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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In normal cells, the PI-3K pathway is tightly controlled, whereas inappropriate activation of PI-3K is common in the pathogenesis of multiple human cancer types, making it a rational and attractive target for drug discovery and development. There are three classes of PI-3K (I, II, and III) categorized on the basis of structure and substrate specificity. The Class I PI-3Ks are most closely associated with human disease and are the targets of sonolisib (PX-866). Four Class I PI-3K isoforms have been identified: alpha (α), beta (β), delta (δ), and gamma (γ). The α and β PI-3Ks are broadly expressed in human tissues, and deregulation of these two family members occurs in many solid tumor types. The δ and γ PI-3Ks are primarily expressed in cells associated with the human immune system, and δ PI-3K is important for lymphoma and leukemia tumor cell growth. Idelalisib (ZydeligTM) blocks the P110δ delta isoform of PI3K and is used as a treatment for some hematological malignancies.
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.
PI3K signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Several factors decide the cellular function to be mediated by the PI3K signaling cascade, e.g., stimulus type, PI3K isoform and the nature of second messenger lipid (31). The class-I PI3K p110α and p110β isoforms are expressed in many mammalian tissues and play important roles in intracellular signaling pathways, while the expression of the p110δ subunit is limited to the leukocytes (32). Both p110α and p110β isoforms are capable of sustaining cell proliferation and survival, with the former being important in glucose metabolism and insulin signaling and the latter being crucial for DNA synthesis/replication and cell mitosis (33). Both the isoforms play roles in sustaining male fertility.
Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Dima A. Sabbah, Rima Hajjo, Sanaa K. Bardaweel, Haizhen A. Zhong
PI3Kδ is highly expressed in leukocytes, though its distribution in neurons and abnormal epithelial cells was much lower [31]. It is expressed in stem cells thus corresponding to immune activity in mast, myeloid, B- and T-cells [31]. Genetic mutations in PIK3CD led to unique diseases such activated p110δ syndrome (APDS) or p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI) [31]. Therefore, selective PI3Kδ inhibitors are a potential treatment for APDS and PASLI [31]. High level of PI3Kδ has been found in solid tumor cells. The overexpression of PI3Kδ reduced PTEN activity and the inhibition of PI3Kδ led to PTEN activation, suppression of AKT phosphorylation, and inhibition of cell growth [32]. Selective PI3Kδ inhibitors are a potential intervention for blood cancer and human B cell malignancies such as chronic lymphocytic leukemia (CLL) treatment [32].
Chemokine receptor CXCR4: An important player affecting the molecular-targeted drugs commonly used in hematological malignancies
Published in Expert Review of Hematology, 2020
Liangliang Li, Ye Chai, ChongYang Wu, Li Zhao
The PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway is closely related to the occurrence and development of DLBCL, and it regulates cell growth, proliferation, and apoptosis [71]. PI3K is a specific class of phosphorylated phosphatidylinositol kinases. According to its different structures and functions, PI3K proteins are divided into types I, II, and III. Type I is considered to be most closely related to the occurrence and development of tumors [72]. PI3K IA is composed of the isoforms p110 (catalytic isoform) and p85 (regulatory isoform). The catalytic isoform includes PI3Kα, PI3Kβ, PI3Kγand PI3Kδ. PI3Kδ signaling is abnormally activated in various B-cell lymphomas including DLBCL and promotes tumor cell proliferation and survival [73]. Since PI3K is an important link in the PI3K/Akt/mTOR signaling pathway, at present, molecular-targeted therapy for the PI3K pathway has become a tumor research hotspot. Some PI3K inhibitors have entered clinical trials for lymphoma treatment. Idelalisib, a p110δ-selective inhibitor, is one of the most effective single-target PI3K inhibitors. It has shown notable antitumor activity with acceptable safety for patients with relapsed indolent NHL [32]. However, due to drug resistance, the clinical efficacy of single-target idelalisib is often limited. Identifying indicators that can predict the response to PI3K inhibitors and performing combination therapy may be potential approaches.
Efficacy and safety of idelalisib for the treatment of indolent B-cell malignancies
Published in Expert Opinion on Pharmacotherapy, 2020
Piotr Smolewski, Dominika Rydygier
New indications for the use of PI3 K inhibitors are also currently assessed. A promising preclinical study by Bhatii et al. [77] investigated the activation of the PI3 K/AKT pathway in a cell line model of resistant Burkitt Lymphoma (BL). The results indicate that cell lines resistant to rituximab and chemotherapy exhibited increased activation of PI3 K/AKT, and that inhibition of AKT or PI3 K results in in vitro anti-lymphoma activity. The PI3 K/AKT pathway is also implicated in the adhesion-mediated survival of acute lymphoblastic leukemia (ALL) cells. PI3 K inhibitors have been evaluated preclinically in this disease [78,79]. Study by Eldfors et al. indicated that idelalisib is effective against TCF3-PBX1 B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL). These findings also demonstrated that TCF3-PBX1 controls the expression of PIK3 CD, the gene encoding p110δ. The ability of TCF3-PBX1 to directly regulate the expression of the idelalisib target p110δ provides important supportive evidence for the use of this drug in TCF3-PBX1 BCP-ALL patients [80].