Abstract 5833: Targeting the transcription co-activator TAZ inhibits MYC-driven medulloblastoma

Abstract

Abstract Medulloblastoma (MB), the most common malignant pediatric brain tumor, results in significant neurological, intellectual and physical disability or death. Four MB subtypes (WNT, SHH, Group 3 and 4) have recently been identified. Group 3 MB, the most aggressive subtype, is more frequently associated with gene amplification and/or protein overexpression of the MYC (c-Myc) oncogene, hereby referred to as MYC-driven MBs. It is still unclear how MB cells activate and maintain high MYC expression, as only a small portion of MYC-high MBs is caused by MYC genomic amplification. MYC-targeted MB therapies are also lacking. Targeting MYC upstream activators is a promising strategy for inhibiting MYC-driven MBs, when compared to direct MYC inhibition that is still challenging. Here, we focus on the transcription co-activator TAZ, a novel MYC upstream activator and a potential therapeutic target for inhibiting MYC-driven MBs. TAZ (transcriptional co-activator with PDZ-binding motif) is an oncogenic driver in multiple human cancers. TAZ and its paralog YAP form complexes with other transcription factors, such as TEAD, to activate downstream gene targets. TAZ and YAP are transcriptional effectors of various signaling pathways, such as the Hippo pathway. We found for the first time that TAZ is an essential MYC activator in MB cells. TAZ but not its paralog YAP is highly expressed in MYC-amplified MB cells and their xenografts. TAZ silencing downregulates MYC and inhibits MB cell proliferation. Enforced TAZ expression induces MYC expression in MB cells and promotes MB cell growth. We further showed that TAZ forms complex with transcription activator TEAD to bind to and transactivate MYC enhancers. For pharmacological TAZ targeting, we found that the FDA-approved drug Verteporfin (VP) inhibits TAZ-TEAD interaction, suppresses MYC expression and inhibits MB cell tumor propagation in vivo. We have also developed a nanoparticle formulation by using DSPE-mPEG2000 micelles to achieve VP delivery cross the blood-brain barrier in mice bearing brain tumor xenografts. In summary, our results provide novel insights into MYC upstream activators in MB, and also identify TAZ as a potential therapeutic target for inhibiting MYC-driven MBs. This knowledge may also be widely applicable to other TAZ/MYC-expressing human cancers, such as glioblastoma. Moreover, our studies support the effectiveness of VP treatment in pre-clinical MB models. These results and also the nanocarrier system for systemic VP delivery provide a solid foundation for VP clinical trials in patients with MB and likely other MYC-driven cancers. Note: This abstract was not presented at the meeting. Citation Format: Yingchao Xue, Mingyao Ying. Targeting the transcription co-activator TAZ inhibits MYC-driven medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5833. doi:10.1158/1538-7445.AM2017-5833