Question

How are phosphatidylinositol 3-kinase inhibitors administered

Answer 1

FfPhosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that play central role in regulation of cell cycle, apoptosis, DNA repair, senescence, angiogenesis, cellular metabolism, and motility [1]. They act as intermediate signaling molecules and are most well known for their roles in the PI3K/AKT/mTOR signaling pathway [2,3]. PI3Ks transmit signals from the cell surface to the cytoplasm by generating second messengers – phosphorylated phosphatidylinositols – which in turn activate multiple effector kinase pathways, including BTK, AKT, PKC, NF-kappa-B, and JNK/SAPK pathways, and ultimately result in survival and growth of normal cells [1-5] (Figure 1). Although the activity of PI3Ks is tightly regulated in normal cells by internal signals such as PTEN (phosphatase and tensin homolog deleted from chromosome 10), it has been recognized that deregulation of the PI3K signaling pathway is associated with development in one-third of human cancers [6-9]. Aberrantly activated PI3K pathway promotes carcinogenesis and tumor angiogenesis [. For example, approximately 30% of breast cancers demonstrated activating missense mutations of PIK3CA, the gene encoding the catalytic p110α subunit of class I PI3K, and the mutated gene provides cells with a growth advantage and promotes tumorigenesis [13]. In addition, dysregulated PI3K pathway signaling has been implicated in conferring resistance to conventional therapies including biologics, hormonal therapy, tyrosine kinase inhibitors, radiation, and cytotoxics in breast cancer, glioblastoma, and non-small cell lung cancer [2,14]. Other genetic aberrations that drive the PI3K pathway in cancer include gene amplification of PI3Ks, loss of the regulatory activity of PTEN, and activating mutations of receptor tyrosine kinases (RTKs) such as EGFR and HER2 [13,15-18]. With this background, PI3K has become recognized within the last decade as a viable target for novel anti-cancer therapy. Successful drug design has yielded several classes of potent, selective, and efficacious small molecule PI3K inhibitors that are currently at different stages of development. Idelalisib, which represents the first-in-class oral PI3K p110-δ inhibitor, was efficacious with an acceptable safety and tolerability profile in early phase studies, and has progressed into phase III clinical trials in patients with advanced indolent non-Hodgkin’s lymphoma (iNHL), chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) ]. In this comprehensive review, we provide an overview of the PI3K signaling pathway in tumorigenesis and highlight recent advances in the design of small-molecule inhibitors of PI3K as novel anti-cancer therapies. In addition, this review discusses the most recent preclinical and clinical studies of inhibitors targeting the different isoforms of the PI3K enzymes in the treatment of hematological and solid malignancies.