Maxwell Devine – Biomedical Science

Project Title: Molecular Underpinnings of Sorafenib In Desmoid Tumors

Project Mentor: James Chen – Internal Medicine & Biomedical Informatics



Introduction: Desmoid tumors (DTs) are rare fibroblastic lesions that are frequently recurrent and locally invasive. These tumors are driven by activation of the beta-catenin (CTNNB1) gene. Recently, the multi-targeting tyrosine kinase inhibitor (TKI) sorafenib has emerged as a powerful front-line strategy. However the mechanism that sorafenib inhibits growth of DTs has yet to be identified. We hypothesized that there is likely a secondary mechanism that sorafenib exploits to decrease CTNNB1 activation. To elucidate this, we performed transcriptomic analyses of sorafenib modulated desmoid models. 


Methods: 9 DT cell lines have previously been brought into culture with stable passage. These cell lines were treated with sorafenib at 10 μM. RNA was collected from parental and treated cells and subsequent RNA sequencing was performed. Differential gene expression was performed using R. Appropriate comparisons for multiplicity were performed. Western blots were performed to confirm changes in expression of key genes at the protein level.  


Results: We first evaluated the effect of sorafenib on CTNNB1 in the DT models. Western blot demonstrated no changes in CTNNB1 in the 4 cell lines tested at 72 hours post-treatment. This was further confirmed on RNA-sequencing. To identify additional gene targets of sorafenib additional differential gene expression analysis was performed resulting in 13 altered genes at an adjusted p < 0.01. The most significantly altered gene, both by p-value and by fold change, was the EGR1 mRNA transcript. EGR1 transcript levels were significantly attenuated by sorafenib treatment (logFC = 2.720, adjusted p-value << 0.0001). Western blot analysis confirmed this decrease. Fifteen independent patient desmoid tumor samples were used to confirm the variability of EGR1 and lack of direct correlation with the CTNNB1 transcript.


Discussion: Here we note that the sorafenib effect on DT did not directly modulate CTNNB1 protein nor expression levels. Sorafenib treatment did decrease EGR1 expression at both the mRNA and protein levels. Prior work has shown that EGR1 may influence CTNNB1 nuclear translocation, and thus modulate its activation affecting cellular proliferation. Confirmatory experiments including functional molecular EGR1 alterations and resultant nuclear extract Westerns to solidify this mechanism are underway. Patient desmoid registry data extraction is also underway.


2 thoughts on “Maxwell Devine – Biomedical Science

  1. Great presentation. My question for you is how do you think this could be implemented in future patientcare? Do you think if physicians understand the mechanism, that they will be more likely to prescribe sorafenib? How can this differ from other antineoplastic medications?

  2. Thank you for this presentation, I found it really interesting! Do you think understanding this mechanism will allow researchers to find more therapies to prevent tumor growth? Also, do you think that this drug, with or without modifications, could also have an effect on other kinds of tumors?

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