Preclinical Cancer Therapeutics 2007

Summary

Preclinical Cancer Therapeutics 2007: Decoding Next Generation Drug Targets for Market Success is a unique and unrivalled 367-page report analysing the performance of numerous important early stage oncology drug candidates, assessing their market viability based on preclinical scientific studies and expert opinion. In the report, analysts decode the necessary parameters of market success for novel and next-generation drug targets. Through their diligent market research and academic insight, founded on years of experience of directing a preclinical research facility for the assessment of drug targets for solid tumours, the authors identify which oncology classes and products are most suited for regulatory approval and commercial success from those that may not fare as well in the global marketplace. The report represents an essential intelligence tool for deciphering capital risk and investment in oncology therapeutics whilst also enabling important decision-making with regard to research and development programmes and strategies, regulatory issues, and marketing challenges. Furthermore, market estimations for drug classes are provided revealing those preclinical and clinical phase compounds that are most likely to succeed in the market and become high-revenue therapeutics for their developers.

Contents

CHAPTER 1. PRECLINICAL CHALLENGES IN THE DEVELOPMENT OF NEW PHARMACOLOGICAL AGENTS TO TREAT CANCER

1.1 Tumour Biology: Oncogenes and Tumour Suppressor Genes
1.2 Genomic Instability and Neoplastic Transformation
1.3 Mechanisms of Drug Resistance
1.4 Identification of Appropriate Molecular/Cancer Targets for Research and Development 34
1.4.1 DNA Binding Targets
1.4.2 Oncogenes and Tumour Suppressor Genes as Targets
1.4.3 Receptor Kinase Pathways as Targets
1.4.4 Hormonal Receptor Targets
1.4.5 Invasion, Metastasis and Angiogenesis Pathways as Targets
1.4.6 Immunological Targets
1.4.7 Methods for the Identification of Genes and Proteins of Interest
1.5 Current Models of Successful New Cancer Treatment Approaches
1.6 Limitations to Current Therapeutic Approaches

CHAPTER 2. TOOLS FOR PRECLINICAL DRUG DEVELOPMENT

2.1 Preclinical Drug Discovery Approaches
2.1.1 Tumour Targeted Approaches: General Considerations
2.1.2 Gene Targeted Therapeutic Approaches
2.1.2.1 Small Molecule Inhibitors
2.1.2.2 Inhibitory RNAs
2.1.2.3 Nanoparticle Technology
2.1.2.4 Immunotherapy: Human Monoclonal Antibodies
2.1.2.5 Recombinant Genetically Engineered Therapeutic Viruses
2.1.3 Biomarkers
2.1.4 Sources of Potential Anticancer Agents for Preclinical Assessment: Non-Gene Targeted Approaches
2.1.5 Medicinal Chemistry: Role in Drug Discovery and Preclinical Therapeutic Assessment
2.2 Preclinical Assessment Tools: General Parameters of Preclinical Response
2.2.1 Preclinical Assessment: Lead Drug Candidate Selection Process
2.2.2 Primary and Secondary Screens: Lead Optimisation
2.3 Types of Preclinical Assessment Models
2.3.1 In Vitro Cell Culture Assays
2.3.2 Biochemical and Histological Methods Used for In-Vitro Assessment
2.3.3 In Vivo Assessment Models
2.3.3.1 In Vivo Preclinical Assessment: Parameters of Preclinical Response
2.4 Imaging Tools for Preclinical Assessment
2.4.1 Tumour Imaging
2.4.2 Imaging Technologies: Preclinical Therapeutic Applications
2.4.3 Pharmacodynamic Applications of Imaging Technologies
2.5 Evaluation of Potential Predictive Clinical Value of Preclinical Assessment Tools

CHAPTER 3. CANCER IMMUNOTHERAPY

3.1 Preclinical Approaches to Active Immunotherapy: General Considerations
3.2 Active Immunotherapy Protocols in Preclinical Development
3.3 Therapeutic Cancer Vaccines in Preclinical Development
3.3.1 Individualised Patient Tumour Vaccines
3.3.2 Therapeutic Virus Vaccines
3.3.3 Protein/Peptide Cancer Vaccines
3.3.4 Dendritic Cell Vaccines
3.4 Artificial Immunostimulatory Antibodies
3.5 Novel Antigenic Tumour Targets in Preclinical Drug Development
3.5.1 Telomerase
3.5.2 Tumour Stem Cell Targets in Preclinical Development
3.5.3 Immunostimulatory Cytokine Therapeutics in Preclinical Development
3.6 Preclinical Approaches to Passive Immunotherapy
3.6.1 Monoclonal Antibody Therapeutics
3.6.2 Mouse Monoclonal Antibodies
3.6.3 Humanised and Fully Human Monoclonal Antibodies
3.6.3.1 Selected Companies Developing Preclinical/Early Clinical Monoclonal Antibody Cancer Therapeutics
3.7 Other Antigen-Targeted Therapies: Significant Highlights
3.8 Genetically Engineered Cytolytic Viruses - 'Smart Viruses'
3.9 Current Challenges to the Development of Effective Immotherapeutic Approaches to Cancer

CHAPTER 4. TARGETED CANCER THERAPEUTICS: SMALL MOLECULE INHIBITORS IN PRECLINICAL DEVELOPMENT

4.1 Strategic Development of Novel Anticancer Agents
4.2 Major Cancer Pathway Sources of Small Molecule Therapeutic Targets: PTEN/PI3K/Akt
4.3 RAS Activated Cell Proliferation Pathway: Important Therapeutic Targets
4.4 Small Molecule Therapeutic Targets: Wnt/Beta-Catenin Pathway
4.5 Other Dysregulated Cell Processes: Potential Therapeutic Interactions
4.5.1 Sonic Hedgehog Pathway
4.5.2 Transforming Growth Factor-Beta
4.5.3 Ubiquitin Proteasome Pathway Targets
4.5.4 Additional Kinase Inhibitors in Preclinical Development
4.5.4.1 Small Molecule Protein Tyrosine Kinase Inhibitors
4.5.4.2 Serine/Threonine Kinase Inhibitors
4.5.5 Small Molecule Inhibitors of Angiogenesis in Preclinical Development
4.5.6 Small Molecule Inhibitors of Heat Shock Proteins in Preclinical Development
4.5.7 Small Molecule Immunotherapeutics
4.6 Future Challenges to the Development of Small Molecule Cancer Therapeutics

CHAPTER 5. HORMONAL AGENTS AS THERAPEUTIC ONCOLOGYTARGETS

5.1 The Steroid Receptor Family
5.1.1 Tamoxifen as an Exemplary Clinical Compound in Current Use
5.1.2 Challenges to Current Clinical Treatment Approaches
5.1.3 The Steroid Superfamily of Receptors
5.1.3.1 Oestrogen Receptor as a Therapeutic Target
5.1.3.2 Selective Oestrogen Receptor Modulators
5.1.3.3 Aromatase Inhibitors
5.1.3.4 The Progesterone Receptor as a Therapeutic Target
5.1.3.5 The Androgen Receptor as a Therapeutic Target
5.1.3.6 Retinoic Acid Receptors and Retinoid X Receptors as Therapeutic Targets
5.1.3.7 Peroxisome Proliferator Activated Receptor as a Therapeutic Target
5.2 Summary of Hormonal Agents in Preclinical Trials

CHAPTER 6. PRECLINICAL ANGIOGENIC CANCER TARGETS

6.1 Angiogenesis Associated with Malignancies
6.2 Characteristics of Tumour Vasculature
6.3 Pro-angiogenic Molecules as Targets
6.3.1 Fibroblast Growth Factor
6.3.2 Vascular Endothelial Growth Factor
6.3.3 Platelet-Derived Growth Factor
6.3.4 Epidermal Growth Factor, Transforming Growth Factor-Alpha, and Epidermal Growth Factor Receptor
6.3.5 Tumour Necrosis Factor-Alpha
6.3.6 Transforming Growth Factor-Beta
6.3.7 Hypoxia-Inducible Factor-1
6.3.8 Angiogenin
6.3.9 Angiopoietin
6.4 Endogenous Inhibitors of Angiogenesis
6.4.1 Endogenous Angiogenesis Inhibitors Derived from Matrix
6.4.1.1 Arresten
6.4.1.2 Canstatin
6.4.1.3 Endostatin
6.4.1.4 Thrombospondin
6.4.1.5 Tumstatin
6.4.1.6 Endorepellin
6.4.2 Endogenous Angiogenesis Inhibitors of Nonmatrix Origin
6.4.2.1 Angiostatin
6.4.2.2 Interferons
6.4.2.3 Interleukins
6.4.2.4 Platelet Factor-4
6.4.2.5 16kDa Prolactin Fragment (16K PRL)
6.4.2.6 Tissue Inhibitors of Matrix Metalloproteinases
6.4.2.7 Troponin I
6.4.2.8 Vasostatin
6.5 Miscellaneous Angiogenesis Targets
6.5.1 Copper
6.5.2 Calcium Channel Modulators
6.6 Monoclonal Antibodies and Angiogenesis
6.6.1 Mechanism of Action
6.6.2 Challenges Encountered in the Use of Monoclonal Antibody Therapy
6.7 Receptor Tyrosine Kinases as Potential Cancer Therapeutic Targets
6.8 Viral Vectors/Gene Therapy Approaches
6.9 Small Molecule Inhibitors
6.10 Preclinical Angiogenesis Agents by Drug Target

CHAPTER 7. PRECLINICAL PROSPECTS FOR HAEMATOPOETIC CANCERS

7.1 Chemotherapy: Historical Perspectives and Treatment Milestones
7.2 The Leukaemias: Overview
7.2.1 Acute Myeloid Leukaemia
7.2.2 Chronic Myeloid Leukaemia
7.2.3 Acute Lymphoblastic Leukaemia
7.2.3.1 Paediatric Leukaemias
7.2.3.2 Acute Lymphoblastic Leukaemia - Adult
7.2.4 Chronic Lymphocytic Leukaemia
7.3 The Lymphomas
7.3.1 Hodgkin's Disease
7.3.2 NonHodgkin's Lymphoma
7.3.2.1 Diffuse Large B-Cell Lymphoma
7.3.2.2 Follicular Lymphoma
7.3.2.3 Burkitt's Lymphoma
7.3.3 Current Treatment Regimens for Lymphoma
7.4 Genes Linked to Leukaemia and Lymphoma: Basis for Rational Drug Design
7.4.1 Genetic Mechanisms Implicated in the Genesis of Leukaemias and Lymphomas: New Paradigms
7.4.1.1 Genetic Origins of Acute Myeloid Leukaemia
7.4.1.2 Genetic Origins of Chronic Myeloid Leukaemia
7.4.1.3 Genetics Origins of Acute Lymphoblastic Leukaemia
7.4.1.4 Genetic Origins of Chronic Lymphocytic Leukaemia
7.4.1.5 Genetics and Other Types of Leukaemia
7.4.2 Genetic Origins of Lymphoma
7.4.2.1 B-Cell NonHodgkin's Lymphoma/Diffuse Large B-Cell Lymphoma
7.4.2.2 Follicular NonHodgkin's Lymphoma
7.5 New Treatment Approaches to Leukaemia and Lymphoma in Preclinical Development
7.5.1 Promising Agents for Acute Myeloid Leukaemia
7.5.2 Promising Preclinical Agents for Chronic Myeloid Leukaemia
7.5.3 Promising Preclinical Agents for Acute Lymphoblastic Leukaemia
7.5.4 Promising Preclinical Agents for Chronic Lymphocytic Leukaemia
7.5.5 Promising Treatment Approaches with Potential Broad-Spectrum Anti-Leukaemic Activity
7.5.6 Promising Treatment Approaches in Development for Other Leukaemias

Chapter 8. PRECLINICAL APPROACHES TO THE TREATMENT OF SOLID TUMOUR MALIGNANCIES

8.1 General Therapeutic Parameters of Solid Tumour Malignancies
8.2 Solid Tumour Biology: Implications for Preclinical Therapeutic Approaches
8.3 Chemotherapy Drugs in Preclinical/Early Stage Development with Broad Spectrum Applications for the Treatment of Solid Tumour Malignancies
8.4 Recent Advances in Solid Tumour Immunotherapy
8.5 Novel Genes Implicated in Solid Tumour Malignancies
8.6 Important Advances in Preclinical Therapeutics for the Most Common Solid Tmour Malignancies
8.6.1 Brain Tumours
8.6.1.1 Important Recent Preclinical Research Findings
8.6.2 Breast Cancer
8.6.2.1 Important Recent Preclinical Research Findings
8.6.3 Colon Cancer
8.6.3.1 Important Recent Preclinical Research Findings
8.6.4 Lung Cancer
8.6.4.1 Important Recent Preclinical Research Findings
8.6.5 Melanoma
8.6.5.1 Important Recent Preclinical Research Findings
8.6.6 Ovarian Cancer
8.6.6.1 Important Recent Preclinical Research Findings
8.6.7 Prostate Cancer
8.6.7.1 Important Recent Preclinical Research Findings
8.6.8 Urinary Tract Cancers
8.6.8.1 Important Recent Preclinical Research Findings

CHAPTER 9. MARKET OUTLOOK FOR THE MOST PROMISING ANTICANCER DRUGS CURRENTLY IN PRECLINICAL/EARLY STAGE CLINICAL DEVELOPMENT

9.1 Market Assessment for Next Generation Anticancer Therapeutics
9.2 The Global Market Value for Oncology Therapeutics
9.2.1 Best-Selling Oncology Products
9.2.1.1 Leading Multinational Companies and Cancer Drugs
9.3 Research and Market Analysis of the Most Promising Anticancer Agents in Late Stage Preclinical/Early Clinical Stage Development
9.4 Market Outlook for Most Promising Pipeline Oncology Products in Major Therapeutic Categories
9.4.1 Market Outlook for Angiogenesis Inhibitors
9.4.2 Market Outlook for Novel Drug Delivery Formulations
9.4.3 Market Outlook for Targeted Therapeutics
9.4.3.1 Aurora Kinase Inhibitors
9.4.3.2 Growth Factor Receptor Inhibitors
9.4.3.3 Hormonal Therapies
9.4.3.4 Histone Deacetylase Inhibitors
9.4.4 Market Outlook for Nanotechnology Products
9.4.5 Market Outlook for Monoclonal Antibodies
9.4.6 Market Outlook for Second-Generation Drugs
9.4.7 Market Outlook for Promising Anticancer Drugs: Concluding Thoughts

BIBLIOGRAPHIC SOURCES

LIST OF TABLES

Table 1.1 Oncogenes and the Types of Cancers Resulting from Their Activation
Table 1.2 Tumour Suppressor Genes and Cancers that Result from Their Inactivation
Table 1.3 Oncogenes and Tumour Suppressor Genes and the Various Proteins Encoded
Table 2.1 Most Common Preclinical Endpoints Used to Assess Therapeutic Efficacy and Safety
Table 2.2 Comparative Asessment of Imaging Modalities Used to Evaluate In Vivo Pre-clinical Tumour Responses.
Table 3.1 Summary of Individualised Therapeutic Cancer Vaccines in Preclinical/Early Stage Clinical Development
Table 3.2 Tumour Antigen Targets in Preclinical Development
Table 3.3 Genetically Engineered Therapeutic Viruses in Preclinical Development
Table 4.1 Small Molecule Pathway Targeted Inhibitors in Development
Table 5.1 Effects of Selective Oestrogen Receptor Modulators (SERMs) on Various Tissue Types
Table 5.2 Tissues that Express Oestrogen Receptor
Table 5.3 Androgens: Sites of Production and Functions
Table 5.4 Summary of Best Potential Approaches to Steroid Receptor Mediated Malignant Diseases
Table 5.5 Key Advantages and Disadvantages of Oestrogen Receptors as Chemo-therapeutic Targets
Table 5.6 Key Advantages and Disadvantages of Androgen Receptors as Chemo-therapeutic Targets
Table 5.7 Key Advantages and Disadvantages of Retinoid X Receptors and Peroxisome
Proliferator Activator Receptors as Chemotherapeutic Targets
Table 5.8 Key Advantages and Disadvantages of Progesterone Receptors as Chemotherapeutic Targets
Table 6.1 Key Physiological Events in the Activation and Resolution Phases of Angiogenesis
Table 6.2 Positive and Negative Regulators of Angiogenesis
Table 6.3 Summary of Preclinical Anticancer Agents by Drug Targets
Table 6.4 Summary of Preclinical Anticancer Agents by Mechanism(s) of Action
Table 7.1 Subtypes of Acute Myeloid Leukaemia
Table 7.2 Revised European and American Lymphoma (REAL) Classification of Leukaemias and Lymphomas
Table 7.3 Genes Implicated in Human Leukaemias
Table 7.4 Genes Implicated in Acute Myeloid Leukaemia: Potential Therapeutic Targets for Preclinical Development
Table 7.5 Genes Identified in Acute Lymphoblastic Leukaemia: Potential Therapeutic Targets for Preclinical Development
Table 7.6 Genes Identified in Chronic Lymphocytic Leukaemia: Potential Therapeutic Targets for Preclinical Development
Table 7.7 Genes Identified in NonHodgkin's Lymphoma: Potential Therapeutic Targets for Preclinical Development
Table 7.8 Novel Therapeutic Agents in Development for Acute Myeloid Leukaemia
Table 7.9 Promising Therapeutic Agents for Chronic Myeloid Leukaemia in Development
Table 7.10 Novel Therapeutic Agents for Acute and Chronic Lymphocytic Leukaemia in Development
Table 7.11 Novel Treatment Approaches in Development with Broad Spectrum Anti-Leukaemic Activity
Table 7.12 Promising New Treatment Approaches in Development for Lymphoma
Table 7.13 Promising Therapeutic Agents for the Treatment of Haematological Malignancies in Preclinical Development
Table 8.1 Promising Agents with Broad Spectrum Therapeutic Applications in Preclinical/ Early Clinical Stage Development
Table 8.2 Important Recently Identified Genes Implicated in Solid Tumour Malignancies
Table 8.3 Major Preclinical Developments in Brain Cancer Therapeutics
Table 8.4 Major Preclinical Developments in Breast Cancer Therapeutics
Table 8.5 Major Preclinical Developments in Colon Cancer Therapeutics
Table 8.6 Major Preclinical Developments in Lung Cancer Therapeutics
Table 8.7 Major Preclinical Developments in Melanoma Therapeutics
Table 8.8 Major Preclinical Developments in Ovarian Cancer Therapeutics
Table 8.9 Major Preclinical Developments in Prostate Cancer Therapeutics
Table 8.10 Promising Agents in Preclinal Development for the Treatment of Solid Tumour Malignancies
Table 9.1 Global Portfolio Revenues and Market Share of Cancer Drugs, 2005 (US$m)
Table 9.2 Summary of Promising Cancer Therapeutics in Preclinical Development by Drug Class
Table 9.3 Summary of Promising Cancer Therapeutics in Phase-I Trials by Drug Class
Table 9.4 Summary of Promising Cancer Therapeutics in Phase-II/II Trials by Drug Class
Table 9.5 Summary of Promising Novel Combination Chemotherapy Approaches in
Clinical Trials

LIST OF FIGURES

Figure 1.1 The Cell Cycle
Figure 1.2 DNA Binding Agents used as Chemotherapeutic Interventions in Cancer
Figure 1.3 Growth Factors that Activate Angiogenesis
Figure 1.4 Immunological Agents
Figure 2.1 General Approach to New Drug Development
Figure 2.2 General Approaches to Drug Discovery: Random Versus Rational Drug Design
Figure 2.3 General Categories of Biotechnology Tools Used in Targeted Drug Discovery
Figure 2.4 General Categories of Drug Discovery Tools Used in Targeted Versus Non-Targeted Approaches
Figure 2.5 General Categories of Preclinical Assessment Parameters
Figure 2.6 In Vitro and In Vivo Preclinical Therapeutic Assessment Models
Figure 2.7 Goals of Preclinical Drug Discovery and Assessment Protocols
Figure 3.1 General Areas of Preclinical Cancer Immunotherapy Research
Figure 3.2 Summary of Active Immunotherapy Approaches
Figure 3.3 General Strategy for Producing Recombinant Therapeutic Viral Vaccines
Figure 3.4 Summary of Passive Immunotherapy Approaches to Cancer
Figure 3.5 Construction of Human Monoclonal Antibodies Using the Method of Phage Display
Figure 4.1 General Cell Pathways that Contain Oncogenic Targets for Small Molecule Therapeutic Inhibitors
Figure 4.2. Key Elements in PTEN/PI3K/Akt Signal Transduction Pathway
Figure 4.3 Key Elements in the Ras/Raf/Mek/ERK Signal Transduction Cascade
Figure 4.4 Key Elements of the Wnt/APC/Beta-Catenin Signal Transduction Pathway
Figure 5.1 Steroid Derivatives of Cholesterol
Figure 5.2 Receptors of the Steroid Superfamily Associated with Malignant Diseases
Figure 5.3 Intermediates in the Androgen-Oestrogen Conversion Pathway
Figure 5.4 Intermediates in the Cholesterol-Progesterone Pathway
Figure 6.1 Pro-Angiogenic Molecules Implicated in Cancer Biology
Figure 6.2 Endogenous Angiogenesis Inhibitors Derived from Matrix
Figure 6.3 Endogenous Angiogenesis Inhibitors of Nonmatrix Origin
Figure 6.4 Key Steps in the Conversion of Plasminogen to Angiostatin
Figure 8.1 General Biological Parameters of Solid Tumours Relevant to Therapeutic Design
Figure 9.1 Drug Development Parameters Critical to Market Success
Figure 9.2 Growth Rates of Best-Selling Cancer Drugs, 2005
Figure 9.3 Best-Selling Cancer Drugs, 2005 (US$m)
Figure 9.4 Market Share of the Top 10 Cancer Drugs, 2005 & 2010
Figure 9.5 Leading Oncology Companies by Chemotherapy Portfolio Revenues, 2005 (US$m)