Author: Vitaly A. Polunovsky
Publisher: Springer Science & Business Media
ISBN: 1603272712
Category : Medical
Languages : en
Pages : 307
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Book Description
The main objective of this book is to provide an up-to-date survey of the rapidly advancing eld of cancer therapy. Moreover, since our knowledge in this area rapidly evolves, some data have got obsolete during the process of book editing. Our understanding of the mechanisms involved in cancer genesis and progression underwent unprecedented expansion during the last decade, opening a new era of cancer treatment – targeted therapy. The surge in this area results in no small part from studies conducted jointly by basic health scientists and clinical investigators. It is our hope that this book will help foster even further collaboration between investigators in these two disciplines. The target of rapamycin (TOR) was rst identi ed in Saccharomyces cerevisiae and subsequently in mammals (mTOR) as a conserved atypical serine/threonine kinase. In mammalian cells, mTOR exists in at least two multi-protein complexes that have critical roles in regulating cellular homeostasis and survival. As with many other areas of science, discovery of TOR signaling was fortuitous. Rapamycin was isolated as a product of the soil bacteria Streptomyces hygroscopicus, identi ed in a soil sample taken from the island of Rapa Nui (Easter Island). Rapamycin was rst discovered to be a potent antifungal agent and next as an immune suppressive drug. It was only later that it was found to be active as an antitumor agent in non-clinical models; although it was not developed for this indication. The history of rapamycin presents one of the rst examples of chemical genetics.
Author: Monica Mita
Publisher: Springer
ISBN: 2817804929
Category : Medical
Languages : en
Pages : 300
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Book Description
This book describes the challenges involved in developing mTOR inhibitors for cancer treatment, starting with an in-depth examination of their molecular mechanism of action, with emphasis on the class side-effects, efficacy and mechanisms of resistance, as well as on promising novel directions for their development, including novel compounds and rational combinations with other anti-neoplastic drugs. Over the last 10 years, inhibitors of mTOR have emerged as a major class of anticancer drugs. Two rapamycin analogs are currently approved for the treatment of renal cell carcinoma, and it is estimated that a variety of other tumor types could benefit from mTOR inhibition, with numerous clinical trials (including pivotal registration trials) already underway. Second-generation small-molecule inhibitors of the pathway have also shown promise in terms of their superior tolerability and efficacy and are undergoing extensive clinical evaluation, with an estimated 30+ compounds currently under evaluation.
Author: Olivier Dormond
Publisher: MDPI
ISBN: 3039210602
Category : Medical
Languages : en
Pages : 480
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Book Description
The mechanistic target of rapamycin (mTOR) is a major signaling intermediary that coordinates favorable environmental conditions with cell growth. Indeed, as part of two functionally distinct protein complexes, named mTORC1 and mTORC2, mTOR regulates a variety of cellular processes, including protein, lipid, and nucleotide synthesis, as well as autophagy. Over the last two decades, major molecular advances have been made in mTOR signaling and have revealed the complexity of the events implicated in mTOR function and regulation. In parallel, the role of mTOR in diverse pathological conditions has also been identified, including in cancer, hamartoma, neurological, and metabolic diseases. Through a series of articles, this book focuses on the role played by mTOR in cellular processes, metabolism in particular, and highlights a panel of human diseases for which mTOR inhibition provides or might provide benefits. It also addresses future studies needed to further characterize the role of mTOR in selected disorders, which will help design novel therapeutic approaches. It is therefore intended for everyone who has an interest in mTOR biology and its application in human pathologies.
Author: Shile Huang
Publisher: MDPI
ISBN: 3039435531
Category : Science
Languages : en
Pages : 204
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Book Description
The mechanistic/mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a central regulator for human physiological activity. Deregulated mTOR signaling is implicated in a variety of disorders, such as cancer, obesity, diabetes, and neurodegenerative diseases. The papers published in this Special Issue summarize the current understanding of the mTOR pathway and its role in the regulation of tissue regeneration, regulatory T cell differentiation and function, and different types of cancer including hematologic malignancies, skin, prostate, breast, and head and neck cancer. The findings highlight that targeting mTOR pathway is a promising strategy to fight against certain human diseases.
Author: Nandini Dey
Publisher: Humana Press
ISBN: 3319342118
Category : Medical
Languages : en
Pages : 307
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Book Description
In the post human-genome project era, cancer specific genomic maps are redesigning tumor taxonomy by evolving from histopathology to molecular pathology. The success of a cancer drug today is fundamentally based on the success in identifying target genes that control beneficial pathways. The overwhelming power of genomics and proteomics has enlightened researchers about the fact that the PI3K-mTOR pathway is the most commonly up-regulated signal transduction pathway in various cancers, either by virtue of its activation downstream of many cell surface growth factor receptors or by virtue of its collateral and compensatory circuitry with RAS-MAPK pathway. Oncogenic signaling in the majority of solid tumors is sustained via the PI3K-AKT-mTOR pathway. Because of its prominent role in many cancer types, the PI3K-mTOR pathway has become a major therapeutic target. The volume includes two complementary parts which address the problem of etiology and disease progression and is intended to portray the very basic mechanisms of the PI3K-AKT-mTOR signaling pathway’s involvement in various facets of the cancer, including stem cell renewal, cell metabolism, angiogenesis, genetic instability, and drug resistance. Significant progress has been made in recent years elucidating the molecular mechanism of cancer cell proliferation, angiogenesis, and drug-resistance in relation to the PI3K-mTOR pathway and this volume provides an in-depth overview of recent developments made in this area.
Author: Alexandre Arcaro
Publisher: Frontiers E-books
ISBN: 288919244X
Category : Biology (General)
Languages : en
Pages : 94
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Book Description
The phosphatidylinositol 3-kinase (PI3K)/mTOR pathway integrates signals from growth factors with nutrient signals and other conditions and controls multiple cell responses, including proliferation, survival and metabolism. Deregulation of the PI3K pathway has been extensively investigated in connection to cancer. Somatic or inherited mutations frequently occur in tumor suppressor genes (PTEN, TSC1/2, LKB1) and oncogenes (PIK3CA, PIK3R1, AKT) in the PI3K/mTOR pathway. The fact that the PI3K/mTOR pathway is deregulated in a large number of human malignancies, and its importance for different cellular responses, makes it an attractive drug target. Pharmacological PI3K inhibitors have played a very important role in studying cellular responses involving these enzymes. Currently, a wide range of selective PI3K inhibitors have been tested in preclinical studies and some have entered clinical trials in oncology. Rapamycin and its analogs targeting mTOR are effective in many preclinical cancer models. Although rapalogs are approved for the treatment of some cancers, their efficacy in clinical trials remains the subject of debate. Due to the complexity of the PI3K/mTOR signaling pathway, developing an effective anti-cancer therapy remains a challenge. The biggest challenge in curing cancer patients with various signaling pathway abnormalities is to target multiple components of different signal transduction pathways with mechanism-based combinatorial treatments.
Author: Rozangela Curi Pedrosa
Publisher: Frontiers Media SA
ISBN: 2832545246
Category : Medical
Languages : en
Pages : 125
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Book Description
The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is an important signaling route that regulates several cell functions. PI3K/AKT/mTOR pathway is a crossroad of cell death and survival, playing a pivotal role in multiple interconnected cell signaling mechanisms implicated in cell metabolism, growth and proliferation, apoptosis, and angiogenesis. Disruptions in the Akt‑regulated pathways and alterations in PTEN expression are associated to Reactive oxygen species (ROS) homeostasis and different types of cancer. Genomic studies have shown that activating mutations in oncogenes as well as inactivating mutations in tumor suppressor genes are present across a variety of malignancies, including constitutive activation of the PI3K/AKT/mTOR pathway. The regulation of the Akt signaling pathway renders multiple challenges and valuable therapeutic targets. The discovery process of Akt, PDK1 and mTOR synthetic and natural products as inhibitors or immune checkpoint inhibitors using various strategies, could led to the identification of small molecule inhibitors with great selectivity, low side‑effects and also low toxicity regarding drug development.
Author: Leonidas C. Platanias
Publisher:
ISBN: 9781780841328
Category :
Languages : en
Pages : 78
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Book Description
Increased understanding of the mTOR signaling pathway in relation to malignant cells has prompted extensive efforts to develop new therapeutic approaches. The six chapters of this book summarize the current status of efforts using mTOR inhibitors for the treatment of several malignancies. First generation mTOR inhibitors (rapalogues) are now approved by the FDA for the treatment of renal cancer, and further new drugs may be approved. There is also hope that the second generation of catalytic inhibitors of mTOR that target both TORC1 and TORC2 complexes will be more powerful and effective antin.
Author: Kenneth Maiese
Publisher: Academic Press
ISBN: 012802755X
Category : Science
Languages : en
Pages : 474
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Book Description
Molecules to Medicine with mTOR: Translating Critical Pathways into Novel Therapeutic Strategies is a one-stop reference that thoroughly covers the mechanistic target of rapamycin (mTOR). mTOR, also known as the mammalian target of rapamycin, is a 289-kDa serine/threonine protein kinase that is ubiquitous throughout the body and has a critical role in gene transcription and protein formation, stem cell development, cell survival and senescence, aging, immunity, tissue regeneration and repair, metabolism, tumorigenesis, oxidative stress, and pathways of programmed cell death that include apoptosis and autophagy. Incorporating a translational medicine approach, this important reference highlights the basic cellular biology of mTOR pathways, presents the role of mTOR during normal physiologic function and disease, and illustrates how the mechanisms of mTOR can be targeted for current and future therapeutic treatment strategies. Coverage of mTOR signaling includes the entire life cycle of cells that impacts multiple systems of the body including those of nervous, cardiovascular, immune, musculoskeletal, endocrine, reproductive, renal, and respiratory origin. Covers the role of mTOR by internationally recognized expert contributors in the field. Provides a clear picture of the complexity of mTOR signaling as well as of the different approaches that could target this pathway at various levels. Includes analysis of the role of mTOR and in both health and disease. Serves as an important resource for a broad audience of healthcare providers, scientists, drug developers, and students in both clinical and research settings.
Author: Gregory Stuart Ducker
Publisher:
ISBN:
Category :
Languages : en
Pages : 200
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Book Description
The mammalian target of rapamycin (mTOR) functions to integrate nutrient and energy availability with extracellular growth factor signals to regulate macromolecular biosynthesis including protein translation and lipogenesis. This essential gene in conserved from yeast to humans and is a core metabolic regulatory element. Aberrant regulation of metabolism is a phenotype recognized as a hallmark of cancer, and it has been shown that increases in translation alone can be oncogenic. Additionally, many of the most common oncogenes in cancer alter the growth factor signaling network upstream of mTOR and these lesions likely activate mTOR in many cancers. Thus, repression of mTOR activity is an emerging therapeutic strategy for human cancer and there is both strong mechanistic and epidemiological evidence to suggest that attenuation of mTOR signaling may be broadly applicable. As a kinase with a defined small-molecule binding pocket, mTOR presents an attractive target for therapeutic intervention because of its conserved role in integrating many different oncogenic lesions and its central requirement for metabolic regulation. The successful application of mTOR inhibitors to clinical oncology will require the development of potent and selective inhibitors of this kinase and equally importantly, an understanding of which oncogenic lesions mark tumors as specifically sensitive to mTOR inhibition as well as independent biomarkers for in vivo efficacy. Fortuitously, mTOR is inhibited with near perfect selectivity by the natural product rapamycin, and analogs of this compound have been approved for the treatment of solid tumors. Rapamycin inhibits mTOR through a non-conserved non-competitive mechanism of action and only blocks the phosphorylation of certain substrates. ATP-competitive inhibitors of mTOR have recently been invented that occupy the kinase active site and block all substrate phosphorylation. In many preclinical models they are significantly more potent than rapamycin and as they enter clinical trials, questions about how to maximize their therapeutic index naturally arise. This may be challenging to ask for mTOR because it is not mutated in cancer and what genetic lesions mark cancers as susceptible or not to mTOR inhibitors has not been determined. To address the question of how best to apply ATP-competitive mTOR inhibitors to human cancer, I performed a large (~650) unbiased cell screen to identify markers for sensitivity and resistance to PP242, a tool compound that has been developed into the phase I clinical drug, MLN0128. In comparison to rapamycin, PP242 was a more effective compound and more cell lines were inhibited. Colon origin was significantly associated with resistance to both drugs. For PP242, mutations in the gene PIK3CA were a marker of sensitivity. I subsequently focused on colon cancer because it gave the strongest mTOR drug dependent signature, and one of resistance. A panel of mTOR and PI3K pathway inhibitors differentiated colon cancer cell lines based on RAS and PIK3CA genotypes. Ordering of colon cancer cell lines by sensitivity to PP242 revealed a striking resistance to mutations in KRAS within the already resistant colon cancer set. I identified that this KRAS specific resistance was due to a specific failure to inhibit phosphorylation of the translational repressor 4E-BP1 even when other mTOR substrates were inhibited. Resistance correlated with the amount of KRAS in the active GTP-bound form and was independent of canonical mitogen activated protein kinase signaling. Finally, introduction of mutant PIK3CA can sensitize even KRAS mutant colon cancer cells to PP242 and the mechanism is correlated with 4E-PB1 phosphorylation. In colon cancer cell lines I identified predictive markers of sensitivity and resistance and a biomarker that reported upon functional inhibition of mTOR in vivo. Cell lines have well documented shortcomings, and I worked to characterize a colon cancer patient-derived xenograft (PDX) model and apply it to early drug discovery to validate these findings. The PDX model uses metastatic colon cancer removed from patients that is then propagated in nude mice. Each patient tumor can be expanded into a cohort of identical tumors, and a drug trial can be conducted on an individual's tumor. In the colon cancer PDX model, PP242 was orally bioavailable and acutely inhibited mTOR signaling in many tumors. In a continuous dosing trial however, sensitivity to the drug paralleled what was observed in cell lines. Single KRAS mutant tumors were refractory to treatment. Overall, failure to durably inhibit 4E-BP1 phosphorylation correlated with failure to respond to treatment. I discovered a set of cell lines that were resistant to the ATP-competitive mTOR inhibitor PP242 and identified a defect in inhibition of 4E-BP1 phosphorylation as giving rise to this phenotype. This mechanism of resistance appears to be common in KRAS mutant colon cancer cell lines as well as patients. The differential inhibition of distinct mTOR substrates I discovered reveals an additional layer of as yet uncharacterized biological control in this kinase signaling pathway. 4E-BP1 is a robust biomarker for ATP-competitive drugs and should be strongly considered for clinical use in trials of these agents.
