Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial

Jiang, Zefei; Li, Wei; Hu, Xichun; Zhang, Qingyuan; Sun, Tao; Cui, Shude; Wang, Shusen; Ouyang, Quchang; Yin, Yongmei; Chen, Geng; Tong, Zhongsheng; Cheng, Ying; Pan, Yueyin; Sun, Yehuan; Wang, Hong; Ouyang, Tao; Gu, Kai; Feng, Jifeng; Wang, Xiaojia; Wang, Shubin; Liu, Tianshu; Gao, Jinghua; Cristofanilli, Massimo; Ning, Zhiqiang; Lu, Xianping

doi:10.1016/s1470-2045(19)30164-0

Cited by 184 publications

(163 citation statements)

References 29 publications

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“…However, HDAC inhibitors have not successfully cleared clinical trials for solid tumors, despite promising collective results in biologic, preclinical and phase I and II studies [58,61]. For example, in phase III trials for advanced hormone receptor-positive breast cancer, chidamide, a HDAC inhibitor, in combination with exemestane, increased the median progression-free survival to 7.4 months in comparison to 3.8 months with placebo and has been recommended for further testing [62]. Other HDAC inhibitors are undergoing trials in solid tumors, including entinostat in phase III trials for locally advanced or metastatic recurrent hormone receptor-positive breast cancer ( Table 2) [63].…”

Section: Hdac Inhibitorsmentioning

confidence: 99%

Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

et al. 2020

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Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide. Histone deacetylase (HDAC) inhibitors showed promising results in hematological malignancies, but they failed in solid tumors such as prostate cancer, despite the overexpression of HDACs in CRPC. Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression. In this review, the pharmacodynamic reasons for the failure of HDAC inhibitors were assessed and placed in the context of the advancements in the understanding of CRPCs, HDACs and resistance mechanisms. The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.

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Section: Hdac Inhibitorsmentioning

confidence: 99%

Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

et al. 2020

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“…The four FDA-approved anti-cancer HDACi vorinostat (SAHA), panobinostat, romidepsin and belinostat are, as of this time, restricted to cutaneous T cell lymphoma (CTCL), and multiple myeloma (a plasma cell malignancy). In addition, entinostat (MS-275) is entering phase III trial in patients with hormone receptor positive advanced breast cancer [3] and tucidinostat has showed increased progression free survival in the same patient group [4]. Within other diseases, the pan-HDACi valproate has been used for decades in epilepsy treatment and HDACi has been suggested as a potential cure for HIV by purging latent reservoirs [5], and a treatment of B-cell driven autoimmunity [6].…”

Section: Introductionmentioning

confidence: 99%

HDACi mediate UNG2 depletion, dysregulated genomic uracil and altered expression of oncoproteins and tumor suppressors in B- and T-cell lines

et al. 2020

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Background: HDAC inhibitors (HDACi) belong to a new group of chemotherapeutics that are increasingly used in the treatment of lymphocyte-derived malignancies, but their mechanisms of action remain poorly understood. Here we aimed to identify novel protein targets of HDACi in Band T-lymphoma cell lines and to verify selected candidates across several mammalian cell lines. Methods: Jurkat T-and SUDHL5 B-lymphocytes were treated with the HDACi SAHA (vorinostat) prior to SILAC-based quantitative proteome analysis. Selected differentially expressed proteins were verified by targeted mass spectrometry, RT-PCR and western analysis in multiple mammalian cell lines. Genomic uracil was quantified by LC-MS/MS, cell cycle distribution analyzed by flow cytometry and class switch recombination monitored by FACS in murine CH12F3 cells. Results: SAHA treatment resulted in differential expression of 125 and 89 proteins in Jurkat and SUDHL5, respectively, of which 19 were commonly affected. Among these were several oncoproteins and tumor suppressors previously not reported to be affected by HDACi. Several key enzymes determining the cellular dUTP/dTTP ratio were downregulated and in both cell lines we found robust depletion of UNG2, the major glycosylase in genomic uracil sanitation. UNG2 depletion was accompanied by hyperacetylation and mediated by increased proteasomal degradation independent of cell cycle stage. UNG2 degradation appeared to be ubiquitous and was observed across several mammalian cell lines of different origin and with several HDACis. Loss of UNG2 was accompanied by 30-40% increase in genomic uracil in freely cycling HEK cells and reduced immunoglobulin class-switch recombination in murine CH12F3 cells. Conclusion: We describe several oncoproteins and tumor suppressors previously not reported to be affected by HDACi in previous transcriptome analyses, underscoring the importance of proteome analysis to identify cellular effectors of HDACi treatment. The apparently ubiquitous depletion of UNG2 and PCLAF establishes DNA base excision repair and translesion synthesis as novel pathways affected by HDACi treatment. Dysregulated genomic uracil

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“…Although the reasons for drug resistance were different in these cell lines (20), HDAC1 was activated in the two MDR cell lines, which was consistent with the results reported by other organizations (29,30).CHI is the international first subtype-selective HDACi independently developed by Microcore Biology. It is mainly used for various types of lymphocyte or myelogenous leukemia (31).CHI has been used in various clinical and preclinical studies in recent years, In 2019, it was approved in combination with isetam for hormone receptor-positive advanced breast cancer (18).Therefore, the inhibition of HDAC is a new therapeutic approach. The clinical and basic research on the use of CHI in the treatment of breast cancer is ongoing (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Chidamide combined with doxorubicin induced p53-driven cell cycle arrest and cell apoptosis reverse multidrug resistance of breast cancer

Cao

Zhao

Yang

et al. 2020

Preprint

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Background: The multidrug-resistant (MDR) phenotype is usually accompanied by an abnormal expression of histone deacetylase (HDAC). Given that HDAC is vital in chromatin remodeling and epigenetics, inhibiting the role of HDAC has become an important approach for tumor treatment. However, the effect of HDAC inhibitors on MDR breast cancer has not been elucidated. This study aimed to evaluate the resistance of two MDR breast cancer cell lines to the HDAC-selective inhibitor chidamide (CHI).Methods: Cell viability, cell cycle and apoptosis were detected by CCK8, crystal violet staining, EDU staining, TUNEL assay, flow cytometry. The expression of HDAC1, H3K9, H3K18, p53, p21, caspase3/7/9 and the Bcl family was analyzed by western blotting and Quantitative real-time PCR. MDR breast cancer growth suppression by CHI and/or doxorubicin (DOX) in vivo was investigated in a tumor xenograft mouse model.Results: The results showed that, CHI combined with DOX showed significant cytotoxicity to MDR breast cancer cells in vitro and in vivo compared with the CHI monotherapy. The cell cycle distribution results showed that CHI caused G0/G1 cell cycle arrest and inhibited cell growth regardless of the addition of DOX. At the same time, Annexin V staining and TUNEL staining results showed that CHI enhanced the number of cell apoptosis in drug-resistant cells. The western blot analysis found that p53 as a tumor suppressor was in a silent state in drug-resistant cells. However, p53 was activated in the CHI-treated and combined treatment groups, which, in turn, activated the p53 up-regulated apoptosis regulator recombinant protein (Puma) and pro-apoptotic protein Bax, downregulated the apoptotic proteins Bcl-xL and Bcl-2, and activated the caspase cascade to induce apoptosis. Conclusion: The irreversible cell stress induced by CHI combined with DOX reduced the expression of HDAC1 and activated caspase-dependent apoptosis and p21-mediated growth arrest pathway, which might have been driven by the activation of p53. This provided a strong theoretical basis for exploring the treatment strategy of the combined use of CHI in patients with breast cancer who did not respond to chemotherapy or had cancer progression.

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Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial

Cited by 184 publications

References 29 publications

Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

HDACi mediate UNG2 depletion, dysregulated genomic uracil and altered expression of oncoproteins and tumor suppressors in B- and T-cell lines

Chidamide combined with doxorubicin induced p53-driven cell cycle arrest and cell apoptosis reverse multidrug resistance of breast cancer

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