Cancer Drug Resistance

Date: January 23, 2009
Pages: 235
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Publisher: Biopharm Reports
Report type: Strategic Report
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Cancer Drug Resistance
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.

This report gives a comprehensive review of resistance-associated changes and mechanisms for 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.

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- B 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.
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

CHAPTER 6 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 PAGE

Table 2.1 (a-o) Launched anti-cancer drugs, showing compound, pharmacology 41-55 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 85-89 drug pharmacological class
Table 4.2 (a-b) Cancer stem cell markers (potential resistance biomarkers) 90-91
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. 118-119
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 120-121 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 122-124 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 133-136 class (i.e. pharmacological mechanisms) and an example of a drug in each class, are indicated.

FIGURES PAGE

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 Report Contents and Sample Pages Cancer Drug Resistance, 2008 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 PAGE

Appendix 1 (a-e) Pipeline candidate anticancer drugs and launched anticancer drugs and their associated pharmacological mechanisms (2000+ molecules) 145-217
Appendix 2 Pipeline anticancer drugs (preclinical–Phase III) with new pharmacological mechanisms of action (330+ molecules) 218-229
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