Targeting Cancer Stem Cells

Summary

Cancer Stem Cell (CSC) research has accelerated in the last two years and considerable efforts are now being made to identify drug molecules that selectively target and destroy these cells. Today, more than 50 developmental molecules or classes are being evaluated in the hope of targeting this subset of cancer cells. More than 40 companies and commercial groups are progressing these activities and around 20 drug-targeting strategies are being evaluated. Efforts are being made to target CSCs using novel single agents as well as combinations, based on new and established classes. This 2010 report gives a comprehensive update on current therapeutic and diagnostic development in this field, on the drug development pipeline and on the most promising research areas in CSC characterisation. New therapeutic and diagnostic opportunities in this field are also presented.


Drug Pipeline: Approximately 20 different strategies, which are described in this report, are being pursued in the hope of discovering ways of selectively targeting CSCs. Recently for example, at the CTRC-AACR San Antonio Breast Cancer Symposium in December 2009, data were presented on the targeting of chemotherapy-resistant breast CSCs with the Merck compound MK-0752, a gamma-secretase inhibitor that targets the Notch pathway. In a study involving 35 women with advanced breast cancer, biopsies revealed reduced numbers of breast CSCs. In this particular case, it was suggested that combination therapies involving agents that also target the Notch pathway (believed to be important in CSC renewal) may offer more powerful strategies for killing resistant CSC populations.

Cancer Diagnostics: CSCs are believed to be causally linked to the development and metastatic spread of cancer. If this is confirmed in the clinic, this will place CSCs at the heart of cancer diagnostics and biomarkers. Scientists have identified a number of surface proteins, such as CD44, CD133 and many others, that may have important utility in both of these areas. A number of intracellular markers found in CSCs may also have diagnostic utility. These developments are described in this report. For example, CD133 mRNA levels in peripheral blood, measured using RT-PCR, have been found to predict colon cancer recurrence. There is a need for new methodologies that isolate and characterise circulating tumour cells (CTCs) in the blood, and can be applied to CSCs. CTC technologies using the EpCam marker to isolate these cells are able to predict breast and colon cancer recurrence. The adaption of these techniques, based on specific CSC phenotypes, may provide sensitive new methods for identifying CSCs in the body. If this is achieved, it will have important implications in therapeutic decision-making and monitoring.

This 2010 report gives a comprehensive and up-to-date review of global R&D on CSCs, and strategies to target them. This includes around 40 companies or commercially based research organisations (including 27 SMEs and 8 international pharmaceutical companies) that are progressing drug discovery activities, including drug pipeline (pre-clinical to Phase III), discovery strategy, candidate molecules, drug targets, clinical trials and related areas.

Contents

Executive Summary

Chapter 1 Cancer Stem Cells
1.1 Summary
1.2 Introduction
1.3 Cancer Stem Cells
1.4 Different Cancers
1.5 Research and Development

Chapter 2 Research and Development
2.1 Summary
2.2 Background
2.3 Research
2.4 Drug Development Pipeline

Chapter 3 Discovery & Pipeline
3.1 Summary
3.2 Targeting CSCs
3.2.1 Resistance
3.2.2 The Stem Cell Niche
3.2.3 Salinomycin
3.2.4 Metabotropic Receptors
3.2.5 Telomerase
3.2.6 Notch
3.2.7 Hedgehog, Wnt and mTOR
3.2.8 Bmi-1 Gene
3.2.9 Viruses
3.2.10 Metastasis and Invasion
3.2.11 MicroRNAs
3.2.12 Interleukin-4
3.2.13 L1CAM
3.2.14 Thymosin beta4 (TB4)
3.2.15 EpCAM
3.2.16 Zoledronate
3.2.17 NK Cells
3.2.18 ALDH1 and CD44(+)/CD24(-)
3.2.19 Caffeine Sensitivity
3.2.20 Metformin
3.2.21 Hypoxia/Cancer Micro Environment
3.2.22 ABCB5
3.2.23 Arachidonate 5-lipoxygenase (5-LO) gene (Alox5)
3.2.24 CSC Markers
3.3 Drug Pipeline
3.3.1 Notch
3.3.2 Epcam
3.3.3 Hedgehog
3.3.4 Lactadherin
3.3.5 Telomerase
3.3.6 EGFR/HER-2
3.3.7 CD133
3.3.8 Adenovirus
3.3.9 Oct4
3.3.10 DLL4
3.3.11 CD44 and CD9
3.3.12 uPAR
3.3.13 The PI3K/Akt pathway
3.3.14 Apoptosis
3.3.15 Reovirus
3.3.16 PI-K3
3.3.17 Interleukin-3 receptor (IL-3R)
3.3.18 CD44/ CD166/EGFR
3.3.19 Other Studies

Chapter 4 Diagnostics
4.1 Summary
4.2 Background
4.3 CSC Markers
4.4 Circulating Tumour Cells
4.5 The Invasiveness Gene Signature
4.6 Hedgehog Activity
4.7 Microarrays
4.8 Sox 2
4.9 Other

Chapter 5 Opportunities
5.1 Summary
5.2 Drug Discovery
5.3 Diagnostics
5.4 Markets

Chapter 6 Patents
6.1 Patents

Chapter 7 Conclusions
7.1 Overview
7.2 Drug Discovery and Pipeline
7.3 Diagnostics

Appendix 1

List of Figures
Figure 2.1 Journal publications relating to Cancer Stem Cells, 2000-2006
Figure 2.2 Patents relating to Cancer Stem Cells, 1999-2006
Figure 2.3 Global academic research groups working on Cancer Stem Cells
Figure 3.1 Development pipeline of CSC-targeting drugs/candidate molecules
Figure 3.2 Development pipeline of CSC-targeting drugs/candidate molecules
Figure 4.1 Diagnostic strategies for the targeting of Cancer Stem Cells
Figure 5.1 Opportunities in the therapeutic targeting of Cancer Stem Cells
Figure 5.2 Opportunities relating to Cancer Stem Cell models
Figure 5.9 Sales (2004) and projected growth of targeted cancer therapies
Figure 6.1(a-h) Patents relating to Cancer Stem Cells, 1999-2007, by year
Figure 7.1 Development pipeline of candidate molecules that target CSCs
Figure 7.2 The challenges of therapeutically targeting Cancer Stem Cells
Figure 7.3 Potential diagnostic strategies for targeting Cancer Stem Cells

List of Tables
Table 2.1 The global CSC drug development pipeline
Table 3.1 Table 3.1 (a-e) CSC markers and potential drug targets currently in research and development = candidate in the drug development pipeline
Table 3.2 Development pipeline of CSC-targeting drugs/candidate molecules
Table 4.1 (a-b) CSC Markers

Appendix 1 (a-g) Summary of 56 research groups working on or in areas relating to cancer stem cells, by organisation, researcher, summary, cancer type and country