Oncotarget, November, Vol.1, No 7
Drug Discovery Approaches to Target Wnt Signaling in Cancer
Joshua C. Curtin and Matthew V. Lorenzi
Oncology Drug Discovery, Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA
Correspondence to: Matthew V. Lorenzi, e-mail: Matthew.Lorenzi@bms.com Keywords: oncotarget, cancer, stem cells, wnt, drug discovery Received: August 8, 2010,
Accepted: October 27, 2010,
Published: October 30, 2010 Copyright: © Curtin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Cancer stem cells (CSCs) represent a unique subset of cells within a tumor that possess self-renewal capacity and pluripotency, and can drive tumor initiation and maintenance. First identified in hematological malignancies, CSCs are now thought to play an important role in a wide variety of solid tumors such as NSCLC, breast and colorectal cancer. The role of CSCs in driving tumor formation illustrates the dysregulation of differentiation in tumorigenesis. The Wnt, Notch and Hedgehog (HH) pathways are developmental pathways that are commonly activated in many types of cancer. While substantial progress has been made in developing therapeutics targeting Notch and HH, the Wnt pathway has remained an elusive therapeutic target. This review will focus on the clinical relevance of the Wnt pathway in CSCs and tumor cell biology, as well as points of therapeutic intervention and recent advances in targeting Wnt/β-catenin signaling.
the majority of anti-cancer agents in the clinic. In some
cases, these agents are initially very effective at reducing or eliminating tumor burden in the patient. However,
tumors often recur, develop resistance and metastasize.
Furthermore, heterogeneity is a hallmark of tumors in the
Due to their similarities to normal stem cells, CSCs
are predicted to rely on pathways that govern development,
self-renewal and cell fate. In embryonic stem cells, these
processes are in large part regulated by three signaling
programs: the Wnt, Notch and Hedgehog (HH) pathways
[8-10]. It is an intriguing finding, therefore, that these
pathways are frequently dysregulated in many types of
cancers, and specifically within subpopulations of these
cancers that possess stem-like properties [2, 11-13].
From a drug development perspective, this provides an
opportunity not only for new classes of targeted agents, but also a novel targeting paradigm: the prospect of targeting
cells responsible for tumor initiation, progression, and
even metastasis. Furthermore, as CSCs often display
an inherent resistance to many standard cytotoxic agents
[14-17], targeting CSCs is also an attractive strategy for
overcoming drug resistance. Agents targeting the Notch
and HH pathways have shown pre-clinical promise, and
are currently being evaluated in clinical trials [18, 19].
Cancer stem cells (CSCs) represent the apex in the
hierarchical model of tumor genesis, heterogeneity and
metastasis [1-4]. Analogous to normal stem cells, CSCs
are thought to possess the capacity for unlimited selfrenewal through symmetric cell division, the ability to give rise to progeny cells through asymmetric division,
and also an innate resistance to cytotoxic therapeutics
(Figure 1) [5, 6]. While the process of differentiation
initiated by a normal stem cell ultimately results in a
specialized progeny with no proliferative potential,
a CSC gives rise to progeny that do not undergo
terminal differentiation but instead exhibit uncontrolled
proliferation. In the case of solid tumors, this process
drives formation of the bulk tumor mass. This model is
in contrast to the clonal evolution model, which...
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