Recent Clinical Trials of mTOR-Targeted Cancer Therapies

Aruni      S. Arachchige Don; X.      F. Steven Zheng

Abstract

The mammalian target of rapamycin (mTOR) is a central component within a complex intracellular signaling network that regulates various processes including cell growth, proliferation, metabolism, and angiogenesis. A hyperactive PI3k/Akt/mTOR signaling pathway is found in many human cancers and alterations in this pathway are associated with the development and progression of cancer. Drugs that target and inhibit mTOR activity are therefore expected to provide therapeutic value in a number of cancer types. Several classes of mTOR-targeted therapeutics are currently being evaluated in cancer clinical trials, including the rapamycins, dual PI3K-mTOR inhibitors, and ATP-competitive mTORC1/2 inhibitors. This review summarizes important findings from recently completed trials of mTOR inhibitors and also discusses preliminary data from ongoing trials.

Keywords: mTOR, mTOR-targeted therapeutics, Rapamycins, Dual PI3K-mTOR inhibitors, ATP-competitive mTORC1/2 inhibitors, Cancer clinical trials, serine/threonine kinase, phosphatidylinositol 3-kinase (PI 3-kinase)-related kinase (PIKK), Raptor, mLst8/GL, mSin1, mSin2, msin3/Rictor, protor, insulin, IGF1, amino acids, glucose, oxidative, DNA damage, ribosome biogenesis, angiogenesis, PIP2, PIP3, PTEN, Phosphatase and tensin homolog deleted on chromosome ten, Akt/PKB (protein kinase B), TSC (tuberous sclerosis protein complex), heterodimer, TSC1 (hamartin)/TSC2 (tuberin), S6K1 gene, Rapamycin (Sirolimus), Streptomyces hygroscopicus, FKBP12, FRB, FKBP12-rapamycin binding, sirolimus, sarcoma, pancreas (adenocarcinoma), colorectal cancer, hepatocellular cancer (HCC), neuroendocrine cancer (NEC), Nab-rapamycin, albumin-bound nabTM-paclitaxel, Abraxane, RCC, NEC, MCL, Advanced gastric cancer, Everolimus, Ridaforolimus, Recurrent malignant glioma, Advanced solid tumors (ovarian, uterine, colorectal, pancreatic, and head and neck cancers), HER2-positive metastatic breast cancer, Advanced low-tointermediate grade neuroendocrine tumors (LGNETs), Sirolimus gefitinib (anti-EGFR agent), Ridaforolimus bevacizumab (anti-VEGF agent), Everolimus trastuzumab (anti-HER2 agent) paclitaxel, Ridaforolimus trastuzumab (anti-HER2 agent), Everolimus Octreotide (somatostatin analog) LAR (long-acting repeatable)