Upstream regulation of TAZ and YAP in sarcomas: towards combinatorial therapy targeting the Hippo Pathway

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Sarcomas are cancers arising within bone and soft tissue which rank among the most difficult cancers to treat. Limb-salvage therapy has reduced the incidence of disfiguring amputations, however many sarcomas involve crucial anatomical structures precluding this approach. Additionally, five year survival for metastatic sarcomas is only 16%, underscoring the need for new therapeutic targets. The Hippo pathway is a highly conserved serine/threonine kinase cascade which negatively regulates the TAZ and YAP transcriptional coactivators. TAZ and YAP have emerged as important oncogenes in a number of cancers including breast, colon, liver, lung, and thyroid cancers. Our preliminary data shows that TAZ/YAP are activated in the majority of sarcomas (66%), something that has not been previously demonstrated. Our long-term goal is to effectively target the Hippo- TAZ/YAP signaling axis in sarcomas for therapeutic benefit and to identify patients who would benefit from such therapy. Our objective in this proposal is to elucidate the upstream mechanisms by which TAZ and YAP are activated in sarcomas in order to identify additional targets for therapy. Our central hypothesis is that TAZ and YAP are activated in sarcomas because of abrogation of the Hippo pathway due to 1) loss of expression of the Hippo kinase components (primary lesion) or 2) activation of the PI3 kinase pathway which suppresses or bypasses the Hippo pathway (secondary lesion). We thus propose the following specific aims: Specific Aim 1: Test the hypothesis that loss of expression of the Hippo kinases is a major modality by which TAZ/YAP are activated to drive sarcomagenesis. Specific Aim 2: Test the hypothesis that the PI3 kinase pathway activates TAZ/YAP to drive sarcomagenesis. The approach is innovative in the applicant's opinion, for the following reasons. Although the Hippo field has focused almost entirely on post-translational mechanisms of regulating the Hippo-TAZ/YAP axis, using an unbiased, tissue based approach, we identified that loss of expression of the Hippo kinases at a protein level is a major mechanism by which the Hippo pathway is dysregulated in sarcomas and other cancers. This same approach and mouse modeling also identified the PI3 kinase pathway as a bona fide activator of TAZ/YAP; the first time this has been shown in vivo or in clinical cancer specimens. The proposed research is significant because it will identify novel therapeutic targets upstream of TAZ/YAP which we anticipate can be used combinatorially with anti-TAZ/YAP approaches in sarcomas and other cancers.