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

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2020 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 9859314
- **Project number:** 5I01BX003644-04
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Munir Tanas
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859314

## Citation

> US National Institutes of Health, RePORTER application 9859314, Upstream regulation of TAZ and YAP in sarcomas:  towards combinatorial therapy targeting the Hippo Pathway (5I01BX003644-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9859314. Licensed CC0.

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