Possible Novel Therapeutic Targets in Lymphangioleiomyomatosis Treatment

Abstract

Lymphangioleiomyomatosis (LAM) is a rare systemic neoplastic disease that exclusively happens in women. Studies focusing on LAM and tuberous sclerosis complex (TSC) have made great progress in understanding the pathogenesis and searching for treatment. The inactive mutation of TSC1 or TSC2 is found in patients with LAM to activate the crucial mammalian target of rapamycin (mTOR) signaling pathway and result in enhanced cell proliferation and migration. However, it does not explain every step of tumorigenesis in LAM. Because cessation of rapamycin would break the stabilization of lung function or improved quality of life and lead to disease recurrent, continued studies on the pathogenesis of LAM are necessary to identify novel targets and new treatment. Researchers have found several aberrant regulations that affect the mTOR pathway such as its upstream or downstream molecules and compensatory pathways in LAM. Some therapeutic targets have been under study in clinical trials. New methods like genome-wide association studies have located a novel gene related to LAM. Herein, we review the current knowledge regarding pathogenesis and treatment of LAM and summarize novel targets of therapeutic potential recently.

A Systematic Review of Lymphangioleiomyomatosis on Diagnosis and Molecular Mechanism

“…E2 binds to its acceptor ER, and proto-oncogene tyrosine-protein kinase Src (c-Src) is phosphorylated by ER, and subsequent c-Src activates Ras. Activated Ras regulates the ERK pathway, in turn triggering kinase activity of proteins Raf, MEK, and ERK [ 47 – 49 ]. E2-stimulated ERK promotes RNA transcription of the Fra1 gene and phosphorylation of Fra1 protein, which in turn inducted ZEB1/2.…”

“…ERK-ZEB1/2 is critical for the EMT process and to control cell proliferation, migration, and invasion. In addition, ERK upregulates the mTORC1 pathway by directly interacting with or repressing the TSC1/2 complex [ 47 ]. Therefore, when drugs targeted on both the E2-ERK and mTORC signaling pathways are combined, treatment for PLAM disease might be more effective.…”

Identification of common genetic features and pathways involved in pulmonary lymphangioleiomyomatosis and ER-positive breast cancer

“…[ 1 , 2 ] The prevalence of S-LAM is approximately 1/0.1 to 0.4 million, and that of TSC-LAM is 1/0.025 million, of which 30 to 80% have combined PLAM. [ 3 , 4 ] Currently, no cure exists for PLAM; rapamycin is the only drug that can stabilize the disease; however, the condition continues to progress after cessation of the drug and requires lung transplantation in the final stages. [ 2 ] Hence, exploring the pathogenic features and mechanisms of PLAM to identify other therapeutic targets is necessary.…”

ZDQ-0620, a Novel Phosphatidylinositol 3-Kinase Inhibitor, Inhibits Colorectal Carcinoma Cell Proliferation and Suppresses Angiogenesis by Attenuating PI3K/AKT/mTOR Pathway

“…With the research on oncogenic signaling pathways that regulate the proliferation, invasion, metastasis and angiogenesis of cancer cells, several possible hot therapeutic targets have been identified recently ( 8 , 9 ). Among them, the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is one of the most frequently activated in human cancers ( 10 ).…”

“…Overactivation of PI3K leads to an increase in PIP3 levels, which in turn activates downstream AKT phosphorylation ( 13 ). In addition, overexpression of AKT has been proved in many cancers including CRC, which has a variety of biological activities, including inhibition of tumor cell apoptosis, promotion of invasion and metastasis, and regulation of tumor angiogenesis ( 8 , 14 ). MTOR, a serine/threonine protein kinase, is a downstream molecule of AKT in the PI3K/AKT pathway and is involved in the regulation of protein synthesis, cell apoptosis, angiogenesis, etc ( 15 ).…”