The mammalian or mechanistic target of rapamycin (mTOR) pathway plays a crucial role in regulation of cell survival, metabolism, growth and protein synthesis in response to upstream signals in both normal physiological and pathological conditions, especially in cancer. Aberrant mTOR signaling resulting from genetic alterations from different levels of the signal cascade is commonly observed in various types of cancers. Upon hyperactivation, mTOR signaling promotes cell proliferation and metabolism that contribute to tumor initiation and progression. In addition, mTOR also negatively regulates autophagy via different ways. We discuss mTOR signaling and its key upstream and downstream factors, the specific genetic changes in the mTOR pathway and the inhibitors of mTOR applied as therapeutic strategies in eight solid tumors. Although monotherapy and combination therapy with mTOR inhibitors have been extensively applied in preclinical and clinical trials in various cancer types, innovative therapies with better efficacy and less drug resistance are still in great need, and new biomarkers and deep sequencing technologies will facilitate these mTOR targeting drugs benefit the cancer patients in personalized therapy.

mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy

Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy.

Glioblastoma (GBM) is a primary neuroepithelial tumor of the central nervous system, characterized by an extremely aggressive clinical phenotype. Patients with GBM have a poor prognosis and only 3–5% of them survive for more than 5 years. The current GBM treatment standards include maximal resection followed by radiotherapy with concomitant and adjuvant therapies. Despite these aggressive therapeutic regimens, the majority of patients suffer recurrence due to molecular heterogeneity of GBM. Consequently, a number of potential diagnostic, prognostic, and predictive biomarkers have been investigated. Some of them, such as IDH mutations, 1p19q deletion, MGMT promoter methylation, and EGFRvIII amplification are frequently tested in routine clinical practice. With the development of sequencing technology, detailed characterization of GBM molecular signatures has facilitated a more personalized therapeutic approach and contributed to the development of a new generation of anti-GBM therapies such as molecular inhibitors targeting growth factor receptors, vaccines, antibody-based drug conjugates, and more recently inhibitors blocking the immune checkpoints. In this article, we review the exciting progress towards elucidating the potential of current and novel GBM biomarkers and discuss their implications for clinical practice.

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Diagnostic and Therapeutic Biomarkers in Glioblastoma: Current Status and Future Perspectives.

Background Phosphoinositide 3-kinase (PI3Ks) is a member of intracellular lipid kinases and involved in the regulation of cellular proliferation, differentiation and survival. Overexpression of the PI3K/Akt/mTOR signalling has been reported in various forms of cancers, especially in colorectal cancers (CRC). Due to their significant roles in the initiation and progression events of colorectal cancer, they are recognized as a striking therapeutic target. Objective The present review is aimed to provide a detailed outline on the role of PI3K/Akt/mTOR pathway in the initiation and progression events of colorectal cancers as well as its function in drug resistance. Further, the role of PI3K/Akt/mTOR inhibitors alone and in combination with other chemotherapeutic drugs, in alleviating colorectal cancer is also discussed. The review contains preclinical and clinical evidence as well as patent literature of the pathway inhibitors which are natural and synthetic in origin. Methods The data were obtained from PubMed/Medline databases, Scopus and Google patent literature. Results PI3K/Akt/mTOR signalling is an important event in colorectal carcinogenesis. In addition, it plays significant roles in acquiring drug resistance as well as metastatic initiation events of CRCs. Several small molecules of natural and synthetic origin have been found to be potent inhibitors of CRCs by effectively downregulating the pathway. Data from various clinical studies also support these pathway inhibitors and several among them are patented. Conclusion Inhibitors of the PI3K/mTOR pathway have been successful for the treatment of primary and metastatic colorectal cancers, rendering the pathway as a promising clinical cancer therapeutic target.

PI3K/ Akt/ mTOR Pathway as a Therapeutic Target for Colorectal Cancer: A Review of Preclinical and Clinical Evidence.

The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around 14 months after presentation. Several key aspects make GB a difficult to treat disease, primarily including the high resistance of tumor cells to cell death-inducing substances or radiation and the combination of the highly invasive nature of the malignancy, i.e., treatment must affect the whole brain, and the protection from drugs of the tumor bulk-or at least of the invading cells-by the blood brain barrier (BBB). TMZ crosses the BBB, but-unlike classic chemotherapeutics-does not induce DNA damage or misalignment of segregating chromosomes directly. It has been described as a DNA alkylating agent, which leads to base mismatches that initiate futile DNA repair cycles; eventually, DNA strand breaks, which in turn induces cell death. However, while much is assumed about the function of TMZ and its mode of action, primary data are actually scarce and often contradictory. To improve GB treatment further, we need to fully understand what TMZ does to the tumor cells and their microenvironment. This is of particular importance, as novel therapeutic approaches are almost always clinically assessed in the presence of standard treatment, i.e., in the presence of TMZ. Therefore, potential pharmacological interactions between TMZ and novel drugs might occur with unforeseeable consequences.

Temozolomide and Other Alkylating Agents in Glioblastoma Therapy.

// Xiaoman Li 1,* , Changjing Wu 1,* , Nianci Chen 2 , Huadi Gu 3 , Allen Yen 4 , Liu Cao 1 , Enhua Wang 3,5 and Liang Wang 3,5 1 Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China 2 Class 9 of the 97th Clinical Medicine of Seven-Year Program, China Medical University, Shenyang, China 3 Department of Pathology, The College of Basic Medical Sciences, China Medical University, Shenyang, China 4 School of Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America 5 Department of Pathology, The First Affiliated Hospital of China Medical University, Shenyang, China * These authors have contributed equally to this work Correspondence to: Liang Wang, email: // Keywords : glioblastoma, EGFR, PI3K/Akt/mTOR pathway, targeted therapy Received : December 05, 2015 Accepted : February 24, 2016 Published : March 07, 2016 Abstract Glioblastoma multiform (GBM) is the most common malignant glioma of all the brain tumors and currently effective treatment options are still lacking. GBM is frequently accompanied with overexpression and/or mutation of epidermal growth factor receptor (EGFR), which subsequently leads to activation of many downstream signal pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt/rapamycin-sensitive mTOR-complex (mTOR) pathway. Here we explored the reason why inhibition of the pathway may serve as a compelling therapeutic target for the disease, and provided an update data of EFGR and PI3K/Akt/mTOR inhibitors in clinical trials.

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PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma

Memapsin 2 (BACE1, β-secretase), a membrane aspartic protease, functions in the cleavage of the type I transmembrane protein, β-amyloid precursor protein (APP), leading to the production of amyloid β (Aβ) in the brain. Since Aβ is closely associated with the pathogenesis of Alzheimer's disease, understanding the biological function, particularly the catalytic activities of memapsin 2, would assist in a better understanding of the disease and the development of its inhibitors. The transmembrane and cytosolic domains of memapsin 2 function in cellular transport and localization, which are important regulatory mechanisms for its activity. The catalytic ectodomain contains a long substrate cleft that is responsible for substrate recognition, specificity, and peptide bond hydrolysis. The substrate cleft accommodates 11 residues of the substrate in separate binding subsites. Besides APP, a number of membrane proteins have been reported to be substrates of memapsin 2. The elucidation for the specificity of these subsites and the amino acid sequences surrounding the memapsin 2 cleavage site in these proteins has led to the establishment of a predictive model that can quantitatively estimate the efficiency of cleavage for any potential substrates. Such tools may be employed for future studies of memapsin 2 about its biological function. Herein, we review the current knowledge on the structure-function relationship of memapsin 2 and its relationship in the biological function.

Liu Cao

Papers

PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma

Structure–activity relationship of memapsin 2: implications on physiological functions and Alzheimer's disease