Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

Abstract

During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents.

Atherosclerotic Calcification: Wnt Is the Hint

“…Current pharmacological therapies targeting Wnt signaling are still in their infancy 148. Indeed, several pharmaceutical molecules that are known to modulate the Wnt signaling pathway have been developed and tested in cancer and neurologic disorder therapy 149, 150. A couple of others are used in the treatment of osteoporosis 151.…”

Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1–Stat3

“…Currently PF-03084014 is in phase I or phase II trials for the treatment of T-ALL, lymphoma, desmoid tumors, and fibromatosis (4,20,21). Although abnormal expression of the Notch pathway has been demonstrated in hepatocellular carcinoma (22), there is no reported study on the anticancer potential of Notch inhibitors on hepatocellular carcinoma from the cellular level to animal models in vivo.…”

“…Therefore, these developmental pathways may be important therapeutic targets for the suppression of CSC self-renewal, proliferation, and tumor progression (4). Over the past few years, new investigational agents have been developed to target CSCs by inhibiting the Notch pathway, although robust antitumor activity has not yet been observed in clinical trials (4).…”

“…Thus, CSCs have become a therapeutic target of prime interest in drug discovery (12). A large number of signaling pathways have been demonstrated to be involved in the induction and maintenance of CSCs, which are highly conserved pathways involved in development and tissue homeostasis, including Notch, Hedgehog (HH), and Wnt pathways (4). Therefore, these developmental pathways may be important therapeutic targets for the suppression of CSC self-renewal, proliferation, and tumor progression (4).…”

“…A large number of signaling pathways have been demonstrated to be involved in the induction and maintenance of CSCs, which are highly conserved pathways involved in development and tissue homeostasis, including Notch, Hedgehog (HH), and Wnt pathways (4). Therefore, these developmental pathways may be important therapeutic targets for the suppression of CSC self-renewal, proliferation, and tumor progression (4). Over the past few years, new investigational agents have been developed to target CSCs by inhibiting the Notch pathway, although robust antitumor activity has not yet been observed in clinical trials (4).…”