Development of Targeted Molecular Therapy for Cancers Harboring BAP1 Mutations
Technical Report,30 Sep 2015,29 Sep 2016
University of Miami Coral Gables United States
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Our objective is to identify therapeutic molecules that block cancer progression, metastasis and death in patients with loss of BRCA1-associated protein molecular therapies that target BAP1 mutations could provide a powerful new strategy for treating these cancers. Unfortunately, there are several obstacles to developing such therapies. First, BAP1 is a tumor suppressor that is inactivated by mutations, such that targeted therapy would need to be directed against effectors of the BAP1 pathway that are deregulated by BAP1 loss. Second, the effectors of BAP1 that are relevant to cancer are not known. Third, BAP1 is difficult to study in cultured cells because the loss of BAP1 results in stem cell-like behavior the cells proliferate slowly, become dedifferentiated and are difficult to propagate. These obstacles led us to shift from using in vitro to in vivo models for studying BAP1. One of the whole-animal models we have investigated is Xenopus laevis African clawed frog, a widely used animal model for studying development. We found that targeted depletion of the Xenopus BAP1 protein xBap1 causes a striking developmental phenotype failure to complete gastrulation at developmental stage 12. Our rationale is that compounds that reverse or rescue the developmental phenotype caused by the loss of BAP1 in Xenopus laevis may also reverse the malignant phenotype caused by loss of BAP1 in human cancers.
- Medicine and Medical Research