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

International Journal of Molecular Sciences, Год журнала: 2019, Номер 20(3), С. 755 - 755

Опубликована: Фев. 11, 2019

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

Язык: Английский

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

Pharmacological Research, Год журнала: 2019, Номер 150, С. 104511 - 104511

Опубликована: Ноя. 3, 2019

Язык: Английский

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

BioMed Research International, Год журнала: 2017, Номер 2017, С. 1 - 13

Опубликована: Янв. 1, 2017

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

Язык: Английский

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Prognostic and Predictive Biomarkers in Gliomas

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(19), С. 10373 - 10373

Опубликована: Сен. 26, 2021

Gliomas are the most common central nervous system tumors. New technologies, including genetic research and advanced statistical methods, revolutionize therapeutic approach to patient reveal new points of treatment options. Moreover, 2021 World Health Organization Classification Tumors Central Nervous System has fundamentally changed classification gliomas incorporated many molecular biomarkers. Given rapid progress in neuro-oncology, here we compile latest on prognostic predictive biomarkers gliomas. In adult patients, IDH mutations positive markers have greatest significance. However, CDKN2A deletion, IDH-mutant astrocytomas, is a marker highest malignancy grade. presence TERT promoter mutations, EGFR alterations, or combination chromosome 7 gain 10 loss upgrade IDH-wildtype astrocytoma glioblastoma. pediatric H3F3A alterations important which predict worse outcome. MGMT methylation clinical significance predicting responses temozolomide (TMZ). Conversely, mismatch repair defects cause hypermutation phenotype poor response TMZ. Finally, discussed liquid biopsies, promising diagnostic, prognostic, techniques, but further work needed implement these novel technologies practice.

Язык: Английский

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

Current Drug Targets, Год журнала: 2019, Номер 20(12), С. 1217 - 1226

Опубликована: Июнь 19, 2019

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

Язык: Английский

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Temozolomide and Other Alkylating Agents in Glioblastoma Therapy

Biomedicines, Год журнала: 2019, Номер 7(3), С. 69 - 69

Опубликована: Сен. 9, 2019

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

Язык: Английский

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Circadian Regulator CLOCK Recruits Immune-Suppressive Microglia into the GBM Tumor Microenvironment

Cancer Discovery, Год журнала: 2020, Номер 10(3), С. 371 - 381

Опубликована: Янв. 9, 2020

Glioblastoma (GBM) is a lethal brain tumor containing subpopulation of glioma stem cells (GSC). Pan-cancer analyses have revealed that stemness cancer correlates positively with immunosuppressive pathways in many solid tumors, including GBM, prompting us to conduct gain-of-function screen epigenetic regulators may influence GSC self-renewal and immunity. The circadian regulator CLOCK emerged as top hit enhancing stem-cell self-renewal, which was amplified about 5% human GBM cases. its heterodimeric partner BMAL1 enhanced triggered protumor immunity via transcriptional upregulation OLFML3, novel chemokine recruiting immune-suppressive microglia into the microenvironment. In models, or OLFML3 depletion reduced intratumoral density extended overall survival. We conclude CLOCK-BMAL1 complex contributes key hallmarks maintenance immunosuppression and, together downstream target represents new therapeutic targets for this disease. SIGNIFICANCE: Circadian drives metabolism promotes infiltration through direct regulation microglia-attracting chemokine, OLFML3. and/or represent GBM.This article highlighted This Issue feature, p. 327.

Язык: Английский

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Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210

Cellular Oncology, Год журнала: 2019, Номер 43(1), С. 123 - 136

Опубликована: Ноя. 12, 2019

Gemcitabine (GEM)-based chemotherapy is the first-line treatment for locally advanced pancreatic cancer. GEM resistance, however, remains a significant clinical challenge. Here, we investigated whether exosomes derived from GEM-resistant cancer stem cells (CSCs) mediate cell-cell communication between that are sensitive or resistant to and, by doing so, regulate drug resistance.GEM-sensitive BxPC-3-derived BxS and PANC-1 were cultured with extracted CSCs isolated BxR (BxR-CSC). The effect of on cell cycle progression, apoptosis miRNA expression was evaluated in cells. Relevant miRNAs associated resistance identified role miR-210 conferring examined vitro vivo.BxR-CSC-derived induced inhibited GEM-induced arrest, antagonized apoptosis, promoted tube formation migration Elevated levels detected BxR-CSCs BxR-CSC-derived compared those BxS-CSCs BxS-CSC-derived exosomes. In addition, increased observed upon exposure dose-dependent manner. Also, series biological changes after transfection mimics, including activation mammalian target rapamycin (mTOR) signaling pathway, these similar triggered exosomes.Our findings suggest horizontal transfer drug-resistant traits GEM-sensitive delivering miR-210.

Язык: Английский

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Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives

Stem Cell Research & Therapy, Год журнала: 2021, Номер 12(1)

Опубликована: Март 24, 2021

Abstract Glioblastoma (GBM) is the highest-grade form of glioma, as well one most aggressive types cancer, exhibiting rapid cellular growth and highly invasive behavior. Despite significant advances in diagnosis therapy recent decades, outcomes for high-grade gliomas (WHO grades III-IV) remain unfavorable, with a median overall survival time 15–18 months. The concept cancer stem cells (CSCs) has emerged provided new insight into GBM resistance management. CSCs can self-renew initiate tumor are also responsible cell heterogeneity induction systemic immunosuppression. idea that could be dependent on innate differences sensitivity clonogenic glial (GSCs) to chemotherapeutic drugs/radiation prompted scientific community rethink understanding therapies directed at eliminating these or modulating their stemness. This review aims describe major intrinsic extrinsic mechanisms mediate chemoradioresistant GSCs based antineoplastic agents from natural sources, derivatives, synthetics used alone synergistic combination conventional treatment. We will address ongoing clinical trials focused promising targets. Although development effective remains challenge molecular oncology, GSC knowledge offer directions future.

Язык: Английский

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Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer

Frontiers in Oncology, Год журнала: 2022, Номер 12

Опубликована: Июль 14, 2022

Sterol regulatory element binding protein-1 (SREBP-1), a transcription factor with basic helix–loop–helix leucine zipper, has two isoforms, SREBP-1a and SREBP-1c, derived from the same gene for regulating genes of lipogenesis, including acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase. Importantly, SREBP-1 participates in metabolic reprogramming various cancers been biomarker prognosis or drug efficacy patients cancer. In this review, we first introduced structure, activation, key upstream signaling pathway SREBP-1. Then, potential targets molecular mechanisms SREBP-1-regulated lipogenesis types cancer, such as colorectal, prostate, breast, hepatocellular were summarized. We also discussed therapies targeting by small molecules, natural products, extracts herbs against tumor progression. This review could provide new insights understanding advanced findings about SREBP-1-mediated cancer its target therapeutics.

Язык: Английский

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