Abstract
The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin-pathway (PI3K/AKT/mTOR-pathway) plays a role in the regulation of cell proliferation, cell survival, angiogenesis and resistance to anti-tumor treatments. In many tumor types the PI3K/AKT/mTOR-pathway is found activated through several different underlying mechanisms. Since this pathway is believed to largely drive the malignant behavior of several of these tumors, mTOR-inhibition is considered an attractive means to apply as anti-tumor treatment. Currently, four mTOR-inhibitors are explored for clinical use: rapamycin, temsirolimus (CCI-779), everolimus (RAD001) and deforolimus (AP23573). As monotherapy, mTOR-inhibitors yield interesting anti-tumor activity against various tumor types at the expense of relatively mild toxicities. This recently resulted in the registration of two mTOR-inhibitors for patients with metastatic renal cell carcinoma (RCC) while randomized studies in other tumors are currently in progress. Furthermore, mTOR-inhibitors are well-suited drugs to combine with other anti-tumor drugs as in preclinical models mTOR-inhibition overcomes chemoresistance. Consequently, mTOR-inhibitor-containing multidrug regimens are subject to clinical studies. As holds true for all anti-tumor therapies, identification of patients who are likely to respond to mTOR-inhibitorcontaining therapies is of utmost importance to avoid over- or undertreatment. Preliminary results suggest that several factors reflecting activation of mTOR in tumors may be used for this purpose. This review addresses the mechanism of action and current clinical experience with mTOR-inhibitors as well as their role in overcoming resistance to conventional therapies. Additionally, potential predictors of outcome to mTOR-inhibition are discussed.
Keywords: Mammalian target of rapamycin (mTOR), rapamycin, temsirolimus, everolimus, deforolimus, resistance
Current Cancer Drug Targets
Title: The Applicability of mTOR Inhibition in Solid Tumors
Volume: 9 Issue: 3
Author(s): I.R. H.M. Konings, J. Verweij, E. A.C. Wiemer and S. Sleijfer
Affiliation:
Keywords: Mammalian target of rapamycin (mTOR), rapamycin, temsirolimus, everolimus, deforolimus, resistance
Abstract: The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin-pathway (PI3K/AKT/mTOR-pathway) plays a role in the regulation of cell proliferation, cell survival, angiogenesis and resistance to anti-tumor treatments. In many tumor types the PI3K/AKT/mTOR-pathway is found activated through several different underlying mechanisms. Since this pathway is believed to largely drive the malignant behavior of several of these tumors, mTOR-inhibition is considered an attractive means to apply as anti-tumor treatment. Currently, four mTOR-inhibitors are explored for clinical use: rapamycin, temsirolimus (CCI-779), everolimus (RAD001) and deforolimus (AP23573). As monotherapy, mTOR-inhibitors yield interesting anti-tumor activity against various tumor types at the expense of relatively mild toxicities. This recently resulted in the registration of two mTOR-inhibitors for patients with metastatic renal cell carcinoma (RCC) while randomized studies in other tumors are currently in progress. Furthermore, mTOR-inhibitors are well-suited drugs to combine with other anti-tumor drugs as in preclinical models mTOR-inhibition overcomes chemoresistance. Consequently, mTOR-inhibitor-containing multidrug regimens are subject to clinical studies. As holds true for all anti-tumor therapies, identification of patients who are likely to respond to mTOR-inhibitorcontaining therapies is of utmost importance to avoid over- or undertreatment. Preliminary results suggest that several factors reflecting activation of mTOR in tumors may be used for this purpose. This review addresses the mechanism of action and current clinical experience with mTOR-inhibitors as well as their role in overcoming resistance to conventional therapies. Additionally, potential predictors of outcome to mTOR-inhibition are discussed.
Export Options
About this article
Cite this article as:
Konings H.M. I.R., Verweij J., Wiemer A.C. E. and Sleijfer S., The Applicability of mTOR Inhibition in Solid Tumors, Current Cancer Drug Targets 2009; 9 (3) . https://dx.doi.org/10.2174/156800909788166556
DOI https://dx.doi.org/10.2174/156800909788166556 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Conventional Anticancer Therapeutics and Telomere Maintenance Mechanisms
Current Pharmaceutical Design Recurrent Hepatitis C After Liver Transplantation
Anti-Infective Agents Efficacy of PD-1 or PD-L1 Inhibitors and Central Nervous System Metastases in Advanced Cancer: A Meta-Analysis
Current Cancer Drug Targets Combining Gene Therapy and Radiation Against Cancer
Current Gene Therapy A Review on Skin Targeted Delivery of Bioactives as Ultradeformable Vesicles: Overcoming the Penetration Problem
Current Drug Targets Important Anti-Cancer Applications of Protein Based Nanoparticles
Current Proteomics Pharmaceutical Perspectives of HECT-TYPE Ubiquitin Ligase Smurf1
Current Pharmaceutical Design Iron Oxide Nanoparticle Platform for Biomedical Applications
Current Medicinal Chemistry Iron Oxide Nanoparticles: An Insight into their Biomedical Applications
Current Medicinal Chemistry Characterization of MHC Ligands for Peptide Based Tumor Vaccination
Current Pharmaceutical Design Metabolic Targets of Cardiac HormonesTherapeutic Anti-Cancer Effects
Current Pharmaceutical Design Cancer-Targeting Multifunctionalized Gold Nanoparticles in Imaging and Therapy
Current Medicinal Chemistry Synthesis, Biological Evaluation and In Silico Study of β-Chloro Vinyl Chalcones as Inhibitors of the TNF-α, IL-6 With Anticancer and Antioxidant Activity
Letters in Drug Design & Discovery Insulin Analogs Revisited
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Novel Systemic Drugs for Cutaneous T-Cell Lymphoma
Recent Patents on Anti-Cancer Drug Discovery Clinical Experience with Antiangiogenic Therapy in Leukemia
Current Cancer Drug Targets Recent Advances in Endocrine Metabolic Immune Disorders Drug Targeting: An Editorial Overview
Endocrine, Metabolic & Immune Disorders - Drug Targets Aspartic Protease Inhibitors as Potential Anti-Candida albicans Drugs: Impacts on Fungal Biology, Virulence and Pathogenesis
Current Medicinal Chemistry Inhibition of c-Met with the Specific Small Molecule Tyrosine Kinase Inhibitor SU11274 Decreases Growth and Metastasis Formation of Experimental Human Melanoma
Current Cancer Drug Targets The SCF-type E3 Ubiquitin Ligases as Cancer Targets
Current Cancer Drug Targets