Cancer Stem Cells: Emerging Therapeutic, Diagnostic and Market Opportunities (2008)

SUMMARY

Overview: Tumours and haematological cancers contain small populations of cells that are believed to play a critical role in the development and progression of the disease. These cells, named Cancer Stem Cells (CSCs), have been found in leukaemia, myeloma, breast, prostate, pancreas, colon, brain and lung cancers. It is also thought that CSCs drive the metastatic spread of cancer. CSCs show resistance to a number of conventional therapies and it is believed that that this explains why it is difficult to completely eradicate the disease and why recurrence is an ever-present threat. If these findings are now confirmed in the clinic, the selective targeting of CSCs will offer a new paradigm in both cancer therapeutics and diagnostics. Currently there are more than 30 CSC R&D programmes in progress, around 50% of which are at Phase I or beyond. Patient data from the first clinical trials of drugs believed to target CSCs, are now being reported. Most CSC R&D programmes are being taken forward by SME's and > 90% of the 70 patents in this area (which more than doubled in 2007) have been filed by Universities. Substantial opportunity for collaboration is this field has recently lead to agreements between SMEs and major pharmaceutical companies. This includes a recent announcement of a collaboration between GSK and Oncomed Pharmaceuticals, Inc.

Drug Discovery and Pipeline: More than ten different strategies are being actively researched to enable the selective therapeutic targeting of CSCs, which are described in this report. In December 2007, clinical data were reported on GSK's Tykerb (which is already approved in the US for breast cancer), that targets the CD44+/CD24+ population of breast cancer cells i.e. breast CSCs. ChemGenix has also recently published clinical data from a Phase II/III CML clinical trial of omacetaxine mepesuccinate, which is believed to target CSCs. Stemline Therapeutics have reported that their investigational CSC-targeting molecule SL-401, has demonstrated single agent anti-tumour activity in acute myeloid leukaemia in a multi-centre Phase I/II dose escalation study. Currently around 30 companies or commercially based research organisations are progressing R&D activities in the CSC field, 65% of which are SME's. This report identifies five "Top-25" pharmaceutical companies that are progressing developments relating to this subset of cancer cells. Of the current 30 R&D programmes, around 50% are at Phase I or beyond. The availability of isolated CSCs to drug discovery companies offers opportunities to identify new drug targets but moreover, to re-examine existing drug libraries that have not been screened against this unique population of cancer cells, or xenograft models developed from them.

Cancer Diagnostics: CSCs are believed to be causally linked to the development and metastatic spread of cancer. If this is confirmed in man, this will place CSCs at the heart of cancer diagnostics and biomarkers. Researchers have identified a number of surface proteins such as CD44, CD133 and many others, that may have important application as biomarkers and diagnostics. Some of these surface proteins are found on a number of different CSCs, whereas others appear to be unique to certain CSCs. A number of intracellular markers found in CSCs, may also have diagnostic utility. These developments are described in this report. 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, that 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. Innovation in advanced microfluidic, chip-based and genetic/phenotypic screening technologies are anticipated in the future. OncoMed Pharmaceuticals have announced the discovery of a gene expression profile of CSCs (breast and other cancers), that correlate with clinical outcome.

This Report: This report gives a comprehensive up-to-date review of global R&D on CSCs and strategies to target them. This includes around 30 companies or commercially based research organisations (including 20 SMEs and five major pharmaceutical companies) that are progressing drug discovery activities, including drug pipeline (pre-clinical to Phase III), discovery strategy, candidate molecules, drug targets, current clinical trials and related areas. Also covered are current developments on the detection of CSCs and new diagnostic approaches. Commercial opportunities in drug discovery and diagnostics relating to CSCs are presented. More than 50 academic research teams from 13 different countries are reviewed, together with leading discoveries in this field. Current patents referring to CSCs (70+ by Dec 2007) are also presented.

TABLE OF CONTENTS

Executive Summary

Chapter 1 Cancer Stem Cells

• 1.1 Introduction
• 1.2 What are CSCs?
• 1.3 Different Cancers
• 1.4 Markets
• 1.5 Unmet Need
• 1.6 Research and Development

Chapter 2 Research and Development

• 2.1 Background
• 2.2 Research
• 2.3 Drug Development

Chapter 3 Drug Discovery

• Summary
• 3.1 Thinking Differently
• 3.2 Resistance to Therapy
• 3.3 The Stem Cell Niche
• 3.4 Metabotropic Receptors
• 3.5 Telomerase
• 3.6 Notch
• 3.7 Hedgehog and Wnt
• 3.8 Bmi-1s
• 3.9 CSC-Targeting Viruses
• 3.10 Metastasis
• 3.11 MicroRNAs
• 3.12 CSC Markers
• 3.13 Drug Pipeline

Chapter 4 Diagnostics

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

Chapter 5 Emerging Markets and Opportunities

• Summary
• 5.1 Drug Discovery
• 5.2 Diagnostics
• 5.3 Markets

Chapter 6 Patents

• Summary
• 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 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 Patents relating to Cancer Stem Cells, 1999-2007, by year (Source: Delphion)
• Figure 7.1 Development pipeline of candidate molecules that target CSCs
• Figure 7.2 Potential strategies for the therapeutic targeting of Cancer Stem Cells
• Figure 7.3 Challenges in the therapeutic targeting of Cancer Stem Cells

List of Tables

• Table 2.1 Overview of the global CSC-targeting 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 candidate drug molecules
• Table 4.1 (a-b) CSC Markers

Appendices

• 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