Table of Contents
Welcome
Table of Contents
Title
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FOREWORD
PREFACE
LIST OF CONTRIBUTORS
HER2 Over-Expression and Gastric Cancer: Molecular Mechanisms and Target Therapies
Abstract
Epidemiology of Gastric Cancer
Treatment of gastric cancer
Pathology of gastric cancer
The HER2 receptor
HER2 in cancer
HER2 in gastric cancer
Preclinical Data
Prognostic Significance
Clinical Application
HER2 testing in gastric cancer
Anti-HER2 therapy
Trastuzumab
Other Agents
Conclusion
Acknowledgements
conflict of interest
REFERENCES
Dietary Phenolics as Cancer Chemopreventive Nutraceuticals: A Promising Paradigm
Abstract
INTRODUCTION
Consumption of Nutraceutical Rich Diet and Cancer Incidence: An Inverse Epidemiological Correlation
Bioavailability and Sources of Phenolic Nutraceuticals
Resveratrol in Cancer Chemoprevention
Genistein in Cancer Chemoprevention
Epigallocatechin-3-gallate (EGCG) in Cancer Chemo-prevention
Curcumin in Cancer Chemoprevention
Luteolin in Cancer Chemoprevention
Conclusion
Acknowledgements
Conflict of Interest
REFERENCES
Flavonoids and their Therapeutic Potential as Anti Cancer Agents: Mechanism, Factors and Regulation
Abstract
1.. Introduction
2.. Biosynthesis, Metabolism, Properties and Analysis of Flavonoids
3.. Flavonoids in Health
3.1.. Flavonoid-Protein Interaction
3.2.. Flavonoids as Ligands and as Enzyme Inhibitors
3.2.1.. Ligand–Receptor Interactions
3.2.1.1.. Estrogen Receptors
3.2.1.2.. Benzodiazepine Receptor
3.2.1.3.. Adenosine Receptor
3.2.2.. ATP-Binding Proteins
3.2.3.. Flavonoids vs Redox Enzymes
3.2.3.1.. Flavonoids vs Xanthine Oxidase
3.2.3.2.. Flavonoids vs LOXs and COXs
3.2.3.3.. Flavonoids vs Peroxidases and Tyrosinases
3.2.4.. Flavonoids vs CytochromeP450
3.3.. Role in ROS Production
3.4.. Flavonoids in Angiogenesis
3.5.. Flavonoids Against Multidrug Resistance
3.6.. Other Modes of Action
4.. Flavonoids in Breast Cancer Treatment
4.1.. In Vitro Studies
4.2.. In Vivo Studies
5.. Flavonoids and other Cancers
6.. Flavonoid Supplements and Adverse Effect
6.1.. Interactions with Trace Elements
6.2.. Interactions with Vitamins
6.3.. Interactions Between Drugs and Flavonoids
Summary and Conclusions
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Antibody-Drug Conjugates as Therapeutic Agents in Oncology: Overview And Perspectives
Abstract
1.. INTRODUCTION
1.1.. Development of Antibody-Drug Conjugates (ADCs): Historical Perspective
1.2.. Development of ADCs Using Polyclonal Antibodies
1.3.. Early Development of ADCs Using Monoclonal Antibodies
2.. LESSONS LEARNT FROM THE CLINICAL TESTING OF THE EARLY GENERATION OF ADCS
3.. TUMOR CELL PROPERTIES RELEVANT FOR THE DESIGN OF ADC THERAPEUTICS
3.1.. Tumor Cell Heterogeneity
3.2.. Antigen Expression Level
3.3.. Tumor Cell Resistance
3.4.. Antigen Distribution
3.5.. Tumor Localization
4.. DEVELOPMENT OF ADCS
4.1.. Target Selection
4.2.. Linker Development
4.2.1.. Cleavable Linkers
4.2.1.1.. Acid Labile Linkers
4.2.1.3.. Enzyme Labile Linkers
4.2.2.. Non-Cleavable Linkers: Thioether-Based Linker
4.3.. Payload Development
4.3.1.. Calicheamicin
4.3.2.. Maytansinoid-Based Derivatives
4.3.3.. Auristatin-Based Derivatives
4.3.4.. Other Payloads Used for ADC Generation
4.3.4.1.. Duocarmycins
4.3.4.2.. SN-38
5.. ADCS IN DIFFERENT STAGES OF CLINICAL TESTING
5.1.. FDA Approved ADCs
5.1.1.. Gemtuzumab Ozogamicin (Trade Name: Mylotarg)
5.1.2.. Brentuximab Vedotin (Trade Name: Adcetris)
5.1.3.. Trastuzumab Emtansine (Trade Name: Kadcyla)
5.2.. ADCs in Advanced Clinical Testing Stage
5.2.1.. Inotuzumab Ozogamicin (CMC-544)
5.3.. Other ADCs in Clinical Development
6.. MECHANISM OF ACTION OF ADCS
6.1.. Internalizing ADCs
6.2.. Bystander Effect
7.. DEVELOPMENT OF NEXT GENERATION OF ADCS AND ALTERNATIVE APPROACHES FOR DRUG DELIVERY
7.1.. Development of the Antibody Component of ADCs
7.1.1.. Development of Antibodies Against Novel Therapeutic Targets
7.1.2.. Optimization of Antibody Structure: Novel Antibody and Non-antibody-based Platforms for the Generation of ADCs
7.1.2.1.. Novel Antibody-based Platforms for the Development of ADCs
7.1.2.2.. Novel Non-Antibody-Based Platforms with Potential for Drug Conjugation
7.1.2.3.. Polymer-Based Immunoconjugates
7.2.. Developments in the Conjugation Methods and Novel Linker Designs for the Generation of Future ADCs
7.2.1.. THIOMAB-based Method for the Development of ADCs
7.2.2.. Novel Linker Types for the Development of ADCs
7.2.2.1.. Traceless Linkers
7.2.2.2.. Hydrophilic Linkers
7.3.. Development of Novel Types of Payloads for ADC Generation
7.3.1. Novel Types of Antibody-Based Conjugates
7.3.2.. Development of ADCs Targeting Molecules Involved in the Resistance to Therapeutic Monoclonal Antibodies
DISCLAIMER
CONFLICT OF INTEREST
DISCLAIMER
ACKNOWLEDGEMENTS
REFERENCES
Strategies for Improving the Systemic Delivery of Oncolytic Adenoviruses and Plasmids: Potential Application of Non-Viral Carriers
Abstract
1- Introduction
2.. Oncolytic Ads
2.1.. Structural Biology of Oncolytic Adenoviral Genome
2.2.. Development of Oncolytic Ads
2.3.. Oncolytic Ad as Anti-Tumor Transgene Delivery System
3.. Major limitations of Oncolytic Ads systemic administration
4.. Development of systemically-injectable adenoviral vector by surface modifications
4.1.. Chemical Conjugation via Amine-Terminated Ad Surface
4.2.. Antibody Attachment for Active Targeting
4.3.. Electrospinning-Mediated Adenovirus Encapsulation
4.4.. Encapsulation Methods with Various Polymers
4.5.. Liposomal Encapsulation
5.. Non-viral strategies for the delivery of nucleic acids
5.1.. Lipidic Carriers
5.1.1.. Liposomes
5.1.2.. Solid Lipid Nanoparticles
5.1.3.. Niosomes
5.2.. Polymeric Carriers
5.2.1.. Polyethylenimine
5.2.2.. Chitosan
5.2.3.. Cyclodextrins
5.2.4.. Dendrimers
5.2.5.. Polymeric Nanoparticles
5.3.. Improving Targeting and Transfection Efficiency of Non-Viral Vectors
5.3.1.. Considerations for Non-Viral Vector Delivery to Specific Organs/Tissues: Size and Zeta Potential
5.3.2.. Improving targeting by Cell Penetrating Peptides
6.. Expert Opinion
conflict of interest
Acknowledgements
References
Peptidyl-Prolyl Isomerase Pin1: A Novel Target for Cancer Therapy
Abstract
Introduction
Regulation of Pin1
Pin1 Structure
Pin1-Induced cis-trans Isomerization of Peptide Bond
Pin1 Interaction with Target Proteins
Emerging Role of Pin1 in Evasion of Anti-tumor Immune Response
Pin1 in DNA Damage Response: Cell Cycle Regulation and Apoptosis
Pin1 as a Molecular Target for Cancer Therapy
Pin1 Inhibitors
Pin1 Inhibitors as Adjuvant to Chemotherapy
Limitations of Using Pin1 as Target
Conclusion
Acknowledgements
conflict of interest
REFERENCES
Targeting the Molecular Circuitry Underlying Glioblastoma Invasion
Abstract
INTRODUCTION
MECHANISMS OF GLIOBLASTOMA MIGRATION (Fig. 1)
Cell Detachment: Cell Surface Adhesion Molecules
Attachment to ECM: Integrins and Tenascin-C
Remodeling and Degradation of ECM: MMPs, ADAM, and ADAMTS
Migration: Growth Factors, Cytokines, and Receptor Tyrosine Kinases (Fig. 2)
Receptor Tyrosine Kinases (RTKs)
G Protein-Coupled Receptors (GPCRs)
INHIBITION OF GLIOBLASTOMA MIGRATION IN CLINICAL TRIALS
SURVIVAL BENEFITS FROM TARGETING EGFR AND C-MET IN CLINICAL TRIALS
CONCLUSION
ACKNOWLEDGEMENTS
CONFLICT OF INTEREST
REFERENCES
State-of-the-Art Nanopharmaceutical Drug Delivery Platforms for Antineoplastic Agents
Abstract
Introduction
Passive tumor Targeting by nanopharmaceuticals
Active tumor Targeting by nanopharmaceuticals
Stimuli-Responsive Nanopharmaceuticals
Liposomes as drug delivery systems for anticancer drugs
Conventional Liposomes
Stealth Liposomes
Targeted Liposomes
pH-Responsive Liposomes
Virosomes and PTD-Modified Liposomes
Enzymatically Triggerable Liposomes
Thermosensitive Liposomes
Sonosensitive Liposomes
Liposomes as Vehicles for Co-delivery of Therapeutic Agents
Representative polymer nanopharmaceuticals
Polymeric Micelles
Dendrimers
Multi-arm Star-Like Polymers
Molecular hosts as anticancer drug delivery systems
Cyclodextrins
Cucurbit[n]urils
Calix[n]arenes
CONCLUSIONS
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Frontiers in Anti-Cancer Drug Discovery
Volume 2
Editor
Prof. Atta-ur-Rahman, FRS
Honorary Life Fellow
Kings College
University of Cambridge
UK
Co-Editor
Prof. M. Iqbal Choudhary
H.E.J. Research Institute of Chemistry
International Center for Chemical and Biological Sciences
University of Karachi
Pakistan
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FOREWORD
Frontiers in Anti-cancer Drug Discovery covers important advances in the field of drug development with particular focus on research on drugs in advanced stages of development, clinical trials and applications. This Volume published under the editorship of Prof. Atta-ur-Rahman aims at providing readers with an update on contemporary research. The research articles are comprehensive and have been written by an impressive group of authors, most of whom are well known for their own contributions in the field of drug research.
This eBook should be of significant interest to Ph.D. students and established researchers. I commend the editor, Prof. Atta-ur-Rahman, and all the contributors for this well written volume which highlights the quest for a cure for cancer.
PREFACE
Cancer remains second leading cause of death, after cardiovascular diseases. Efforts to understand cancer at the molecular level have led to the emergence of many new disciplines at the interface of chemistry and biology. The discovery of new molecular targets and new molecular entities which can modulate the molecular functions, combined with the advent of enabling technologies for early diagnosis and disease progression, as well as better drug delivery vehicles, create a new hope for the treatment of most cancers, if not all, in the near future. The eBook entitled “Frontiers in Anti-Cancer Drug Discovery”, is an excellent show case of the various approaches the researchers are undertaking to address the issue of cancer prevention and treatment. All chapters, with the exception of chapters 2 and 3, address a distinct issue and provide research based solutions.
Chapter 1 contributed by Michael Luis and Ramon Andrade de Mello, reviews the importance of human epidermal growth factor receptor 2 (HER2) as a potential target for the treatment of the second most common cancer type, gastric cancer. The authors support their hypothesis of HER2 as an important target for drug discovery and development by numerous studies, conducted in recent past. HER2 and its role in gastric cancer progression and development of resistance against cancer chemotherapies are presented in a reader friendly manner.
Chapter 2 and 3 contributed by Mohammad F. Ullah et al., and Priya Batra et al., respectively, highlight the importance of natural products in cancer chemoprevention and treatment. Chapter 2 provides an excellent overview of scientific and clinical studies conducted on cancer’s preventive role of dietary phenolics. They have mentioned the examples of various well known plant phenolic constituents, obtained from fruits and dietary herbs, and describe their chemopreventive role by modulating the essential cellular pathways involved in cancer proliferation and metastasis. In chapter 3, the authors have also focused on a class of plant phenolics, flavonoids of dietary origin and reviewed their possible action in the prevention and treatment of various cancers. Interactions of plantbased flavonoids with proteins and other dietary components are also reviewed.
Chapter 4 contributed by Milos Dokmanovic et al., focuses on an emerging class of therapeutics, anti-body drug conjugates (ADC). The authors have taken a holistic view of the topic by describing the history, current status of development and future prospects. These recent developments have made it possible to use ADC as serious candidates for cancer treatment. The results of recent clinical trials and synthetic strategies to develop novel ADCs have also been nicely described in this chapter.
Mireia Agirre et al., in chapter 5 address the potential and prospects of virotherapy against cancer. This new approach, though it has suffered from a lot of technical hurdles, now appears to be practical and promising. Specially interesting is the fact that synthetic viruses have the capacity to manipulate aderoviruses to target cancer cells. This makes the field scientifically exciting and therapeutically promising.
Chapter 6 by Rohit Mathur et al., identifies peptidyl-prolyl isomerase PIN1 as a novel target for cancer treatment. PIN1 up-regulation in tumor cell and its role in protein post phosphorylation events makes it an attractive target for drug discovery. PIN1 inhibitors as anti-cancer agents and as adjuvants deserve special attention.
Sean M. Lawless et al., review the details of molecular cascade involved in the glioblastoma invasion in chapter 7. Glioblastoma is among the deadliest of human cancers with an amazing tendency to invade other regions of the brain. The authors have reviewed the molecular mechanisms involved in glioblastoma invasion and identified numerous molecular targets for possible drug development.
Last but not least, chapter 8 contributed by Georgi Ts. Momekov et al., reviews an exciting development in drug delivery. The use of nanopharmaceutical agents holds great promise. Drug delivery vehicles with nanoparticles not only have improved therapeutic indices but also improved stability and solubility and lower toxicity associated with cancer chemotherapy.
This delightful feast of well written scientific articles on topics of general relevance, makes this ebook a “must to read” for practitioners, scientists, and students. We must thank the contributing authors for making this volume an important treatise of scientific knowledge. We are also profoundly grateful to the editorial staff, particularly Mr. Mahmood Alam (Director Publication) and Ms. Hira Aftab (Assistant Manager) for their hard work and persistent efforts.
LIST OF CONTRIBUTORS
Atta-ur-RahmanHonorary Life Fellow, Kings College, University of Cambridge, UKM. Iqbal ChoudharyH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, PakistanPriya BatraDepartment of Biotechnology, Maharishi Markandeshwar University, Mullana-Ambala, 133203, IndiaRajesh NaithaniCancer Research Centre, Himalayan Institute and Hospital Trust, UK, IndiaAnil K. SharmaDepartment of Biotechnology, Maharishi Markandeshwar University, Mullana-Ambala, 133203, IndiaMichael LuisDepartment of Medical Oncology, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, Porto, 4200-072, PortugalRamon Andrade de MelloDepartment of Medical Oncology, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, Porto, 4200-072, PortugalRohit MathurDepartment of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, 77030, USAAnant N. BhattDivision of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110054, IndiaSeema GuptaDepartment of Radiation Oncology, University of Miami, Miami, 33136, USAB.S. DwarakanathDivision of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110054, IndiaSean M. LawlessCenter for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, USAJohnny C. AkersCenter for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, USAChun-Lin ChenCenter for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, USARui LiuDepartment of Neurosurgery, Navy General Hospital of People's Liberation Army, Beijing, 100037, ChinaBob CarterCenter for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, USAClark C. ChenCenter for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, USAGeorgi Ts. MomekovFaculty of Pharmacy, Medical University-Sofia, 2 Dunav Str., Sofia, 1000, BulgariaDenitsa B. MomekovaFaculty of Pharmacy, Medical University-Sofia, 2 Dunav Str., Sofia, 1000, BulgariaPlamen T. PeykovFaculty of Pharmacy, Medical University-Sofia, 2 Dunav Str., Sofia, 1000, BulgariaNikolay G. LambovFaculty of Pharmacy, Medical University-Sofia, 2 Dunav Str., Sofia, 1000, BulgariaMohammad F. UllahDepartment of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, KSAShowket H. BhatDepartment of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, KSAEram HussainDepartment of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, KSAFaisel Abu-DuhierDepartment of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, KSAHusain Y. KhanDepartment of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, 202002, IndiaMohammad AatifDepartment of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, 202002, IndiaAamir AhmadDepartment of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Hudson Webber Cancer Research Center, Detroit, 48201, USAS. M. HadiDepartment of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, 202002, IndiaMilos DokmanovicLaboratory of Molecular Oncology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, USAM. Khair ElZarradLaboratory of Molecular Oncology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, USADianne S. HirschLaboratory of Molecular Oncology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland, USAWen Jin WuLaboratory of Molecular Oncology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland, USAMireia AgirreNanoBioCel Group, University of the Basque Country, Vitoria, SpainJon ZarateNanoBioCel Group, University of the Basque Country, Vitoria, SpainGustavo PurasNanoBioCel Group, University of the Basque Country, Vitoria, SpainLuis Alfonso RojasTraslational Research laboratory, IDIBELL-Institut Català d´Oncologia, L´Hospitalet de Llobregat, Barcelona, SpainRamon AlemanyTraslational Research laboratory, IDIBELL-Institut Català d´Oncologia, L´Hospitalet de Llobregat, Barcelona, SpainJosé Luis PedrazNanoBioCel Group, University of the Basque Country, Vitoria, Spain
HER2 Over-Expression and Gastric Cancer: Molecular Mechanisms and Target Therapies
Michael Luis1,Ramon A. de Mello*,1,2
1Department of Medical Oncology, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal; 2Department of Medicine, Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, 4200-319, Porto, Portugal
Abstract
Gastric cancer is the second leading cause of cancer related-death worldwide. In 2008, it was estimated 990.000 new cases and 738.000 related-deaths. Considering the poor prognosis of advanced gastric cancer, new therapeutic regimens with acceptable toxicity have been pursued. Interesting insights have emerged from the investigation of human epidermal growth factor receptor 2 (HER2) as a potential therapeutic target. HER2 is a transmembrane tyrosine kinase receptor which is activated through dimerization, leading to a cascade of events that involves the activation of molecular pathways concerning regulation of cell proliferation, differentiation and survival, including the MAPK and PI3K pathways. The importance of addressing HER2 as a therapeutic target is underscored by consistent molecular and pathological findings: upregulated HER2/neu relates to carcinogenesis and is found in both primary tumours and metastasis. HER2 over-expression has been reported in breast, stomach, lung, salivary gland, ovary, colon, prostate and pancreatic cancers. In the particular case of breast cancer, recognition of the molecular signature of HER2 over-expression is widely used to tailor therapeutics involving molecular therapies with antibodies targeting HER2, therefore establishing HER2 status as a prognostic factor and a predictor of response to therapy. However, the correlation between the expression of HER2 and the prognosis of gastric cancer is still controversial. HER2 over-expression is currently estimated to occur in about 7-34% of gastric cancers. In this behalf, it is important to stress the recent development of validated methods in identifying HER2 over-expression in gastric cancer. In this chapter the authors will address the molecular mechanisms of HER2's oncogenicity, the assessment of HER2 over-expression and its clinico-pathological significance, resistance mechanisms and future perspectives emanating from clinical trials in this regard.
Keywords:: Gene amplification, monoclonal antibodies, biomarkers, erbB-2, HER2 protein, stomach neoplasms, trastuzumab, lapatinib.
*Address correspondence to Ramon A. de Mello: Department of Medical Oncology, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal; Tel: +351 91 204 0770; E-mail:
[email protected]Acknowledgements
The authors wish to thank Ana Tavares, Andreia Coelho and Inês Chora who contributed in the elaboration of this chapter.
conflict of interest
The authors state that there is no conflict of interest.
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