Although desmoid clinical biology has been well characterized, the molecular biology of those tumors tumor remains poorly understood, perhaps because of the global lack of needed research bioresources such as desmoid cells and human desmoid tissue banks needed for the high throughput research necessary to identify mutated genes and abnormal proteins driving desmoid tumor inception, progression, invasion, treatment resistance, and recurrence. In studies conducted within the premise of our DTRF- funded seed grants we were able to establish a large desmoid tissue and cell strain repository in our former lab and have identified WKDW ȕ-catenin mutations are highly prevalent in sporadic desmoid tumors and that a specific mutation, S45F possibly significantly correlates with dismal patient outcome. Moreover, Hamada et al. have shown that CTNNB1 S45F mutation predicts poor efficacy of meloxicam treatment for DT. Those interesting initial observations led further investigation by our group.
We performed a gene array which we included 44 desmoid tumor tissues (14 tumors harboring the 45F mutation, 16 tumors with a 41A mutation and 14 wild type tumors), 14 corresponding normal tissues and 14 desmoid cell strains (8 cells strains with a 41A mutation and 6 cell strains with a 45F mutation). Our initial results showed that the mutation T41A was enriched with pro apoptosis gene and that negative apoptosis regulator genes were upregulated in the mutation S45F. In the current application we suggest to continue our studies and propose a two-pronged research design consisting of distinct yet interrelated components that will address current knowledge deficits. Our studies will focus on reestablishing and characterizing new human desmoid tumor cell strains, recreating a desmoid tumor tissue repository as well as establishing a desmoid tumor mice model in our new lab at the Ohio State University. Furthermore, understanding that the deregulation of the beta-catenin pathway is potentially a significant contributor to tumorigenesis and progression and the limitation of direct therapeutic targeting of E-catenin we would attempt to identify potential targets that could reactivate the apoptosis which may be related to the aggressive behavior of the desmoid tumors harboring the CTNNB1 S45F mutation. Identifying genes and their cognate proteins whose alteration would explain the aggressive behavior of some desmoid tumors might provide future targets for novel molecular therapies relevant to patients burdened by this devastating disease.