Scholarlink

<p>Uveal melanoma (UM) is the most common adult primary intraocular malignancy, with a strong predilection for hepatic metastasis, occurring in approximately 50% of cases. Metastatic UM is highly resistant to therapy and is almost invariably fatal. The strongest genetic driver of UM metastasis is loss of function of the tumor suppressor BRCA-associated protein 1 (BAP1), which leads to widespread epigenetic dysregulation. To identify novel therapeutic strategies, we investigated whether targeting the epigenome of UM could reveal new vulnerabilities. We performed a high-throughput compound screen using a curated epigenetic inhibitor library and identified BET (bromodomain and extra-terminal domain) inhibition as a particularly promising approach. While previous clinical trials with BET inhibitors for UM treatment have failed, we found substantial heterogeneity in the efficacy of different BET inhibitors in UM. Notably, the BET inhibitor mivebresib (ABBV-075) significantly improved survival rates by 50% in a metastatic UM xenograft mouse model and prevented detectable metastases in the bones, spinal cord, and brain. Transcriptomic analysis revealed a strong overlap between BET and histone deacetylase (HDAC) inhibition, an approach currently under clinical evaluation for UM treatment. BET and HDAC inhibitors reversed gene expression signatures associated with high metastatic risk and induced a neuron-like phenotype in UM cells. These findings establish BET inhibition as a potent and previously underappreciated vulnerability for metastatic UM.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Identification of targetable epigenetic vulnerabilities for uveal melanoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月12日

查看全文
  • Gulum Yenisehirli,
  • Sebastian Borges,
  • Steffanie S. Braun,
  • Ashley N. Zuniga,
  • Gabriela I. Quintana,
  • Jeffim N. Kutsnetsoff,
  • Renata L. Volonterio,
  • Sara Rodriguez,
  • Emily V. Adis,
  • Sofia Lopez,
  • James J. Dollar,
  • Vasileios Stathias,
  • Claude-Henry Volmar,
  • Efe Karaca,
  • Shaun P. Brothers,
  • Daniel Bilbao,
  • J. William Harbour,
  • Zelia M. Correa,
  • Stefan Kurtenbach

摘要

Uveal melanoma (UM) is the most common adult primary intraocular malignancy, with a strong predilection for hepatic metastasis, occurring in approximately 50% of cases. Metastatic UM is highly resistant to therapy and is almost invariably fatal. The strongest genetic driver of UM metastasis is loss of function of the tumor suppressor BRCA-associated protein 1 (BAP1), which leads to widespread epigenetic dysregulation. To identify novel therapeutic strategies, we investigated whether targeting the epigenome of UM could reveal new vulnerabilities. We performed a high-throughput compound screen using a curated epigenetic inhibitor library and identified BET (bromodomain and extra-terminal domain) inhibition as a particularly promising approach. While previous clinical trials with BET inhibitors for UM treatment have failed, we found substantial heterogeneity in the efficacy of different BET inhibitors in UM. Notably, the BET inhibitor mivebresib (ABBV-075) significantly improved survival rates by 50% in a metastatic UM xenograft mouse model and prevented detectable metastases in the bones, spinal cord, and brain. Transcriptomic analysis revealed a strong overlap between BET and histone deacetylase (HDAC) inhibition, an approach currently under clinical evaluation for UM treatment. BET and HDAC inhibitors reversed gene expression signatures associated with high metastatic risk and induced a neuron-like phenotype in UM cells. These findings establish BET inhibition as a potent and previously underappreciated vulnerability for metastatic UM.