Anti-Tumor Effects of The Notch Pathway In Gastrointestinal Stromal Tumors

<p>Gastrointestinal Stromal Tumors (GIST) are sarcomas driven by gain-of-function mutations of <em>KIT </em>or<em> PDGFRA</em>. Although, the introduction of tyrosine kinase inhibitors has dramatically changed the history of this disease, evidences emerge that inhibition of KIT<em> </em>or PDGFRA are<em> </em>not sufficient to cure patients. The developmental pathway Notch has a critical role in the cell fate, regulating cell proliferation and differentiation. Dysregulation of Notch pathway has been implicated in a wide variety of cancers functioning as a tumor promoter or a tumor suppressor in a cell context dependent manner.</p> <p>Given that Notch activation deregulates the morphogenesis of mesenchymal cells in the GI track, that Notch acts as a tumor suppressor in neuroendocrine tumors, and finally that the cell of origin of GIST are the Interstitial Cell of Cajal that arise from a mesenchymal origin with some neuroendocrine features, we hypothesized that Notch pathway signaling may play a role in growth, survival and differentiation of GIST cells. To test this hypothesis, we genetically and pharmacologically manipulated the Notch pathway in human GIST cells. In this study, we demonstrated that constitutively active intracellular domain of Notch1 (ICN-1) expression potently induced growth arrest and downregulated KIT expression. We have performed a retrospective analysis of 15 primary GIST patients and found that high mRNA level of <em>Hes1,</em> a major target gene of Notch pathway, correlated with a significantly longer relapse-free survival.</p> <p>Therefore, we have established that treatment with the FDA approved histone deacetylase inhibitor SAHA (Vorinostat) caused dose-dependent upregulation of <em>Notch1</em> expression and a parallel decrease in viability in these cells. Retroviral silencing of downstream targets of Notch with dominant negative <em>Hes-1 </em>as well as pharmacological inhibition of Notch pathway with a γ-secretase inhibitor partially rescued GIST cells from SAHA treatment.</p> <p>Taken together these results identify anti-tumor effect of <em>Notch1</em> and a negative cross-talk between Notch1 and KIT pathways in GIST<em>. </em>Consequently, we propose that activation of this pathway with HDAC inhibitors may be a potential therapeutic strategy for GIST patients.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2012

Author dc:creator

• Dumont, Amaury G

Contributors dc:contributor

• Dennis P. Hughes, M.D., Ph.D.
• Jonathan C. Trent, M.D., Ph.D.
• Russell R. Broaddus, M.D., Ph.D.

• GIST Notch KIT Sarcomas HES
• Cancer Biology
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/306

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1340