Author: Yosef Yarden
Publisher: Springer
ISBN: 3319679325
Category : Medical
Languages : en
Pages : 242
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Book Description
This volume comprehensively covers the multiplicity and diversity of mechanisms underlying patient resistance to currently approved anti-cancer drugs, including tyrosine kinase inhibitors and monoclonal antibodies, blockers of growth factor receptors and their downstream pathways, which play essential functions in cancer progression. Each chapter will cover a specific group of targets and the cognate drugs, along with molecular modes of innate and evolving resistance.
Author: James W. Janetka
Publisher: John Wiley & Sons
ISBN: 1119300207
Category : Science
Languages : en
Pages : 488
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Book Description
International experts present innovative therapeutic strategies to treat cancer patients and prevent disease progression Extracellular Targeting of Cell Signaling in Cancer highlights innovative therapeutic strategies to treat cancer metastasis and prevent tumor progression. Currently, there are no drugs available to treat or prevent metastatic cancer other than non-selective, toxic chemotherapy. With contributions from an international panel of experts in the field, the book integrates diverse aspects of biochemistry, molecular biology, protein engineering, proteomics, cell biology, pharmacology, biophysics, structural biology, medicinal chemistry and drug development. A large class of proteins called kinases are enzymes required by cancer cells to grow, proliferate, and survive apoptosis (death) by the immune system. Two important kinases are MET and RON which are receptor tyrosine kinases (RTKs) that initiate cell signaling pathways outside the cell surface in response to extracellular ligands (growth factors.) Both kinases are oncogenes which are required by cancer cells to migrate away from the primary tumor, invade surrounding tissue and metastasize. MET and RON reside on both cancer cells and the support cells surrounding the tumor, called the microenvironment. MET and RON are activated by their particular ligands, the growth factors HGF and MSP, respectively. Blocking MET and RON kinase activation and downstream signaling is a promising therapeutic strategy for preventing tumor progression and metastasis. Written for cancer physicians and biologists as well as drug discovery and development teams in both industry and academia, this is the first book of its kind which explores novel approaches to inhibit MET and RON kinases other than traditional small molecule kinase inhibitors. These new strategies target key tumorigenic processes on the outside of the cell, such as growth factor activation by proteases. These unique strategies have promising potential as an improved alternative to kinase inhibitors, chemotherapy, or radiation treatment.
Author: Daniele Focosi
Publisher: Springer
ISBN: 3319460919
Category : Medical
Languages : en
Pages : 194
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Book Description
The volume will serve as a primer on tyrosine kinase signaling and its importance in cancer. The volume will first introduce the common denominators of small-molecule and antibody-derived inhibitors, as well as the general phenomenon of resistance. The volume will then detail resistance to the most commonly used classes of tyrosine kinase inhibitors, and will focus specific chapters on resistance to BCR-ABL1, FLT3, angiokinase family members, and ALK inhibitors.
Author: Doriano Fabbro
Publisher: Springer Science & Business Media
ISBN: 158829384X
Category : Medical
Languages : en
Pages : 300
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Book Description
Protein tyrosine kinases as targets for cancer and other indications / Mark Pearson, Carlos Garcia-Echeverria, Doriano Fabbro -- Inhibitors of signaling interfaces: targeting Src homology 2 domains in drug discovery / Carlos Garcia-Echeverria -- PI 3-kinase inhibition: a target for therapeutic intervention / Peter M. Finan, Stephen G. Ward -- Src as a target for pharmaceutical intervention: potential and limitations / Mira Susa ... [et al.] -- Activated FLT3 receptor tyrosine kinase as a therapeutic target in leukemia / Blanca Scheijen, James D. Griffin -- JAK kinases in leukemias/lymphomas and multiple myeloma / Renate Burger, Martin Gramatzki -- Glivec (Gleevec, Imatinib, STI571): a targeted therapy for CML / Elisabeth Buchdunger, Renaud Capedeville -- Platelet-derived growth factor: normal function, role in disease, and applications of PDGF antagonists / Tobias Sjoblom ... [et al.] -- Structural biology of protein tyrosine kinases / Sandra W. Cowan-Jacob ... [et al.] -- Testing of signal transduction inhibitors in animal models of cancer / Terence O'Reilly, Robert Cozens -- Phosphoproteomics in drug discovery and development / Michel F. Moran.
Author: Kapil Mehta
Publisher: Springer Science & Business Media
ISBN: 0387894454
Category : Medical
Languages : en
Pages : 372
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Book Description
It was estimated that in 2008, 1,437,180 patients would receive a new cancer diagnosisand 565,650individualswould die of cancer (Jemal et al. 2008).Since the vast majority of patients dying of cancer will have had anticancer therapy, both c- ventional chemotherapy and novel targeted therapy, it can be concluded that these patients are dying with drug resistant cancer. The term multidrug resistance is also apt – in that these patients die after having undergone multiple rounds of different and structurally unrelated cancer therapies. However, for some, the concept of m- tidrug resistance is a worn out idea, stemming from disappointment with the drug resistancereversalstrategiesthatwerecarriedoutinthe1990susingpumpinhibitors to block drug resistance mediated by P-glycoprotein, product of the MDR-1 gene. However, if one takes the larger de?nition – multidrug resistance as simultaneous resistance to multiple structurally unrelated anticancer therapies – its existence c- not be denied. The purpose of this book is to explore new concepts related to drug resistance in cancer, including resistance to the new molecularly targeted agents. Perhaps new terminology is needed for resistance that occurs following therapy with the targeted agents: Novel Targeted Agent Resistance (NTR). Alternatively, we can return to the original de?nition of multidrug resistance as simply the res- tance to multipleagents that occurs in the course of normalcancer progression.This resistance is likely to be mediated by many factors.
Author: Allison Claas
Publisher:
ISBN:
Category :
Languages : en
Pages : 156
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Book Description
Targeted cancer therapeutics have seen constraint in clinical efficacy due to resistance. Indicators for resistance may include genetic mutations or protein-level overexpression of targeted or bypass receptor tyrosine kinases (RTKs). While the latter is often attributed to gene amplification, genetic characterization of tumor biopsies has failed to explain substantial proportions of resistance. We hypothesize that post-synthesis mechanisms governing RTK levels may represent underappreciated contributors to drug resistance. We have developed an experimental and computational model for the simultaneous analysis of synthesis and post-synthesis mechanisms contributing to protein level changes. The experimental component quantitatively measures processes operating on multiple time scales in a multi-plexed fashion, with methods generalizable to any membrane bound protein. Parameter distribution estimation by fitting data to an integrative cellular model quantifies native RTK processes and enables the study of treatment induced mechanistic changes. It has been reported that triple negative breast cancer cell lines up-regulate many RTKs in response to Mek inhibition, although reported with conflicting mechanisms. Upon integrated analysis, we find both Axl and Her2 have increased lysate levels after Mek inhibition with 3 Mek inhibitors, Selumetinib, Binimetinib, and PD0325901. Axl changes are attributed to a decrease in proteolytic shedding and protein degradation, and Her2 changes are attributed to decreased synthesis. Met shows a decrease in proteolytic shedding similar to Axl, but compensating synthesis and degradation mechanisms counteract the effect. Contrastingly, Erk inhibition shows minor effects on RTK reprogramming, with Erk dimer inhibitor DEL-22379 exhibiting RTK specific protease effects and highlighting RTK specific outcomes of decreased endocytosis. This quantitative model enables prediction of combination therapies with mechanistic process inhibitors. Our predictions match experimental observations that Axl lysate level increases with Mek inhibition remains unchanged in the presence of transcriptional inhibition, supporting a role for post-synthesis mechanisms. Through additional combination with an Axl inhibitor, we are able to further the anti-proliferative and anti-migratory effect of Mek and transcriptional inhibition in TNBC. This study not only provides a novel and broadly applicable quantitative framework for characterizing RTK level changes, but also emphasizes the RTK, pathway target, and inhibitor variation of RTK reprogramming in drug resistance.
Author: Huan Ren
Publisher: BoD – Books on Demand
ISBN: 1789848083
Category : Medical
Languages : en
Pages : 136
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Book Description
Protein tyrosine kinase (PTK) deregulation contributes to growth of cancer and many other diseases. The development of small-molecule tyrosine kinase inhibitors (TKIs) that target the deregulated PTKs, such as epidermal growth factor receptor (EGFR) in non-small-cell lung cancer (NSCLC) and Bcr-ABL in chronic myeloid leukemia (CML), has revolutionized disease management. In this book, we examine a few aspects of PTKs and cancer, considering efficacy, predictive markers to therapeutic response, limitations, and future directions in TKI treatment. In this rapidly evolving field, overcoming therapeutic resistance is most challenging, and multi-targeting directs the next-generation TKIs and combination therapy as ongoing strategies in cancer treatment.
Author: Mario Mandalà
Publisher: Springer
ISBN: 3030105075
Category : Medical
Languages : en
Pages : 297
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Book Description
A major objective of this book is to reveal unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive and prognostic biomarkers to enable patient stratification and tailor treatments. It offers to the readers an updated overview on the possible reasons of failure of new and promising therapeutic opportunities.
Author: Ganji Purnachandra Nagaraju
Publisher: Springer
ISBN: 9811314861
Category : Medical
Languages : en
Pages : 241
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Book Description
The aim of this book is to provide comprehensive overview of the role of different tyrosine kinases in the progression and metastasis of various cancers of the gastrointestinal tract such as esophagus, liver, pancreas, stomach, and colorectal. Activation of various signaling pathways and tyrosine kinases are responsible for resistance to chemo and radiotherapy in these gastrointestinal malignancies. Targeting these tyrosine kinases, which regulate the activities of survival pathways in growth, and metastasis is a rational strategy in gastrointestinal cancer therapy. Each chapter embedded in this book covers information pertaining to a specific tyrosine kinase and its impact on various malignancies, which is not only significant for basic and clinical research investigations but will also be valued by students at advanced undergraduate to postgraduate levels.
Author: John D. Haley
Publisher: Springer Science & Business Media
ISBN: 1597453560
Category : Medical
Languages : en
Pages : 393
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Book Description
The epidermal gro wth factor (EGF ) receptor and its downstream signal transduction networks have been implicated in the ontology and maintenance of tumor tissues, which has motivated the discovery and development of molecularly targeted anti-EGF receptor therapies. Over decades of study, the EGF receptor structure, its ligand binding domains, the physical biochemistry underlying its intrinsic tyrosine kinase catalytic function and the modular interactions with SH2, PTB, and SH3 domain containing signaling adaptor p- teins required for signal transduction, have been extensively dissected. Not only is the EGF receptor the nexus of many streams of information, but it also forms one part of a calcul- ing device by forming dimers and oligomers with the other three receptors in its family in response to at least eleven ligands (some of which are expressed in multiple forms with overlapping or quite distinct functions). This phenomenon, while recruiting to the inner surface of the cell membrane and activating multiple second messenger proteins, also allows the possibility of cross talk between these systems, permitting a further layer of information to be exchanged. Less well described are the cross re gulation of the EGF receptor and other anti-apoptotic, mitogenic and metabolic signaling systems. The study of these systems has yielded new surprises. One hurdle in these efforts has been that signal transduction pathways have frequently been defined in the generic absence of their tissue-specific or cell-interaction specific context.
