Abstract
Simple SummaryThe Hedgehog signaling pathway is aberrantly activated in many myeloid malignancies, and pathway inhibition is clinically beneficial in specific patients with acute myeloid leukemia. However, even with the approval of these agents, the role of Hedgehog signaling in other myeloid disorders is less clear. In this review, we summarize the laboratory studies that have examined Hedgehog signaling in normal and malignant hematopoiesis as well as the clinical studies that have been carried out in several myeloid leukemias. Finally, we explore potential strategies to further expand the use of pathway inhibitors as therapies for these diseases.Myeloid malignancies arise from normal hematopoiesis and include several individual disorders with a wide range of clinical manifestations, treatment options, and clinical outcomes. The Hedgehog (HH) signaling pathway is aberrantly activated in many of these diseases, and glasdegib, a Smoothened (SMO) antagonist and HH pathway inhibitor, has recently been approved for the treatment of acute myeloid leukemia (AML). The efficacy of SMO inhibitors in AML suggests that they may be broadly active, but clinical studies in other myeloid malignancies have been largely inconclusive. We will discuss the biological role of the HH pathway in normal hematopoiesis and myeloid malignancies and review clinical studies targeting HH signaling in these diseases. In addition, we will examine SMO-independent pathway activation and highlight potential strategies that may expand the clinical utility of HH pathway antagonists.
Highlights
The Hedgehog (HH) signaling pathway is highly conserved and required for normal embryonic development in both invertebrates and vertebrates [1,2]
One approved clinical indication for HH pathway inhibitors is the treatment of acute myeloid leukemia (AML), and in this review we will discuss the role of HH signaling in normal hematopoiesis and malignancies arising from hematopoietic stem cells (HSCs) as well as future strategies to expand the clinical utility of pathway inhibition
In the HR-myelodysplastic syndrome (MDS) patients, glasdegib and LDAC (G-LDAC) was associated with a 22.8% reduction in the risk of death compared to LDAC alone, but the small number of MDS patients limited the approval of G-LDAC to AML
Summary
The Hedgehog (HH) signaling pathway is highly conserved and required for normal embryonic development in both invertebrates and vertebrates [1,2]. Along with other developmental signaling pathways, including Notch and Wnt, it specifies both early patterning and polarity events and the subsequent formation of specific organs by spatially and temporally regulating cell proliferation and differentiation. Aberrant HH signaling has been identified in a wide range of malignancies, and translational efforts have led to the development of several pathway antagonists. One approved clinical indication for HH pathway inhibitors is the treatment of acute myeloid leukemia (AML), and in this review we will discuss the role of HH signaling in normal hematopoiesis and malignancies arising from hematopoietic stem cells (HSCs) as well as future strategies to expand the clinical utility of pathway inhibition
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