Modulation of YAP/ TAZ by statins to improve survival in epithelioid hemangioendothelioma (EHE).

Abstract

e23527 Background: EHE is a rare soft tissue tumor of endothelial origin. It is distinguished by the pathognomonic WWTR1-CAMTA1 fusion (WWTR1 is the gene symbol for TAZ) seen in 90% of the tumors. YAP1-TFE3 fusion is less common and seen in 10% of the tumors. YAP and TAZ are critical downstream effectors of the Hippo pathway that regulate tumor development, progression, invasion and metastasis by modulating the expression of many Hippo pathway targets. Recent studies have shown that inhibition of HMG-CoA reductase, a key enzyme of the mevalonate pathway, can regulate YAP/ TAZ by preventing their nuclear accumulation and inhibiting their transcriptional activity. This has led to interest in the role of statins, which inhibit HMG-CoA reductase, as a modulator of YAP/ TAZ that could benefit patients with sarcoma, particularly EHE. Methods: A retrospective analysis was performed on patients with a diagnosis of EHE at M D Anderson Cancer Center. Patients were identified using the electronic database system and screened for statin use using EMRs. Demographic and clinical characteristics were tabulated. KM method was used to assess overall survival and log rank test was used to test survival differences between the statin use and non- statin use groups. All statistical analysis was performed using STATA 14. Results: 226 patients with EHE were identified. 27 of them had recorded statin use during the course of their disease. The median OS for the statin use group was not reached and the mean OS was 221 months. The median OS for the non- statin use group was 123.9 months, while the mean OS was 160 months. The difference in OS was not statistically significant between the two groups. The median follow-up time for our cohort was 36.6 months. Conclusions: Our findings indicate a trend towards improved survival for patients with EHE who have received statins over the course of their disease. Our study is limited by a small number of patients who received statins. Prospective studies are required to assess the therapeutic benefit of statins in EHE. [Table: see text]

WWTR1(TAZ)-CAMTA1 reprograms endothelial cells to drive epithelioid hemangioendothelioma

“…We further showed that LATS1/2 regulate the subcellular localization of TAZ-CAMTA1 and that pharmacological intervention that is known to affect YAP/TAZ activity, such as statin treatment, could inhibit the activity of the TAZ-CAMTA1 fusion protein. Indeed, a retrospective analysis of patients with EHE showed that statin use was associated with increased survival, although the underlying mechanism was not investigated (Subramaniam et al 2020). Together, these findings suggest that mechanisms that activate Hippo signaling and/or inhibit YAP/ TAZ activity may provide a new avenue of therapy to inhibit TAZ-CAMTA1 activity in patients with EHE.…”

The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises

“…Statins, used as standard treatment against hypercholesterolemia, have been known to inhibit the YAP/TAZ pathway. The inhibition of the hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase and the mevalonate pathway have been demonstrated to regulate YAP activation [ 154 ]. Statins may affect YAP nuclear localization by inducing phosphorylation, cytoplasmic retention, degradation, and the target genes’ decreased transcription by TEA domains [ 155 ].…”

Unraveling the Biology of Epithelioid Hemangioendothelioma, a TAZ–CAMTA1 Fusion Driven Sarcoma

“…Driskill et al demonstrated, in a heterologous cell-line model, that simvastatin abrogates the anchorage-independent growth of TC-transformed cells and suppresses the expression of TC transcriptional targets, suggesting that the Mevalonate/Rho axis may regulate TAZ–CAMTA1 activity [ 92 ]. This work was further supported by a recent retrospective review from the MD Anderson Cancer Center, which aimed to identify whether prognosis was affected in EHE patients who were on statins for other indications [ 106 ]. This study showed a greater median survival among patients on statin therapy than among those not on statin therapy.…”