Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer.
Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer.
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基于网络的HDAC6活性评估预测了乳腺癌中HDAC6抑制剂ricolinostat的临床前和临床反应。
DOI：
10.1038/s43018-022-00489-5
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发表时间：
2023-02
期刊：
影响因子：
22.7
通讯作者：
Silva, Jose
中科院分区：
文献类型：
--
作者：
Zeleke, Tizita Z.;Pan, Qingfei;Chiuzan, Codruta;Onishi, Maika;Li, Yuxin;Tan, Haiyan;Alvarez, Mariano J.;Honan, Erin;Yang, Min;Chia, Pei Ling;Mukhopadhyay, Partha;Kelly, Sean;Wu, Ruby;Fenn, Kathleen;Trivedi, Meghna S.;Accordino, Melissa;Crew, Katherine D.;Hershman, Dawn L.;Maurer, Matthew;Jones, Simon;High, Anthony;Peng, Junmin;Califano, Andrea;Kalinsky, Kevin;Yu, Jiyang;Silva, Jose
与泛组蛋白去乙酰化酶抑制剂相比，抑制个体组蛋白去乙酰化酶（HDAC）正成为耐受性良好的抗癌策略。通过临床前研究，我们证明了对主要HDAC 6抑制剂（HDAC 6 i）ricolinstat的敏感性可以通过基于计算网络的算法（HDAC 6评分）预测。对约3，000例人类乳腺癌（BC）的分析表明，其中约30%可以从HDAC 6 i治疗中获益。因此，我们设计了Ib期剂量递增临床试验以评估ricolinostat加nab-紫杉醇在转移性BC患者中的活性（NCT 02632071）。研究结果表明，这两种药物可以安全地联合使用，在HR+/HER 2 −疾病患者中发现了临床活性，HDAC 6评分具有作为预测生物标志物的潜力。对其他肿瘤类型的分析也鉴定了多个对HDAC 6 is具有预测敏感性的群组。从机制上讲，我们已经将HDAC 6 i/s的抗癌活性与其诱导c-Myc超乙酰化（ac-K148）的能力联系起来，从而促进其在敏感癌细胞中的蛋白酶体介导的降解。Silva及其同事开发了一种基于网络的HDAC 6评分，可以预测临床前模型对HDAC 6抑制剂ricolinstat的敏感性，以及在Ib期临床试验中接受ricolinstat的HR+/HER 2 −乳腺癌患者。
Inhibiting individual histone deacetylases (HDAC) is emerging as well-tolerated anticancer strategy compared with pan-HDAC inhibitors. Through pre-clinical studies, we demonstrated that the sensitivity to the leading HDAC6 inhibitor (HDAC6i) ricolinstat can be predicted by a computational network-based algorithm (HDAC6-score). Analysis of ~3,000 human breast cancers (BCs) showed that ~30% of them could benefice from HDAC6i therapy. Thus, we designed a phase Ib dose-escalation clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in metastatic BC patients (NCT02632071). Study results showed that the two agents can be safely combined, that clinical activity is identified in patients with HR+/HER2− disease, and that the HDAC6-score has potential as predictive biomarker. Analysis of other tumor types also identified multiple cohorts with predicted sensitivity to HDAC6is. Mechanistically, we have linked the anticancer activity of HDAC6i/s to their ability to induce c-Myc hyperacetylation (ac-K148) promoting its proteasome-mediated degradation in sensitive cancer cells. Silva and colleagues develop a network-based HDAC6 score which could predict sensitivity to the HDAC6 inhibitor ricolinstat in preclinical models, as well as patients with HR+/HER2− breast cancer that received ricolinstat in a phase Ib clinical trial.
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DOI：
10.1001/jama.2011.593
发表时间：
2011-05-11
期刊：
JAMA
影响因子：
--
作者：
Hatzis C;Pusztai L;Valero V;Booser DJ;Esserman L;Lluch A;Vidaurre T;Holmes F;Souchon E;Wang H;Martin M;Cotrina J;Gomez H;Hubbard R;Chacón JI;Ferrer-Lozano J;Dyer R;Buxton M;Gong Y;Wu Y;Ibrahim N;Andreopoulou E;Ueno NT;Hunt K;Yang W;Nazario A;DeMichele A;O'Shaughnessy J;Hortobagyi GN;Symmans WF
通讯作者：
Symmans WF
影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
影响因子：
9
作者：
Cao J;Lv W;Wang L;Xu J;Yuan P;Huang S;He Z;Hu J
通讯作者：
Hu J
影响因子：
8.8
作者：
Carroll, Richard G.;Hollville, Emilie;Martin, Seamus J.
通讯作者：
Martin, Seamus J.