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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Alpelisib (PiqrayTM) (Figure 6.91), developed by Novartis, is a PI3K inhibitor with a specificity for the Class 1 alpha-isoform (p110α). Following an earlier priority review designation, it was approved by the FDA in 2019 for the treatment of breast cancer in combination with the endocrine agent fulvestrant to treat postmenopausal women and men with HR+ve/HER2-ve PIK3CA-mutated, advanced, or metastatic breast cancer following progression on (or after) an endocrine-based regimen. The FDA also approved the Therascreen PIK3CA RGQ PCR KitTM companion assay, a pharmacogenomic test to detect the PIK3CA mutation in a tissue and/or liquid biopsy to select patients suitable for treatment. Structure of alpelisib (PiqrayTM).
Markers of Sensitivity and Resistance to EGFR Inhibitors in Colorectal Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Jose G. Monzon, Janet E. Dancey
PIK3CA gene encodes the p110 alpha kinase domain of PI3K. The encoded lipid kinase regulates signaling pathways downstream of the EGFR [25]. The PIK3CA gene is mutated in 20% of CRCs with mutations frequently occurring in exon 9 and 20 [24]. In preclinical models, these mutations result in activation of the EGFR pathway and are oncogenic in cellular models. In various colon cancers cell lines, activating PIK3CA mutations appear to confer resistance to cetuximab [118].
CLOVES Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The catalytic subunit p110 of class I PI3K has three isoforms (p110α, p110β, and p110δ), which are encoded by the PIK3CA, PIK3CB, and PIK3CD genes, respectively. Similarly, the adaptor/regulatory subunit p85of class I PI3K consists of five isoforms (p85α, p55α, p50α, p85β, and p55γ), which are encoded by the PIK3R1, PIK3R2, and PIK3R3 genes.
Design, synthesis, and biological evaluation of new thieno[2,3-d] pyrimidine derivatives as targeted therapy for PI3K with molecular modelling study
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Fatma M. Elmenier, Deena S. Lasheen, Khaled A. M. Abouzid
The cytotoxic activity of the most promising synthesised compounds (IIIa, IIIj and VIb) was also evaluated against the breast cancer (T-47D) cell line, by SRB assay (Routine Analysis) (0.01,0.1,1,10,100 μM). T-47D was chosen to perform further cytotoxic activity as it is a tumour cell with the PIK3CA mutation52. PIK3CA gene responses for making (p110α) protein which is a subunit of PI3K53. The PIK3CA mutation overexpresses in breast cancer54–57. T-47D is a Breast Ductal Carcinoma cell line was obtained from Nawah Scientific Inc., (Mokatam, Cairo, Egypt). Cells were maintained in DMEM media supplemented with 100 mg/ml of streptomycin, 100 units/ml of penicillin, and 10% of heat-inactivated foetal bovine serum in humidified, 5% (v/v) CO2 atmosphere at 37 °C. Cytotoxic activity is expressed in terms of IC50 and is provided in (Table 1).
The evidence to date on umbralisib for the treatment of refractory marginal zone lymphoma and follicular lymphoma
Published in Expert Opinion on Pharmacotherapy, 2022
Janelle Schweitzer, Meghan Hoffman, Solomon A. Graf
Phosphoinositide 3-kinases (PI3Ks) are central players in highly conserved signaling pathways in eukaryotes[9]. Through second messenger signal transduction PI3Ks activate, among other targets, protein kinase B (AKT) and Bruton’s tyrosine kinase (BTK) that in turn mediate cell survival, metabolism, differentiation, and motility[10]. Class I PI3Ks are heterodimers of a regulatory subunit and one of 4 isoforms of a p110 catalytic subunit (α, β, γ, and δ). p110α and p110β are expressed broadly in mammalian tissues; p110δ and p110γ are expressed preferentially – though not exclusively – in the hematopoietic compartment[11]. PI3K-p110δ (PI3Kδ) activity promotes growth and survival of malignant B-cells in iB-NHLs and in combination with PI3K-p110γ (PI3Kγ) is thought to support the B-cell tumor microenvironment through recruitment of tumor-associated CD4 + T-cells and tumor-associated macrophages that stimulate B-cells and down-regulate immune response[12].
Screening for PIK3CA mutations among Saudi women with ovarian cancer
Published in Journal of Obstetrics and Gynaecology, 2021
Wedad Saeed Al-Qahtani, Manal Abduallah Alduwish, Ebtesam M Al-Olayan, Nada Hamad Aljarba, Al-Humaidhi Em, Fatimah Gh. Albani, Dalia Mostafa Domiaty, Aljohara M. Al-Otaibi, Somaya M. Al Qattan, Alanood S. Almurshedi, Abdelbaset Mohamed Elasbali, Hussain Gadelkarim Ahmed, Bassam Ahmed Almutlaq
This may be due to the paucity of sufficient tumours available or variations of pathological classification during grading. A trend for the association of PIK3CA mutations with tumour type has been found (p = .032). Mutations were found to be more frequent in serous and endometrioid tumours compared to other subtypes. None of the mucinous tumours were found to harbour PIK3CA mutations. These variations in mutations might be due to the different developmental pathways adopted by the different tumours. The results validate some earlier studies (Campbell et al. 2004; Bozhanov et al. 2010). Patients with PIK3CA mutations were found to harbour more p110α+ tumours compared to patients without the mutated gene. There are several reports on PIK3CA mutations with overall survival outcomes. In the present study, Kaplan–Meier analysis showed that mutated PIK3CA is an indicator of poor survival outcome (p = .017).