Abstract
Simple SummaryElevated GLI1 expression levels are associated with improved survival in NB patients and GLI1 overexpression exerts tumor-suppressive traits in cultured NB cells. However, NB cells are protected from increased GLI1 levels as they have lost the ability to form primary cilia and transduce Hedgehog signals. This study identifies an isoxazole (ISX) molecule with primary cilia-independent GLI1-activating properties, which blocks NB cell growth. Mechanistically, ISX combines the removal of GLI3 repressor and the inhibition of class I HDACs, providing proof-of-principle evidence that small molecule-mediated activation of GLI1 could be harnessed therapeutically in the future.Although being rare in absolute numbers, neuroblastoma (NB) represents the most frequent solid tumor in infants and young children. Therapy options and prognosis are comparably good for NB patients except for the high risk stage 4 class. Particularly in adolescent patients with certain genetic alterations, 5-year survival rates can drop below 30%, necessitating the development of novel therapy approaches. The developmentally important Hedgehog (Hh) pathway is involved in neural crest differentiation, the cell type being causal in the etiology of NB. However, and in contrast to its function in some other cancer types, Hedgehog signaling and its transcription factor GLI1 exert tumor-suppressive functions in NB, rendering GLI1 an interesting new candidate for anti-NB therapy. Unfortunately, the therapeutic concept of pharmacological Hh/GLI1 pathway activation is difficult to implement as NB cells have lost primary cilia, essential organelles for Hh perception and activation. In order to bypass this bottleneck, we have identified a GLI1-activating small molecule which stimulates endogenous GLI1 production without the need for upstream Hh pathway elements such as Smoothened or primary cilia. This isoxazole compound potently abrogates NB cell proliferation and might serve as a starting point for the development of a novel class of NB-suppressive molecules.
Highlights
Neuroblastoma (NB), a pediatric cancer affecting the peripheral nervous system, is the most common type of malignancy to be diagnosed in the first year of life [1,2].NB originates from embryonic neural crest cells failing to terminally differentiate along the sympathoadrenal lineage, giving rise to an expanding pool of premature neuroblasts.This process is triggered by several genetic events such as MYCN gene amplification or activating ALK mutations, among others [3,4,5,6]
We identified an isoxazole molecule (ISX) which is capable of inducing GLI1 expression in cilia-less human and mouse cells and which functions through the combined abrogation of GLI3 repressor and Histone deacetylase (HDAC) class I functionality, resulting in pronounced growth-inhibitory effects in NB cells
In line with earlier findings [17], the positive association of GLI1 levels with survival was selective for patients without MYCN gene amplification (Figure S2D,E)
Summary
NB originates from embryonic neural crest cells failing to terminally differentiate along the sympathoadrenal lineage, giving rise to an expanding pool of premature neuroblasts. This process is triggered by several genetic events such as MYCN gene amplification or activating ALK mutations, among others [3,4,5,6]. NB stages 1 and 4s have a low risk and a 5-year survival of more than 90%, stage 4 is associated with a high risk and a poor survival of patients, if they are older or harbor MYCN amplifications [7].
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