Tumour-initiating cells
Challenges and opportunities for anticancer drug discovery
The conventional approach for anticancer drug discovery is to target cell proliferation rather than self renewal and/or differentiation, and so is often biased to select targets with homogeneous expression patterns and potent compounds that kill the bulk tumour cells. In addition, some traditional preclinical models may not reflect clinical complexities such as tumour hierarchy. Tumour-initiating cells (popularly known as cancer stem cells) that depend on a niche and developmental pathways involving paracrine or juxtacrine signalling may demand more sophisticated drug discovery platforms than the two-dimensional tissue culture or subcutaneous xenograft models that have traditionally been used to characterize autonomous tumour cells and autocrine signalling in cancer. The large body of evidence in support of the cancer stem cell hypothesis and the related therapeutic strategies require adjustments to anticancer drug discovery platforms to make them more clinically relevant wrote Bin-Bing S Zhou of the Oncology Discovery, Wyeth Research and collaborators in the Abbott Laboratories and The Hospital for Sick Children, Toronto, Canada in an article published in the October 2009 issue of Nature Reviews Drug Discovery.
Many aspects of the aberrant differentiation that is associated with poor prognosis in cancer can be best explained by the cancer stem cell hypothesis. This is underscored by the fact that, in clinical trials for advanced cancers, tumour regression often does not translate into clinically significant increases in patient survival. Efficacy against minimal residual disease, metastasis, delayed relapse and tumour-free survival are expected to correlate with the mechanism-based activity of agents that target tumour-initiating cells.
Given that tumour regression might not be the most relevant early end point, biomarkers for tumour-initiating cells in patients who are receiving cancer therapy need to be developed. However, translating the markers that are used to enrich for tumour-initiating cells into clinical biomarkers is not necessarily straightforward. Circulating tumour cells, although extremely rare, are a potential alternative to invasive biopsies as a source of tumour tissue for the detection, characterization and monitoring of tumour-initiating cells from solid tumours. A microchip technology that is based on microfluidics was shown to be sensitive and able to detect circulating tumour cells in almost all of the examined patients with recurrent carcinomas.
It is also important to study the relevance to tumour-initiating cells of current biomarkers: both PSA and CA125 are expressed in differentiated tumour cells; it is still unclear whether they are surrogate only to a bulk tumour cell population or to a tumour-initiating cell population as well. If genetic (for example, gene amplification) or epigenetic (for example, promoter methylation) changes or multiple changes of related pathways could be used to predict the dependence of a tumour-initiating cell on certain oncogenic pathways, some of the self-renewal signalling molecules could represent an Achilles' Heel of cancer. Inhibitors of these pathways would have considerable antitumour activity alone. In this regard, a diagnostic procedure to prescreen patients with such genetic or epigenetic changes might be essential for drug development.
Among various agents that target self-renewal pathways, small molecules that target the Hedgehog pathway are in early clinical studies, and have shown promising results. The SMO antagonist cyclopamine was shown to lead to rapid regression of basal cell carcinoma in all four patients in which it was tested. In addition, an orally-administered small-molecule antagonist of SMO, GDC-0449, has shown limited toxicity and partial responses in advanced basal cell carcinoma tumours in a phase I clinical trial. It is advancing to phase II trials for metastatic colorectal cancer and other advanced epithelial tumours. The majority of patients with basal cell carcinoma have genetic mutations in Hedgehog pathway mediators; it is unclear whether GDC-0449 will be as effective in other tumour types that do not have such mutations or whether it must be combined with other agents to show clinical activity. This combination approach could be further complicated by the emerging role of Hedgehog signalling in tumour stromal cells. GDC-0449 and other SMO antagonists will therefore provide an interesting test of clinical strategies in targeting renewal signalling.
There are several antibodies against cell surface markers of tumour-initiating cells in clinical studies. EPCAM is highly expressed in numerous solid tumours, and was recently shown to be expressed on tumour-initiating cells from breast, prostate, colon and pancreatic cancer. EPCAM-specific mAbs have shown a limited efficacy in clinical trials, suggesting that immune tolerance or ADCC stimulated by these mAbs by itself might not be effective in killing EPCAM-overexpressing tumour cells in clinical settings. To overcome the limitations of the naked antibodies, catumaxomab was designed to bind to both human EPCAM (the target on the tumour) and human CD3 (the target on T cells), bringing cancer cells into proximity with the immune-system cells that can destroy them. In addition, catumaxomab induces ADCC and is undergoing advanced study in patients with malignant ascites. Conversely, mAbs against CD44 can differentiate tumour-initiating cells and have single-agent activity in certain preclinical models. It remains to be seen whether these mAbs will show single-agent activity in clinical settings or whether they will also need to be coupled with cytotoxic approaches.
Tumours with populations of proliferating progenitor-like cells may take a long time to regress, even if tumour-initiating cells are destroyed. For some cancers, continued although limited proliferation of bulk tumour cells might be sufficient to cause irreversible pathological damage. It is necessary to kill all cancer cells that have the potential to contribute to disease, particularly for cancers with little evidence of hierarchical organizations. Genetic and epigenetic instability could also confound the effectiveness of agents that otherwise efficiently target tumour-initiating cells. It may be important to combine agents that target tumour-initiating cells with conventional agents that reduce the bulk of the tumour, and the optimal manner of combination could depend on the therapeutic window of the agents, the life span of the bulk tumour cells, and the nature and stability of the tumour hierarchy in that particular tumour type.
More work is required to understand how current, partially effective, chemotherapeutic and tumour-targeted agents affect different levels of the tumour hierarchy. Some combination treatment strategies have already emerged from preclinical studies. In the future, combination therapy, including cytotoxic, tumour-targeted drugs and agents that target tumour-initiating cells, may be aimed at tumour-initiating cells, rapidly proliferating tumour cells and their niches — simultaneously or sequentially. It is hoped that this new strategy will result in the rapid removal of all tumour cell subpopulations and avoid the possible repopulation of the tumour mass by tumour-initiating cells or by originally differentiated tumour cells that have regained renewal activity. Although the paths for developing agents that target tumour-initiating cells are not straightforward, the cancer stem cell hypothesis provides an important framework for drug discovery and cancer treatment, with the potential to find novel antitumour activities, to have an impact on cancers with undifferentiated phenotypes and to yield long-term benefits for many patients with cancer.
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