Activation of hedgehog (Hh) signaling could predict early disease progression in chronic lymphocytic leukemia (CLL) and offer a new therapeutic target, according to investigators.
Approximately 11% of treatment-naive patients had mutations associated with Hh signaling, reported lead author Emanuela M. Ghia, PhD, of the University of California, San Diego, and colleagues. In addition to early progression, Hh signaling was associated with expression of GLI1, which could be a future therapeutic target. In support of this possibility, in vitro experimentation with a GLI1 inhibitor showed high cytotoxicity for GLI1-positive CLL cells.
“Targeting GLI1 could block ligand-independent and ligand-dependent Hh pathway activation and perhaps overcome the apparent resistance to SMO inhibitors,” the investigators wrote in Blood.
Using the HALT Pan-Leukemia Gene Panel, which includes 103 genes, the investigators tested for mutations in cell samples from 841 patients with treatment-naive CLL. Specifically, the investigators focused on mutations that did not map to seven well-known signaling/metabolic pathways, such as Wnt and Notch.
This strategy revealed that 89 patients (11%) had nonsynonymous mutations in genes that drive Hh signaling. These mutations were highly associated with GLI1 expression (x2 test; P less than .0001), which stands to reason, as GLI1 is the main effector of the Hh signaling pathway. Of note, 62 of the 161 patients (38%) who did not test positive for an Hh pathway mutation still tested positive for GLI1, suggesting that they had Hh pathway activation, albeit without an identifiable mutational cause.
These findings are clinically significant, as GLI1 overexpression has been linked to numerous types of cancer and is an adverse prognostic indicator for acute myeloid leukemia and several carcinomas, the investigators wrote.
Considering these associations with other cancer types, the investigators looked for a relationship between GLI1 expression and outcomes in CLL. Comparing 103 patients with GLI1-positive disease with 107 GLI-negative patients revealed that GLI1 positivity was significantly associated with shorter median treatment-free survival (4.7 vs. 6.4 years; P = .002). Additional analysis showed that this prognostic relationship was present regardless of IgVH mutational status.
Based on these findings, the investigators concluded that “[a]ctivation of the Hh pathway can strongly influence disease progression in CLL.”
Two additional tests showed that GLI1-positivity was associated with cell survival. First, silencing GLI1 with a GLI1-specific small interfering RNA led to decreased cell viability. Second, GANT61, a small molecule inhibitor of GLI1, was highly cytotoxic for GLI1-positive cells. According to the investigators, these findings suggest that GLI1 could be a future therapeutic target.
“[T]his report shows that the Hh pathway frequently is activated in CLL and associated with relatively rapid disease progression, while identifying a new avenue for therapeutic intervention for patients with this disease,” they concluded.
The study was funded by the National Institutes of Health, the Cancer Stem Cell Consortium, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other groups. The investigators reported having no competing financial interests.
SOURCE: Ghia EM et al. Blood. 2019 Jun 20;133(25):2651-63.