Therapeutic Potential of CUDC-907 (Fimepinostat) for Hepatocarcinoma Treatment Revealed by Tumor Spheroids-Based Drug Screening

Liao, Wei; Yang, Wenqiang; Xu, Jiangang; Yan, Zhengming; Pan, Mingxin; Xu, Xiaoping; Zhou, Shuqin; Zhu, Yu; Lan, Jianqiang; Zeng, Min; Han, Xu; Shao, Li; Yang, Li; Liang, Kangyan; Gao, Yi; Peng, Qing

doi:10.3389/fphar.2021.658197

Cited by 12 publications

(7 citation statements)

References 35 publications

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“…In our study, we observed a dose-dependent inhibition of NB spheroidal tumor growth by CUDC-907. Similar results were observed in in vitro hepatocarcinoma, pancreatic cancer, and thyroid cancer spheroidal models, and were found comparable with in vivo studies in these cancers [ 17 , 33 , 35 ]. Our results demonstrated the effect of CUDC-907 in inhibiting the PI3K/AKT, HDACs, and enhancing the H3K9Ac levels in NB.…”

Section: Discussionsupporting

confidence: 89%

“…In the present study, we use a dual PI3K and HDAC inhibitor, CUDC-907 or Fimepinostat, and show its potency in inhibiting NB growth. CUDC-907 is a first-in-class, oral small molecule dual HDAC (class I and II) and PI3K (class Iα, β, and δ) inhibitor that can simultaneously target multiple oncogenic signaling pathways [ 17 , 18 ]. CUDC-907 is effective in multiple cancer types, including acute myeloid leukemia, relapsed or refractory diffuse large B-cell lymphoma, prostate cancer, thyroid cancer, and multiple myeloma [ 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…CUDC-907 is effective in multiple cancer types, including acute myeloid leukemia, relapsed or refractory diffuse large B-cell lymphoma, prostate cancer, thyroid cancer, and multiple myeloma [ 19 , 20 , 21 ]. FDA designated CUDC-907 for fast track development for patients with relapsed diffuse large B-cell lymphoma [ 17 ]. Our preclinical results in NB demonstrate that CUDC-907 potently inhibits NB growth by inhibiting the PI3K signaling pathway and HDACs.…”

Section: Introductionmentioning

confidence: 99%

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Dual Targeting of PI3K and HDAC by CUDC-907 Inhibits Pediatric Neuroblastoma Growth

Chilamakuri

Agarwal

2022

Cancers

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The dysregulation of PI3K, HDACs, and MYCN are well known for promoting multiple cancer types, including neuroblastoma (NB). Targeting the upstream regulators of MYCN, including HDACs and PI3K, was shown to suppress cancer growth. In the present study, we analyze different NB patient datasets to reveal that high PI3K and HDAC expression is correlated with overall poor NB patient survival. High PI3K level is also found to be associated with high MYCN level and NB stage progression. We repurpose a dual inhibitor CUDC-907 as a single agent to directly target both PI3K and HDAC in NB. We use in vitro methodologies to determine the efficacy and selectivity of CUDC-907 using six NB and three control fibroblast cell lines. Our results show that CUDC-907 significantly inhibits NB proliferation and colony growth, induces apoptosis, blocks cell cycle progression, inhibits MYCN, and enhances H3K9Ac levels by inhibiting the PI3K/AKT signaling pathway and HDAC function. Furthermore, CUDC-907 significantly inhibits NB tumor growth in a 3D spheroid tumor model that recapitulates the in vivo tumor growth. Overall, our findings highlight that the dual inhibition of PI3K and HDAC by CUDC-907 is an effective therapeutic strategy for NB and other MYC-dependent cancers.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dual Targeting of PI3K and HDAC by CUDC-907 Inhibits Pediatric Neuroblastoma Growth

Chilamakuri

Agarwal

2022

Cancers

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“…Kaliszczak et al (2016) demonstrated that cotreatment of HCT116 with HDAC6i and pan-AKT inhibitor/dual PI3K/mTOR inhibitor enhanced anti-tumor effects both in vitro and in vivo [ 58 ]. Other studies reveal that dual inhibition with HDACi and/or PI3K/AKT/mTOR inhibitor effectively reduced tumor cell proliferation in cancer cells, e.g., prostate cancer, multiple myeloma, relapsed or refractory diffuse large B-cell lymphoma, neuroblastoma, hematologic tumor(s), hepatocarcinoma and breast cancer cells [ 59 , 60 , 61 , 62 , 63 ].…”

Section: Involvement Of Hdac6 In Tumor Growth Survival and Progressionmentioning

confidence: 99%

Evaluation of the Therapeutic Potential of Histone Deacetylase 6 Inhibitors for Primary and Metastatic Uveal Melanoma

Sundaramurthi

Giricz

Kennedy

2022

IJMS

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Patients diagnosed with metastatic uveal melanoma (MUM) have a poor survival prognosis. Unfortunately for this rare disease, there is no known cure and suitable therapeutic options are limited. HDAC6 inhibitors (HDAC6i) are currently in clinical trials for other cancers and show potential beneficial effects against tumor cell survival in vitro and in vivo. In MUM cells, HDAC6i show an anti-proliferative effect in vitro and in preclinical xenograft models. The use of HDAC6 inhibitors as a treatment option for MUM should be explored further. Therefore, this review discusses (1) what is known about HDAC6i in MUM and (2) whether HDAC6 inhibitors offer a potential therapeutic option for MUM.

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“…HDAC inhibitors (HDACi) can induce acute hyperacetylation of histones and generate the re-expression of tumor-suppressor genes to inhibit tumor growth. Many HDACi have been proven to have potent anti-tumor effects in several hematological and solid malignancies ( 24 , 25 ). Recently, researchers have found that histone acetylation is closely related to the TME.…”

Section: Introductionmentioning

confidence: 99%

Histone Acetylation Regulator-Mediated Acetylation Patterns Define Tumor Malignant Pathways and Tumor Microenvironment in Hepatocellular Carcinoma

Liao

Luo

et al. 2022

Front. Immunol.

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BackgroundHistone acetylation modification is one of the most common epigenetic methods used to regulate chromatin structure, DNA repair, and gene expression. Existing research has focused on the importance of histone acetylation in regulating tumorigenicity, tumor progression, and tumor microenvironment (TME) but has not explored the potential roles and interactions of histone acetylation regulators in TME cell infiltration, drug sensitivity, and immunotherapy.MethodsThe mRNA expression and genetic alterations of 36 histone acetylation regulators were analyzed in 1599 hepatocellular carcinoma (HCC) samples. The unsupervised clustering method was used to identify the histone acetylation patterns. Then, based on their differentially expressed genes (DEGs), an HAscore model was constructed to quantify the histone acetylation patterns and related subtypes of individual samples. Lastly, the relationship between HAscore and transcription background, tumor clinical features, characteristics of TME, drug response, and efficacy of immunotherapy were analyzed.ResultsWe identified three histone acetylation patterns characterized by high, medium, and low HAscore. Patients with HCC in the high HAscore group experienced worse overall survival time, and the cancer-related malignant pathways were more active in the high HAscore group, comparing to the low HAscore group. The high HAscore group was characterized by an immunosuppressive subtype because of the high infiltration of immunosuppressive cells, such as regulatory T cells and myeloid-derived suppressor cells. Following validation, the HAscore was highly correlated with the sensitivity of anti-tumor drugs; 116 therapeutic agents were found to be associated with it. The HAscore was also correlated with the therapeutic efficacy of the PD-L1 and PD-1 blockade, and the response ratio was significantly higher in the low HAscore group.ConclusionTo the best of our knowledge, our study is the first to provide a comprehensive analysis of 36 histone acetylation regulators in HCC. We found close correlations between histone acetylation patterns and tumor malignant pathways and TME. We also analyzed the therapeutic value of the HAscore in targeted therapy and immunotherapy. This work highlights the interactions and potential clinical utility of histone acetylation regulators in treatment of HCC and improving patient outcomes.

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Therapeutic Potential of CUDC-907 (Fimepinostat) for Hepatocarcinoma Treatment Revealed by Tumor Spheroids-Based Drug Screening

Cited by 12 publications

References 35 publications

Dual Targeting of PI3K and HDAC by CUDC-907 Inhibits Pediatric Neuroblastoma Growth

Dual Targeting of PI3K and HDAC by CUDC-907 Inhibits Pediatric Neuroblastoma Growth

Evaluation of the Therapeutic Potential of Histone Deacetylase 6 Inhibitors for Primary and Metastatic Uveal Melanoma

Histone Acetylation Regulator-Mediated Acetylation Patterns Define Tumor Malignant Pathways and Tumor Microenvironment in Hepatocellular Carcinoma

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