Abstract
Drug resistance is the single most important cause of cancer treatment failure
and carries a massive burden to patients, healthcare providers, drug
developers and society. It is estimated that Multidrug Resistance (MDR) plays
a major role in up to 50% of cancer cases. Today, most drug therapies involve
multiple agents, as it is almost universally the case that single drugs (or
single-target drugs) will encounter resistance.
Drug resistance presents some of the greatest challenges to the treatment and
eradication of cancer. There are many studies and reports on drug resistance
in cancer cells, but comparatively little is known about the underlying
mechanisms. This includes a comprehensive review of resistance-associated
changes and mechanisms for all approved cancer drugs (60 drug classes) and
Phase III candidates, as well as an examination of how developers are tackling
drug resistance using novel agents and new drug combinations. This report
looks at every general class of cancer drug in the pipeline or launched
(around 400, representing 2000+ agents) and has identified all new drug
classes from Preclinical through to Phase III, that will provide new
strategies to tackle resistance. The entire cancer drug development pipeline
is also tabulated, allowing the reader to compare current drug classes
alongside new classes coming through the pipeline. This report provides a
comprehensive and up-to-date review of cancer resistance today and the
strategies being developed to combat these mechanisms.
This new report includes i) A Global Resistance Map: a presentation and review
of resistance mechanisms or resistance-associated changes at the gene, protein
or functional level reported for currently approved cancer drugs, covering 60
general cancer drug classes and 190 agents ii) Drug Pipeline: a presentation
of the entire anticancer drug development pipeline (2000+ agents from approx.
400 general drug classes), from preclinical to launched, including mechanisms
of action of individual drugs iii) New Drug Mechanisms: new cancer agents in
the development pipeline (i.e. drug mechanisms not previously developed in any
previous drug development phase), representing 157, 56, 84 and 37 new drug
classes at preclinical, phase I, phase II and phase III, respectively iv)
Strategies to Combat Cancer Drug Resistance: including targeting, bypassing or
exploiting resistance mechanisms, current and new drug combinations and novel
drugs offering new ways to target drug resistance. v) Resistance Biomarkers: a
presentation of current findings at the gene and/or protein level for all
currently launched anticancer drugs, that offer potential resistance
biomarkers for drug discovery, diagnostics and therapy decisions.
Cancer Drug Resistance: Anticancer drugs fail to kill cancer cells for
a number of reasons. These include kinetic factors, where drugs fail to reach
tumours, are poorly absorbed or metabolically deactivated. Drug resistance
mechanisms are either innate, where they are intrinsic to the cancer or
acquired, which occurs due to adaptive changes in response to therapy and due
to the selection of survival phenotypes. Today, new drug combinations are
central to the strategy to combat resistance and this report estimates (from
trials in the US & UK) that 40-50% of current cancer drug trials involve
multiple drug combinations. These include combinations of established small
molecule drugs with others, with new agents or with immunotherapeutic
molecules.
Targeting Resistance Mechanisms: Advancing knowledge at the gene and
protein level in cancer cells is enabling scientists to better understand
interconnected pathways involved cell cycle control, cell signaling and cell
death and this is enabling viability-critical targets or target combinations
to be more readily identified. In developing new combination drug therapies, a
key goal is to identify targets that together represent an Achilles Heel to
the cell. For example, scientists have reported that BRCA1 or BRCA2 mutant
cells, which show defective DNA maintenance, are very sensitive to inhibitors
of another genome maintenance pathway. These studies showed that inhibitors of
the enzyme PARP (Poly(ADP-Ribose) polymerase) are able to kill cells that are
defective in BRCA1 or BRCA2 at very low concentrations, compared to normal
cancer cells. This illustrates the potential of targeting co-supportive or
co-dependent pathways. Resistance data (at the gene and protein level), cited
in this report, provides a comprehensive and detailed update of scientists'
findings on cancer drug resistance, to assist efforts to better understand and
target the associated mechanisms.
Further Information: This report also reviews all current phase III
anticancer drugs, focusing on novel drug classes that are creating interest in
their potential to combat drug resistance. This includes immunotherapeutic
drugs (500+ agents in development or launched), second-generation targeted
therapies (i.e. multi-target drugs; 15+ prominent candidates in development)
and other drug classes such as the NF-κB inhibitors (30+candidates in
development), heat shock protein inhibitors (40+ candidates in development),
HDAC inhibitors and many others. This report also includes an in-depth
discussion with Michael M. Gottesman M.D. (Head, Molecular Cell Genetics,
Multidrug Resistance Unit, Centre for Cancer Research, US National Cancer
Institute) and cites more than 260 References.
Table of Contents
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)
