Cancer Drug Resistance

Chapter 1 Cancer Drug Resistance

This chapter gives a brief introduction to cancer drug resistance and identifies areas covered later in the report.
1.1 Introduction
1.2 Resistance Mechanisms
1.3 Innate Resistance
1.4 Acquired Resistance
1.5 Cancer Stem Cells
1.6 Resistance Biomarkers
Chapter 1 References

Chapter 2 Cancer Resistance and the Current Drug pipeline

This chapter presents a comprehensive review of resistance mechanisms and/or resistance-associated changes at the gene or protein levels in cancer cells. These have been identified in a number of cancers and all classes of currently approved anticancer drugs have been included as part of this review. In total, this represents around 60 different anticancer drug classes (based on their general pharmacological mechanisms of action) and includes approximately 190 individual cancer drugs. This chapter also presents the current cancer drug pipeline (preclinical through to phase III) by agent, pharmacological mechanism and development phase and identifies new drug types (i.e. based on new general pharmacological mechanisms) being developed to target cancer in new and more effective ways.
2.1 Cancer Drugs
2.2 Pharmacological Mechanisms
2.3 New Pharmacological Mechanisms
2.4 Launched Anti-Cancer Drugs
2.4.1 Adenosine Deaminase Inhibitors
2.4.2 Androgen antagonists
2.4.3 Angiogenesis inhibitors
2.4.4 Antimetabolite & Antifolates
2.4.5 Aromatase inhibitors
2.4.6 Bcl2 antagonists
2.4.7 Bcr-Abl inhibitors
2.4.8 Beta tubulin antagonists
2.4.9 B-raf kinase inhibitors
2.4.10 Cancer cell lysis
2.4.11 CD20 Antagonists
2.4.12 Cyclin G1 inhibitors
2.4.13 Cysteine Protease Stimulants
2.4.14 DNA antagonists
2.4.15 DNA synthesis inhibitors
2.4.16 DNA topoisomerase ATP hydrolysing inhibitors
2.4.17 DNA topoisomerase inhibitors
2.4.18 Endothelial growth factor antagonists
2.4.19 Endothelial growth factor receptor kinase inhibitors
2.4.20 Epidermal growth factor receptor 2 antagonists
2.4.21 Epidermal Growth Factor Receptor Antagonists
2.4.22 ErbB-1 tyrosine kinase inhibitors
2.4.23 ErbB-2 tyrosine kinase inhibitors
2.4.24 Estrogen antagonists
2.4.25 Farnesyltransferase Inhibitors
2.4.26 Histone Deacetylase Inhibitors
2.4.27 Hypoxanthine Phosphoribosyltransferase Inhibitors
2.4.28 Immunostimulants
2.4.29 Interferons
2.4.30 Interferon Alpha 2 Agonists
2.4.31 Interferon Alpha 2A Agonists
2.4.32 Interferon Alpha 2b Agonists
2.4.33 The Interleukins
2.4.34 LHRH agonists
2.4.35 LHRH Antagonists
2.4.36 Lymphocyte Inhibitors
2.4.37 Membrane integrity antagonists
2.4.38 Microtubule disruptions
2.4.39 Microtubule Inhibitors
2.4.40 Microtubule stimulants
2.4.41 mTOR kinase inhibitors
2.4.42 p53 Stimulants
2.4.43 Proteasome Inhibitors
2.4.44 Radical Formation Agonists
2.4.45 Retinoic acid alpha receptor agonists
2.4.46 Retinoic Acid Receptor Agonists
2.4.47 Retinoid X alpha receptor agonists
2.4.48 Retinoid X Receptor Agonists
2.4.49 Ribonuclease Stimulants
2.4.50 RNA directed RNA Polymerase Stimulants
2.4.51 RNA Synthesis Inhibitors
2.4.52 Thymidylate Synthase Inhibitors
2.4.53 Tubulin Antagonists
2.4.54 Tumour Necrosis Factor Alpha Agonists
2.4.55 Drugs with Unidentified Pharmacological Activity
Chapter 2 References

Chapter 3 Drug Resistance and Cancer Stem Cells

Chapter 3 presents a review of Cancer Stem cells (CSCs), a subset of cancer cells in tumours that have been strongly implicated in cancer drug resistance. This chapter also includes proposed resistance mechanisms associated with CSCs, drug discovery strategies for the targeting of these cells, the current CSC-targeting drug development pipeline and the potential of these cells in cancer diagnostics.
3.1 Cancer Stem Cells
3.2 What are Cancer Stem Cells?
3.3 Different Cancers
3.4 Drug Resistance
3.5 Drug Discovery
3.5.1 EGFR/HER2 tyrosine kinase inhibitors
3.5.2 Proposed Migration of CSCs
3.5.3 The Stem Cell Niche
3.5.4 Metabotropic Receptors
3.5.5 Telomerase
3.5.6 Notch
3.5.7 Hedgehog and Wnt
3.5.8 Bmi-1 Gene
3.5.9 CSC-Targeting Viruses
3.5.10 Metastasis and Invasion
3.5.11 MicroRNAs
3.6 Clinical Development
3.7 Diagnostics
3.7.1 Circulating Tumour Cells
3.7.2 The Invasiveness Gene Signature
3.7.3 Hedgehog Activity
3.7.4 Microarrays
3.7.5 Sox2
3.7.6 Other
Chapter 3 References

Chapter 4 Cancer Resistance Biomarkers

Chapter 4 presents the findings on drug resistance-associated changes or resistance mechanisms described Chapter 2, as potential resistance biomarkers. Cell markers reported to characterise CSCs and to differentiate them from non-tumourigenic cancer cells, are also presented.
4.1 Cancer Resistance Biomarkers
4.2 Cancer Stem Cells Markers
Chapter 4 References

Chapter 5 Strategies to Combat Cancer Drug Resistance

Chapter 5 presents current developments and strategies designed to combat resistance to anticancer agents and includes pipeline drugs, novel drugs, drug combinations, multiple-targeting drugs, direct targeting and avoidance of resistance mechanisms, CSCs and other areas. This chapter includes a review of all phase III anticancer candidates.
5.1 Background
5.2 Novel Drugs
5.2.1 Drug Pipeline
5.2.2 Immunotherapy
5.2.3 Cancer Stem Cells
5.3 New Drug Combinations
5.4 Targeting Resistance Mechanisms
5.4.1 Transport Proteins
5.4.2 Current Anticancer Drugs
5.5 Avoiding Drug Resistance
5.5 Predictive Methods
Chapter 5 References

Chapter6 Discussion

Chapter 6 presents a discussion on the information and data presented in Chapters 1-5 of this report, focussing in particular on the practical steps being taken to combat resistance to cancer drugs.
6.1 Overview
6.2 Resistance Map
6.3 Drug Pipeline
6.4 Cancer Stem Cells
6.5 Resistance Biomarkers
6.6 Strategies to Combat Resistance
6.7 Opportunities
6.8 Speculative Comments

Tables

Table 2.1 (a-o) Launched anti-cancer drugs, showing compound, pharmacology and drug resistance mechanisms
Table 3.1 Development pipeline of csc-targeting candidate drug molecules
Table 4.1 (a-e) Cancer resistance biomarkers by cancer, associated drug and drug pharmacological class
Table 4.2 (a-b) Cancer stem cell markers (potential resistance biomarkers)
5.1 Immunotherapies in development (preclinical to phase III)
5.2 Development pipeline of csc-targeting candidate drug molecules
Table 5.3 (a-b) Substrates and inhibitors of ABC binding cassette transporters.
Cells could be selected in increasing concentrations of a cytotoxic drug, which
could result in the increased expression of a specific ABC transporter (see green boxes representing drug-gene pairs in which an ABC transporter was found to be overexpressed in cell lines selected for resistance to the respective drug). Resistant cells overexpressing a single ABC transporter often show characteristic cross-resistance to other, structurally unrelated, drugs (red boxes). The ability of ABC transporters to alter cell survival, drug transport and/or drug accumulation can be inhibited or altered by various modulators (yellow boxes). White boxes denote unexplored or absent drug-gene relationships (Source (Adapted From): Targeting Multidrug Resistance in Cancer, Gergely Szakacs, Jill K Patterson, Joseph A Ludwig, Catherine Booth-Genthe and Michael M Gottesman Nature Reviews (Drug Discovery), 200, Vol 5, 219-234)
Table 5.4 (a-b) Characteristics and results of completed and Phase III clinical trials with ABC transporter inhibitors (Source (Adapted From): Targeting Multidrug Resistance in Cancer, Gergely Szakacs, Jill K Patterson, Joseph A Ludwig, Catherine Booth-Genthe and Michael M Gottesman Nature Reviews (Drug Discovery), 200, Vol 5, 219-234)
Table 5.3 (a-c) Cellular and molecular mechanisms found to be associated with drug resistance of approved cancer drugs
Table 6.1 Examples of combinations of anticancer drugs used in the treatment of several common cancer
Table 6.2 (a-d) Resistance mechanisms reported for anticancer drugs. Drug class (i.e. pharmacological mechanisms) and an example of a drug in each class,
are indicated.

Figures

Figure 2.1a Cancer drugs (according to cancer type) in the drug development pipeline (pre-clinical to Phase III) or fully launched
Figure 2.1b Cancer drugs (according to cancer type) in the drug development pipeline (pre-clinical to Phase III) or fully launched.
Figure 2.2 Cancer drugs in the global drug development pipeline (pre-clinical to Phase III) or Registered/fully launched
Figure 2.3 Cancer drugs by the number of different pharmacological mechanisms in each phase considered individually.
Figure 2.4 Cancer drugs by the number of New pharmacological mechanisms in each phase.
Figure 5.1 Strategies for Combating Cancer Drug Resistance
Figure 5.2 Cancer drugs by the number of new pharmacological mechanisms in each drug development phase
Figure 5.3 Immunotherapies in development
(Preclinical to Phase III) or launched

Appendices

Appendix 1 (a-e) Pipeline candidate anticancer drugs and launched anticancer drugs and their associated pharmacological mechanisms (2000+ molecules)
Appendix 2 Pipeline anticancer drugs (preclinical-Phase III) with new pharmacological mechanisms of action (330+ molecules)