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Published on: January 12, 2020
Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors
Hui Shang1,2, Danielle Braggio1,3,4, Ya-Jung Lee1
1Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Background:
Desmoid tumors (DTs) are rare mesenchymal lesions that can recur repeatedly. When it is feasible, DTs are surgically resected; however, this often results in high recurrence rates. Recently, treatment with PF-03084014, a potent γ-secretase inhibitor, has been shown to have antitumor activity in several tumor types by affecting the WNT/β-catenin pathway. Consequently, Notch pathway inhibition by PF-03084014 might be a promising approach for DT treatment.
Methods:
The expression of Notch pathway components was analyzed in DT tissues and cell strains with immunohistochemistry and Western blotting, respectively. A panel of DT cell strains was exposed to PF-03084014 and evaluated for cell proliferation. Antitumor effects were assessed via cell cycle, apoptosis, and migration and invasion analysis. Cells treated with PF-03084014 were characterized with a gene array analysis combined with Ingenuity Pathway Analysis.
Results:
The results showed that Notch pathway components were expressed at different levels in DTs. Hes1 (Hes Family BHLH Transcription Factor 1) was overexpressed in DT tumors versus dermal scar tissue, and PF-03084014 caused significant decreases in Notch intracellular domain and Hes1 expression in DT cell strains. PF-03084014 decreased DT cell migration and invasion and also caused cell growth inhibition in DT cell strains, most likely through cell cycle arrest. Gene array analysis combined with Ingenuity Pathway Analysis showed that Wnt1-inducible signaling pathway protein 2 possibly regulated Notch and WNT pathways after treatment with PF-03084014 through integrin.
Conclusion:
Our findings suggest that the Notch pathway is an important DT therapeutic target. Furthermore, PF-03084014 has significant antitumor activity against DTs, and it may be an alternative strategy for DT treatment.
Insights
PF-03084014, a Notch pathway inhibitor, shows promise in treating desmoid tumors (DTs). This drug reduced DT cell growth, migration, and invasion, suggesting it as a potential new therapy for these rare tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Desmoid tumors (DTs) are rare mesenchymal neoplasms with high recurrence rates after surgical resection.
- The WNT/β-catenin pathway is implicated in DT development.
- PF-03084014, a γ-secretase inhibitor, targets the Notch pathway and has shown antitumor activity in other cancers.
Purpose of the Study:
- To investigate the role of the Notch pathway in desmoid tumors.
- To evaluate the efficacy of PF-03084014 as a potential treatment for desmoid tumors.
Main Methods:
- Analysis of Notch pathway component expression in DT tissues and cell lines using immunohistochemistry and Western blotting.
- Assessment of PF-03084014's effects on DT cell proliferation, cell cycle, apoptosis, migration, and invasion.
- Gene array analysis and Ingenuity Pathway Analysis to elucidate molecular mechanisms.
Main Results:
- Notch pathway components are differentially expressed in DTs, with Hes1 overexpression observed.
- PF-03084014 significantly reduced Notch intracellular domain and Hes1 expression in DT cells.
- PF-03084014 inhibited DT cell proliferation, migration, and invasion, likely via cell cycle arrest.
- Gene array analysis suggested Wnt1-inducible signaling pathway protein 2 mediates Notch and WNT pathway regulation by PF-03084014.
Conclusions:
- The Notch pathway represents a viable therapeutic target for desmoid tumors.
- PF-03084014 demonstrates significant antitumor activity against desmoid tumors, offering a potential alternative treatment strategy.
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