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Preclinical Cancer Therapeutics 2007: Decoding Next Generation Drug Targets for Market Success

  • ID: 362286
  • Report
  • November 2006
  • 367 Pages
  • Spectra Intelligence
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This 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
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Contents List
List of Tables
List of Figures
List of Abbreviations
Executive Summary
Objectives of the Report
Research Methodology


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
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


2.1 Preclinical Drug Discovery Approaches
2.1.1 Tumour Targeted Approaches: General Considerations
2.1.2 Gene Targeted Therapeutic Approaches Small Molecule Inhibitors Inhibitory RNAs Nanoparticle Technology Immunotherapy: Human Monoclonal Antibodies 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 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


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 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


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 Small Molecule Protein Tyrosine Kinase Inhibitors 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


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 Oestrogen Receptor as a Therapeutic Target Selective Oestrogen Receptor Modulators Aromatase Inhibitors The Progesterone Receptor as a Therapeutic Target The Androgen Receptor as a Therapeutic Target Retinoic Acid Receptors and Retinoid X Receptors as Therapeutic Targets Peroxisome Proliferator Activated Receptor as a Therapeutic Target
5.2 Summary of Hormonal Agents in Preclinical Trials


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 Arresten Canstatin Endostatin Thrombospondin Tumstatin Endorepellin
6.4.2 Endogenous Angiogenesis Inhibitors of Nonmatrix Origin Angiostatin Interferons Interleukins Platelet Factor-4 16kDa Prolactin Fragment (16K PRL) Tissue Inhibitors of Matrix Metalloproteinases Troponin I 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


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 Paediatric Leukaemias 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 Diffuse Large B-Cell Lymphoma Follicular Lymphoma 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 Genetic Origins of Acute Myeloid Leukaemia Genetic Origins of Chronic Myeloid Leukaemia Genetics Origins of Acute Lymphoblastic Leukaemia Genetic Origins of Chronic Lymphocytic Leukaemia Genetics and Other Types of Leukaemia
7.4.2 Genetic Origins of Lymphoma B-Cell NonHodgkin’s Lymphoma/Diffuse Large B-Cell Lymphoma Follicular NonHodgkin’s Lymphoma
7.5 New Treatment Approaches to Leukaemia and Lymphoma in Preclinical
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


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 Tumour Malignancies
8.6.1 Brain Tumours Important Recent Preclinical Research Findings
8.6.2 Breast Cancer Important Recent Preclinical Research Findings
8.6.3 Colon Cancer Important Recent Preclinical Research Findings
8.6.4 Lung Cancer Important Recent Preclinical Research Findings
8.6.5 Melanoma Important Recent Preclinical Research Findings
8.6.6 Ovarian Cancer Important Recent Preclinical Research Findings
8.6.7 Prostate Cancer Important Recent Preclinical Research Findings
8.6.8 Urinary Tract Cancers Important Recent Preclinical Research Findings


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 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 Aurora Kinase Inhibitors Growth Factor Receptor Inhibitors Hormonal Therapies 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



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 Assessment 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 TherapeuticTargets 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


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)
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This report provides a unique, comprehensive view of the state-of-the-art of cancer therapeutics in preclinical research and development. It presents an encompassing view of the field of translational research as it relates to the latest pharmacological approaches to the treatment of cancer. Today, the path from ‘bench to bedside’ is not only fast-paced but also exciting. There are many new approaches and novel technologies applied to the development of new cancer treatments. The plethora of investigational cancer products currently in preclinical assessment is unprecedented in the history of medicine and warrants a thoughtful analysis of products that may change the market landscape for cancer therapies. Important advances in our understanding of the genetics and biology of cancer have become the focus of targeted therapeutic approaches and personalised medicines designed to target the ‘genetic signature’ of individual cancers. Most importantly, it is essential to evaluate the emerging therapeutic advances n regard to their potential for therapeutic efficacy in the treatment of specific types of cancer. Such analytical and predictive assessments provide an essential guide to future directions of preclinical therapeutic research and development approaches that may ultimately yield the most promising cancer approaches, failures, and the potential for commercial blockbusters in the oncology market.

In this report, Preclinical Cancer Therapeutics 2007: Decoding Next Generation Drug Targets for Market Success, the reader will be provided with a high-level expert analysis of the current challenging milieu for cancer research and drug development. Based on the review of recent preclinical and clinical data, top prospects for market success are identified through new oncology drug approaches and novel agents that are on-track for significant commercial prosperity.

Chapter 1 provides a comprehensive overview of tumour biology, oncogenetics, the mechanisms of neoplastic transformation and the role of various elements of malignancy as potential drug targets. The Chapter also discusses the current challenges to cancer research and drug development and reveals models of success for cancer therapies and in addition to the limitations of current therapeutic approaches.

Chapter 2 presents an overview of the novel tools of technology responsible for the vast expansion in the rate and novelty of pharmacological drug design in the treatment of cancer. Important themes covered in this chapter include rational drug design approaches, recombinant DNA technologies applied to drug discovery, and tumour-targeted approaches. Taken together, these therapeutic approaches and their associated technologies provide the core of current drug development trends and are the basis of future drug discovery and development. Each of these important drug discovery technologies is explored in detail, particularly as they relate to the development of new cancer medicines.

Cancer immunology is one of the most important areas of cancer biology as it impacts the genesis of cancer as well as many important therapeutic modalities. Chapter 3 provides an overview of our current state of understanding of the important immunological components of oncogenesis, particularly as they relate to the development of novel therapeutics for the treatment of many types of cancer. Of major importance is the monoclonal antibody technology that has emerged at the forefront of cancer therapeutic technologies and has produced such clinical successes as Herceptin and Avastin. In addition to a comprehensive review of the latest technologies and therapeutic advances in tumour immunotherapy, the chapter also provides an expert assessment of the development of preventive and genetically engineered therapeutic cancer vaccines.

Chapter 4 provides a comprehensive assessment of one of the most important areas of preclinical therapeutic cancer research - small molecule inhibitors, which target specific abnormal gene products and pathways in malignant cells. This exciting area of preclinical cancer research has produced one of the great therapeutic success stories of recent times, the introduction of Gleevec for the treatment of patients with chronic myeloid leukaemia. The success of this small molecule targeted therapeutic has ushered in a new era in the treatment of cancer and has turned a once fatal illness into a manageable disease. Most importantly, the drug’s introduction represents not an isolated discovery, but rather a new paradigm for the development of targeted cancer therapeutics. The Chapter discusses in-depth these important advances and the development of the ‘next generation’ small molecule inhibitors and their promise in the treatment of many diverse forms of cancer.

Hormonal anticancer therapeutics are introduced in Chapter 5 as a further important class of drug to successfully treat cancer. The steroid superfamily of receptors is discussed in detail in regard to their utility as next generation drug targets. Selective oestrogen receptor modulators, aromatase inhibitors, and androgen receptors, for example, are critically discussed with regard to their roles as promising anticancer therapeutics.

Angiogenesis is a critical mechanism in the neoplastic pathway and is importantly associated with malignancy. Chapter 6 discusses the molecular characteristics of tumour vasculature and the role of the pro-angiogenic elements in tumour survival and metastases. The Chapter further analyses the potential pro-angiogenic molecules that hold great promise as druggable targets based on current preclinical research and early phase drug development data. Molecules of interest include angiogenin, canstatin, growth factors, and receptor tyrosine kinases. The chapter also provides an assessment of the challenges encountered in monoclonal antibody drug development and gene therapy approaches to cancer.

Chapter 7 provides a comprehensive analysis of preclinical prospects for haematopoetic cancers. It highlights some of the most important recent developments initiated by the successful introduction of Gleevec for the treatment of chronic myelogenous leukaemia. The dramatic clinical success afforded by this targeted small molecule therapeutic has become a paradigm for the development of targeted therapeutic approaches to the treatment of cancer. This Chapter explores the research and development of next generation targeted therapeutics that expand on the successes of Gleevec and include therapeutics that are currently in development for the treatment of refractory
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