Acute myeloid leukemia – strategies and challenges for targeting oncogenic Hedgehog/GLI signaling

Abstract

Treatment of acute myeloid leukemia (AML), an aggressive and heterogeneous hematological malignancy, remains a challenge. Despite advances in our understanding of the complex genetics and biology of AML pathophysiology, these findings have been translated to the clinic with only limited success, and poor outcomes persist for the majority of patients. Thus, novel treatment strategies are clearly needed for achieving deeper and prolonged remissions and for avoiding the development of resistance. Due to its profound role in (cancer) stem cell biology and differentiation, the Hedgehog (HH)/Glioma-associated Oncogene Homolog (GLI) signaling pathway may be an attractive novel therapeutic target in AML. In this review, we aim to provide a critical and concise overview of the currently known potential and challenges of HH/GLI targeting. We describe the biological role of the HH/GLI pathway in AML pathophysiology. We specifically focus on ways of targeting non-canonical HH/GLI signaling in AML, particularly in combination with standard treatment regimens, which may overcome some hurdles observed with approved HH pathway inhibitors in solid tumors.

Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high‐risk MDS: Phase 2 study results

“…The Hedgehog (Hh) signaling pathway is critical for embryogenesis, and is typically repressed after birth . In normal tissue, Hh activation is dependent on the transmembrane protein Smoothened (SMO) .…”

“…The Hedgehog (Hh) signaling pathway is critical for embryogenesis, and is typically repressed after birth . In normal tissue, Hh activation is dependent on the transmembrane protein Smoothened (SMO) . Hh ligand‐binding results in the Patched receptor releasing SMO, which then moves from an intracellular vesicle into the primary cilium .…”

“…In normal tissue, Hh activation is dependent on the transmembrane protein Smoothened (SMO) . Hh ligand‐binding results in the Patched receptor releasing SMO, which then moves from an intracellular vesicle into the primary cilium . Activated glioma (GLI)‐associated proteins then translocate to the nucleus and promote target gene transcription .…”

An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination

“…Wnt, Hedgehog NFkB). The passive diffusion of small drugs to all cells implies a lack of selectivity in their biodistribution to cancer sites; therefore, the achievement of therapeutic concentrations in cancer cells is limited by associated toxicity in normal tissues [40,41].…”

The sound of tumor cell-microenvironment communication – composed by the Cancer Cluster Salzburg research network

“…The current knowledge of HH/GLI signaling in AML has been summarized in the review by Aberger et al [11]. AML is highly aggressive and only limited possibilities in treatments are available.…”