Desmoid tumors (DTs) are rare mesenchymal lesions with a high rate of local recurrence. Their common feature is a deregulated WNT pathway, mainly caused by gain-of-function mutations in exon 3 of the CTNNB1 gene (encoding for beta-catenin), resulting in nuclear accumulation of beta-catenin. Even though it is controversial, several studies have shown that the mutation S45F strongly correlates with increased propensity for desmoid recurrence as compared to T41A mutation. Therefore, it is important to investigate the differences between these 2 genetic alterations in order to identify potential targes for novel molecular therapies. In studies conducted within the premise of our previously funded DTRF seed grant, we were able to establish a desmoid tissue and cell strain repository. Furthermore, we showed that the difference between the CTNNB1 T41A and S45F mutations is not due to differential protein expression levels, since beta-catenin is equally expressed in both mutations. Our gene array analysis showed that pro-apoptotic genes are downregulated and anti-apoptotic genes are upregulated in the cells with the S45F mutation when compared to the T41A mutation. Moreover, we showed that there is no significant induction of apoptosis in the S45F mutated desmoid cell strains when compared to the T41A mutated cells. Interestingly, the impairment of apoptosis appears to be specific to the CTNNB1 S45F mutation and not to desmoid tumors per se. Interim results are not promising, confirming our initial observation. However, these findings are in need of further investigation to identify the molecular mechanisms driving the differences in the induction of apoptosis between the T41A and S45F mutated tumors. Once we understand these differences, these findings may potentially have an impact on patients in the clinic. Finally, we have also started evaluating the effects of agents commonly used for the treatment of DT such as Sorafenib and Imatinib, as potential alternative therapies for patients harboring the beta-catenin S45F mutation. In the second year, we propose to: 1) continue establishing and characterizing human desmoid tumor cell strains, creating a desmoid tumor tissue repository in our new institution as well as to continue trying to establish a desmoid tumor mice model; 2) unravel the molecular mechanism behind the differences in the induction of apoptosis between the CTNNB1 T41A and S45F mutation, and 3) evaluate the efficacy of other therapies for patients harboring the beta-catenin S45F mutation, such as Sorafenib and Imatinib.
LAY VERSION OF ABSTRACT- Reactivation of apoptosis: a potential therapeutic target for desmoid tumors with CTNNB1 S45F mutation
