Apoptosis 2009: Opportunities in Cancer and Other Diseases

Table of Contents

Front Cover

List of Tables and Figures

About Biophoenix

About the Authors

Legal Notice

Executive Summary

Chapter 1 Apoptosis and its regulation

• 1.0 Chapter summary
• 1.1 Introduction to apoptosis
• 1.2 Apoptosis versus necrosis
• 1.3 Other modes of cell death
  • 1.3.1 Autophagy
  • 1.3.2 Mitotic catastrophe
  • 1.3.3 Anoikis
• 1.4 Mechanisms of apoptosis
• 1.5 Key molecular players in apoptosis
  • 1.5.1 TNF family and death receptors
  • 1.5.2 Apoptosis adaptor proteins
  • 1.5.3 Caspases and other proteases
  • 1.5.4 BCL2 family
  • 1.5.5 IAPs and other regulators of caspases
  • 1.5.6 Intracellular kinases
  • 1.5.7 Transcription factors and regulators
• 1.6 Apoptotic pathways
  • 1.6.1 Extrinsic pathway
  • 1.6.2 Intrinsic pathway
  • 1.6.3 The perforin/granzyme pathway
  • 1.6.4 Execution pathway
• 1.7 Targeting dysregulated apoptosis
• 1.8 Apoptosis pipeline audit

Chapter 2 Assays and biomarkers of apoptosis

• 2.0 Chapter summary
• 2.1 Introduction
• 2.2 Analysis of cytomorphological parameters
• 2.3 Analysis of mitochondrial parameters
• 2.4 Biomarker-based assays of apoptosis
  • 2.4.1 Commonly assayed biomarkers
    • 2.4.1.1 Externalized phosphatidylserine
    • 2.4.1.2 Nucleosomal DNA
    • 2.4.1.3 Caspases
    • 2.4.1.4 Cytochrome c
    • 2.4.1.5 Other protein biomarkers
    • 2.4.1.6 Cytokeratins (cancer)

Chapter 3 Indirect apoptogens in development for cancer

• 3.0 Chapter summary
• 3.1 Introduction to cancer
• 3.2 Overview of anticancer pharmacotherapies
• 3.3 Detecting apoptotic effects of new drugs
• 3.4 Drugs in development with apoptotic effects
• 3.5 First generation indirect apoptogens
  • 3.5.1 Radio- and chemo-sensitizers
  • 3.5.2 Alkylating and other DNA-binding agents
  • 3.5.3 Antimetabolites
  • 3.5.4 Topoisomerase inhibitors
  • 3.5.5 Antitumor antibiotics
  • 3.5.6 Microtubule-targeting agents
• 3.6 Second generation indirect apoptogens
  • 3.6.1 Hormone antagonists
  • 3.6.2 Biotherapies
    • 3.6.2.1 Monoclonal antibodies
    • 3.6.2.2 Ribonucleases
    • 3.6.2.3 Peptides
    • 3.6.2.4 Non-antisense oligonucleotides
    • 3.6.2.5 Oncolytic viruses
    • 3.6.2.6 Immunotherapies
  • 3.6.3 Focus on kinase inhibitors

Chapter 4 Direct apoptogens in development for cancer

• 4.0 Chapter summary
• 4.1 Promoting apoptosis of cancer cells
• 4.2 Gene targets of apoptogens in development
  • 4.2.1 TNF family and death receptors
    • 4.2.1.1 TNFRSF10A
      • 4.2.1.1.1 Description of target
      • 4.2.1.1.2 Drugs in development
    • 4.2.1.2 TNFRSF10B
      • 4.2.1.2.1 Description of target
      • 4.2.1.2.2 Drugs in development
    • 4.2.1.3 TNFSF10
      • 4.2.1.3.1 Description of target
      • 4.2.1.3.2 Drugs in development
    • 4.2.1.4 FAS
      • 4.2.1.4.1 Description of target
      • 4.2.1.4.2 Drugs in development
    • 4.2.1.5 FASLG
      • 4.2.1.5.1 Description of target
      • 4.2.1.5.2 Drugs in development
    • 4.2.1.6 TNFRSF1A
      • 4.2.1.6.1 Description of target
      • 4.2.1.6.2 Drugs in development
  • 4.2.2 Caspases
    • 4.2.2.1 CASP9
      • 4.2.2.1.1 Description of target
      • 4.2.2.1.2 Drugs in development
    • 4.2.2.2 CASP3
      • 4.2.2.2.1 Description of target
      • 4.2.2.2.2 Drugs in development
  • 4.2.3 BCL2 family
    • 4.2.3.1 BCL2
      • 4.2.3.1.1 Description of target
      • 4.2.3.1.2 Drugs in development
    • 4.2.3.2 BCL2L1
      • 4.2.3.2.1 Description of target
      • 4.2.3.2.2 Drugs in development
    • 4.2.3.3 MCL1
      • 4.2.3.3.1 Description of target
      • 4.2.3.3.2 Drugs in development
    • 4.2.3.4 BAD
      • 4.2.3.4.1 Description of target
      • 4.2.3.4.2 Drugs in development
  • 4.2.4 IAPs and regulators
    • 4.2.4.1 XIAP
      • 4.2.4.1.1 Description of target
      • 4.2.4.1.2 Drugs in development
    • 4.2.4.2 BIRC3
      • 4.2.4.2.1 Description of target
      • 4.2.4.2.2 Drugs in development
    • 4.2.4.3 BIRC5
      • 4.2.4.3.1 Description of target
      • 4.2.4.3.2 Drugs in development
    • 4.2.4.4 DIABLO
      • 4.2.4.4.1 Description of target
      • 4.2.4.4.2 Drugs in development
    • 4.2.4.5 CFLAR
      • 4.2.4.5.1 Description of target
      • 4.2.4.5.2 Drugs in development
  • 4.2.5 Transcription factors and regulators
    • 4.2.5.1 NFKB1
      • 4.2.5.1.1 Description of target
      • 4.2.5.1.2 Drugs in development
    • 4.2.5.2 TP53
      • 4.2.5.2.1 Description of target
      • 4.2.5.2.2 Drugs in development
    • 4.2.5.3 HDM2
      • 4.2.5.3.1 Description of target
      • 4.2.5.3.2 Drugs in development
    • 4.2.5.4 STAT3
      • 4.2.5.4.1 Description of target
      • 4.2.5.4.2 Drugs in development
  • 4.2.6 Kinases in the PI3K/AKT pathway
    • 4.2.6.1 PIK3CA/PIK3CD/PIK3CG
      • 4.2.6.1.1 Description of target
      • 4.2.6.1.2 Drugs in development
    • 4.2.6.2 AKT1
      • 4.2.6.2.1 Description of target
      • 4.2.6.2.2 Drugs in development
    • 4.2.6.3 BTK
      • 4.2.6.3.1 Description of target
      • 4.2.6.3.2 Drugs in development
    • 4.2.6.4 PRKD1
      • 4.2.6.4.1 Description of target
      • 4.2.6.4.2 Drugs in development
  • 4.2.7 Histone deacetylases
    • 4.2.7.1 HDAC (1-5, -7, -8, and -11)
      • 4.2.7.1.1 Description of target
      • 4.2.7.1.2 Drugs in development
  • 4.2.8 Other targets
    • 4.2.8.1 IL24
    • 4.2.8.2 AIFM1
    • 4.2.8.3 RLN1
• 4.3 Proteasome inhibitors
• 4.4 HSP inhibitors

Chapter 5 Other apoptosis modulators in development

• 5.0 Chapter summary
• 5.1 CNS diseases
  • 5.1.1 Apoptosis agents in development
    • 5.1.1.1 Apoptosis antagonists
    • 5.1.1.2 Apoptosis agonists
• 5.2 Chronic inflammation and autoimmunity
  • 5.2.1 Apoptosis agents in development
    • 5.2.1.1 Apoptosis agonists
    • 5.2.1.2 Apoptosis antagonists
• 5.3 Other apoptosis agents in development

Chapter 6 Commercial Outlook: Patent and Market Analysis

• 6.0 Chapter Summary
• 6.1 Patent Analysis
  • 6.1.1 Preamble
  • 6.1.2 Uses of Patent Information
  • 6.1.3 The Apoptosis Patent Dataset
  • 6.1.4 Apoptosis Patents by Filing and Publication Years
  • 6.1.5 Apoptosis Patents by Leading Assignees
  • 6.1.6 Focus on Cytovia / Maxim / EpiCept
  • 6.1.7 Apoptosis Patents by Forward Citations
  • 6.1.8 Apoptosis Patents by Activity
• 6.2 Market Analysis
  • 6.2.1 Preamble
  • 6.2.2 Cancer
    • 6.2.2.1 Disease burden
    • 6.2.2.2 Anticancer drug landscape
  • 6.2.3 Non-cancer apoptosis modulators
  • 6.2.4 World pharmaceutical market
  • 6.2.5 Market outlook for apoptotic drugs
    • 6.2.5.1 Drug and Target Types
    • 6.2.5.2 Focus on Velcade (bortezomib)
    • 6.2.5.3 Focus on Gendicine
    • 6.2.5.4 Direct apoptogens
    • 6.2.5.5 Indirect apoptogens

Chapter 7 Trends and opportunities

• 7.0 Chapter summary
• 7.1 Apoptosis modulation offers varied opportunities
• 7.2 New directions in cancer drug development
• 7.3 Combinatorial approaches to cancer drug resistance
• 7.4 Focus on apoptosis-resistant cancer stem cells
• 7.5 Key role for biomarkers of apoptosis in cancer
• 7.6 Prospects for apoptosis modulators in other areas

Appendix 1 Abbreviations and Acronyms

• A1.1 Key gene targets for apoptotic modulation
• A1.2 Other scientific/medical terms
• A1.3 Institutions

Appendix 2 Research Methodology

Appendix 3 List of Tables and Figures

List of Tables and Figures

• Figure 1.1 Apoptotic pathways
• Table 1.1 Genes involved in apoptotic processes or signalling pathways (according to the PANTHER database)
• Figure 1.2 Apoptotic genes by molecular function
• Table 1.2 Apoptosis pipeline audit: Pharmacology
• Table 1.3 Apoptosis pipeline audit: Indications
• Table 1.4 Apoptosis pipeline audit: Originating companies
• Table 1.5 Apoptosis pipeline audit: Development status
• Table 1.6 Apoptosis pipeline audit: Molecular targets
• Figure 1.3 Apoptosis drug target landscape
• Table 1.7 Apoptosis pipeline audit: Type of agent
• Table 3.1Anticancer agents in development with apoptotic effects by therapy
• Table 3.1b Anticancer agents in development with apoptotic effects by status
• Table 4.1 Anticancer agents in development with PANTHER-classified apoptotic targets by status
• Table 4.2 TNF family and death receptor agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.3 Caspase agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.4 BCL2 family agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.5 IAP and regulator agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.6 Transcription factor and regulator agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.7 PI3K/AKT kinase agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.8 Histone deacetylase agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.9 Other agents in anticancer development with PANTHER-classified apoptotic targets
• Table 4.10 Overview of proteasome inhibitors (PIs) by status
• Table 4.11 Overview of heat shock protein (HSP) inhibitors by status
• Table 5.1Non-cancer agents in development with apoptosis-modulating effects by therapy type
• Table 5.1b Non-cancer agents in development with apoptosis-modulating effects by status
• Table 5.2 TNF-related agents in development for the treatment of inflammation/autoimmunity
• Table 6.1 Apoptosis Patents by Filing and Publication Years
• Table 6.2 Leading Assignees for WIPO Patent Applications
• Table 6.3 Leading Assignees for US Published Patent Applications
• Table 6.4 Leading Assignees for Granted US Patents
• Table 6.5 Assignees with >6 Apoptosis Filings in both the US and WIPO
• Table 6.6 The 25 Most Frequently Cited Apoptosis Patents
• Table 6.7 Apoptosis Patent Activity among 10 Leading Assignees
• Table 6.8 Apoptosis Patent Activity Across the Entire Dataset
• Table 6.9 Cancer incidence and mortality for the regions of the world
• Table 6.10 The most common cancers worldwide
• Table 6.11 Global Pharma Market by Region in 2008 and 2013 ($USM)
• Table 6.12 Global Pharma Market by Application in 2008 and 2013 ($USM)
• Table 6.13 Apoptosis Market by Application in 2008 and 2013 ($USM)
• Table 6.14 Apoptosis Market by Region in 2008 and 2013 ($USM)