report transposable elements in the human genome and can be useful in understanding the correlation between genome polymorphism and phenotype and disease.
Renal Cancer
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Sabrina H. Rossi, Grant D. Stewart
Genetics:Usually sporadic, but also includes familial syndromes associated with each type.Type 1Sporadic cases: gains (trisomy and tetrasomy) in chromosomes 7 and 17, and loss of chromosome Y in males.Hereditary cases: Hereditary papillary RCC syndrome (HPRCC). Mutations in the c-MET (Chm 7q) proto-oncogene (Table 23.3).Type 2Hereditary cases: Hereditary leiomyomatosis and RCC (HLRCC) syndrome. Mutations in the Fumurate Hydratase gene (Chm 1q) (Table 23.3).
Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
Several MET pathway inhibitors like HGF inhibitors (ficlatuzumab), anti-MET monoclonal antibodies (onartuzumab), and MET tyrosine kinase inhibitors (crizotinib, tivantinib) are currently being studied in combination with EGFR-TKIs [50, 56] (Table 3). A study by Mok et al. involving 188 Asian patients with stage IIIB/IV lung adenocarcinoma, who received either ficlatuzumab and gefitinib or gefitinib alone, did not find any statistically significant improvement with the combination [56]. However, preliminary results in a subset of patients with both EGFR sensitizing mutations and low c-Met biomarker levels showed that the combination had a trend towards ORR and PFS improvement, and for prolonged OS in those with high stromal HGF (P = 0.03) [56]. In another phase II study, onartuzumab, a monovalent antibody against c-MET-, was associated with improved PFS and OS in the MET-positive population while the MET-negative patients had worse outcomes [57]. Sequist et al. compared erlotinib alone with the combination of erlotinib and tivantinib (ARQ 197), a non-patients in the study had MET gene copy number ≥ 4, equally distributed between the treatment arms. There were no statistically significant differences in PFS or OS, though the combination of erlotinib and tivantinib had a trend towards benefit in patients with increased MET gene copy number [58] (Table 3).
HGF-Based CAR-T Cells Target Hepatocellular Carcinoma Cells That Express High Levels of c-Met
Published in Immunological Investigations, 2023
Haiyan Ma, Wenwen Wei, Dandan Liang, Xing Xu, Dong Yang, Qiong Wang, Yun Wang, Quan Wei, Bin Sun, Xudong Zhao
Originally characterized as the polypeptide product of the MET gene (MET proto-oncogene) located within human chromosome 7q31.2 (https://www.ncbi.nlm.nih.gov/gene), c-Met is functionally classified as a member of the transmembrane receptor tyrosine kinase family of signaling proteins (Ma et al. 2019). This is expressed by epithelial, endothelial cells, neurons, hepatocytes, and hematopoietic cells. The signaling activities of c-Met is essential to cellular processes including proliferation, survival, motility and morphogenesis (Bouattour et al. 2018; Fu et al. 2021). Correspondingly, aberrant c-Met expression and signaling is widely observed in several cancer types, and such abnormalities in gene function are implicated in the development and progression of solid tumor malignancies (Puccini et al. 2019). In patients with advanced HCC, overexpression of c-Met as well as its exclusive natural ligand, hepatocyte growth factor (HGF), are putative predictors of poor prognosis (Forner et al. 2018). This has led researchers to develop c-Met/HGF signaling inhibitors, such as HGF-neutralizing antibodies, HGF antagonists, as well as c-Met tyrosine kinase inhibitors to treat c-Met-positive tumors, with mixed results (Bouattour et al. 2018). Given that c-Met CAR is effective in restricting the growth of breast, gastric and lung cancers in vitro and in vivo (Czyz 2018; Holmes et al. 2007; Organ and Tsao 2011; Stamos et al. 2004; Uchikawa et al. 2021; Yang et al. 2017), it is plausible that CAR-T cell therapy that targets c-Met signaling may also be a viable treatment option for HCC.
An updated patent review of small-molecule c-Met kinase inhibitors (2018-present)
Published in Expert Opinion on Therapeutic Patents, 2022
Cilong Chu, Zixuan Rao, Qingshan Pan, Wufu Zhu
In various types of cancer, there are multiple reasons for abnormal conduction of the HGF/c-Met signaling pathway, such as protein overexpression, gene mutations, gene amplification, and autocrine or paracrine ligand stimulation. This abnormal signaling would create favorable conditions for tumor cell survival, growth, angiogenesis and other activities [16–18]. HGF and c-Met overexpression is present in most solid tumors (lung cancer, breast cancer, etc.). Causes of HGF and c-Met overexpression include dysregulated paracrine signaling of HGF, hypoxia, gene amplification, and skipping mutations [19]. Activating mutations in c-Met have been found in a variety of cancers including ovarian and hepatocellular carcinoma, and in particular, c-Met exon 14 skipping mutations will inhibit degradation of the c-Met receptor, resulting in increased oncogenic activity [20]. In addition, hypoxia will base-activate c-Met transcription and further amplify HGF/c-Met signaling, thereby allowing tumor cells to acquire the ability to grow aggressively. In addition, c-Met amplification is strongly associated with poor patient prognosis and acquired resistance to drugs targeting members of the epidermal growth factor family [21].
Development of bispecific anti-c-Met/PD-1 diabodies for the treatment of solid tumors and the effect of c-Met binding affinity on efficacy
Published in OncoImmunology, 2021
Qingyun Yuan, Qiaoyan Liang, Zujun Sun, Xingxing Yuan, Weihua Hou, Yuxiong Wang, Huijie Wang, Min Yu
The c-Met tyrosine kinase receptor encoded by the MET proto-oncogene, also known as the hepatocyte growth factor (HGF) receptor, is activated in multiple malignancies through MET amplification, mutation, receptor overexpression, and/or a ligand-dependent mechanism.7 Dimerization and activation of c-Met receptor after binding with HGF would promote the proliferation, migration, and invasion of tumor cells.7–9 A previous preclinical study reported that abnormal activation of the c-Met signaling pathway is associated with poor clinical outcomes, and hence, c-Met-targeted therapy could be credible for cancer treatment.10 Although several c-Met tyrosine kinase inhibitors (TKIs) have been used clinically with positive therapeutic effects,11,12 HGF produced in the tumor microenvironment results in innate and acquired resistance to TKIs.13 An alternative approach to the blocking of the HGF/c-Met pathway is the development of therapeutic antibodies; however, it is difficult to produce effective antibodies against both HGF-dependent and HGF-independent c-Met signaling. Moreover, bivalent anti-c-Met antibodies may promote receptor dimerization and activation,14 and monovalent antibodies may lack potency.15