Cancer Stem Cells

Overview

A substantial body of evidence indicates that tumours contain a unique subset of cancer cells that drive the development of cancer. These cells, Cancer Stem Cells (CSCs), have been identified in leukaemia, myeloma, breast, prostate, pancreas, colon, brain and lung cancers and are believed to be responsible for the development and metastatic spread of this disease. If these findings are now confirmed in the clinic, the selective targeting of CSCs will offer a new paradigm in 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

A number of strategies are being explored to identify drug molecules that selectively target CSCs. These include the targeting of cell surface proteins on these cells (e.g. CD44/CD24, IL-3, EpCAM), signaling pathways including Hedgehog, Notch and Wnt, the stem cell niche, drug resistance mechanisms, telomerase, microRNA's, an adenovirus that targets p16INK4/Rb and others. In Dec 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, a drug that 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 CSCs. Of the current 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 druggable targets and to re-examine existing drug libraries that have not been screened against this subset of cells, or xenograft models developed from them.

Cancer Diagnostics

CSCs are causally linked to the development and metastatic spread of cancer. If this is confirmed in man, this will likely place CSCs at the heart of cancer diagnostics. Surface proteins may provide important diagnostic biomarkers and of those reported, CD133 and CD44 are found on CSCs from a number of cancers and may provide broad-based utility. Other CSC markers include ADH1, CD117, CD90, CD45 and CD71 (Breast), CD138 (multiple myeloma), CD34 and CD38 (leukaemia), CXCR4 (pancreas) CD44/CD133 (prostate), EpCAM (Breast) and others.

Intracellular markers such as the enzyme telomerase, hedgehog proteins and others may also prove to be important. CD133 mRNA levels in peripheral blood, measured using RT-PCR, have been found to predict colon cancer recurrence. There is also 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 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 also 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.