Showing papers on "Vorinostat published in 2023"

Reversible epigenetic alterations mediate PSMA expression heterogeneity in advanced metastatic prostate cancer

Abstract: Prostate-specific membrane antigen (PSMA) is an important cell surface target in prostate cancer. There are limited data on the heterogeneity of PSMA tissue expression in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, the mechanisms regulating PSMA expression (encoded by the FOLH1 gene) are not well understood. Here, we demonstrate that PSMA expression is heterogeneous across different metastatic sites and molecular subtypes of mCRPC. In a rapid autopsy cohort in which multiple metastatic sites per patient were sampled, we found that 13 of 52 (25%) cases had no detectable PSMA and 23 of 52 (44%) cases showed heterogeneous PSMA expression across individual metastases, with 33 (63%) cases harboring at least 1 PSMA-negative site. PSMA-negative tumors displayed distinct transcriptional profiles with expression of druggable targets such as MUC1. Loss of PSMA was associated with epigenetic changes of the FOLH1 locus, including gain of CpG methylation and loss of histone 3 lysine 27 (H3K27) acetylation. Treatment with histone deacetylase (HDAC) inhibitors reversed this epigenetic repression and restored PSMA expression in vitro and in vivo. Collectively, these data provide insights into the expression patterns and regulation of PSMA in mCRPC and suggest that epigenetic therapies — in particular, HDAC inhibitors — can be used to augment PSMA levels.

PX‐12 synergistically enhances the therapeutic efficacy of vorinostat under hypoxic tumor microenvironment in oral squamous cell carcinoma in vitro

Abstract: Hypoxia is a characteristic feature of solid tumors, including oral squamous cell carcinoma (OSCC), which causes therapeutic resistance. The hypoxia‐inducible factor 1‐alpha (HIF‐1α) is a key regulator of hypoxic tumor microenvironment (TME) and a promising therapeutic target against solid tumors. Among other HIF‐1α inhibitors, vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor (HDACi) targeting the stability of HIF‐1α, and PX‐12 (1‐methylpropyl 2‐imidazolyl disulfide) is a thioredoxin‐1 (Trx‐1) inhibitor preventing accumulation of HIF‐1α. HDACis are effective against cancers; however, they are accompanied by several side effects along with an emerging resistance against it. This can be overcome by using HDACi in a combination regimen with Trx‐1 inhibitor, as their inhibitory mechanisms are interconnected. HDACis inhibit Trx‐1, leading to an increase in the production of reactive oxygen species (ROS) and inducing apoptosis in cancer cells; thus, the efficacy of HDACi can be elevated by using a Trx‐1 inhibitor. In this study, we have tested the EC50 (half maximal effective concentration) doses of vorinostat and PX‐12 on CAL‐27 (an OSCC cell line) under both normoxic and hypoxic conditions. The combined EC50 dose of vorinostat and PX‐12 is significantly reduced under hypoxia, and the interaction of PX‐12 with vorinostat was evaluated by combination index (CI). An additive interaction between vorinostat and PX‐12 was observed in normoxia, while a synergistic interaction was observed under hypoxia. This study provides the first evidence for vorinostat and PX‐12 synergism under hypoxic TME, at the same time highlighting the therapeutically effective combination of vorinostat and PX‐12 against OSCC in vitro.

Harnessing Epigenetics for Breast Cancer Therapy: The Role of DNA Methylation, Histone Modifications, and MicroRNA

Abstract: Breast cancer exhibits various epigenetic abnormalities that regulate gene expression and contribute to tumor characteristics. Epigenetic alterations play a significant role in cancer development and progression, and epigenetic-targeting drugs such as DNA methyltransferase inhibitors, histone-modifying enzymes, and mRNA regulators (such as miRNA mimics and antagomiRs) can reverse these alterations. Therefore, these epigenetic-targeting drugs are promising candidates for cancer treatment. However, there is currently no effective epi-drug monotherapy for breast cancer. Combining epigenetic drugs with conventional therapies has yielded positive outcomes and may be a promising strategy for breast cancer therapy. DNA methyltransferase inhibitors, such as azacitidine, and histone deacetylase inhibitors, such as vorinostat, have been used in combination with chemotherapy to treat breast cancer. miRNA regulators, such as miRNA mimics and antagomiRs, can alter the expression of specific genes involved in cancer development. miRNA mimics, such as miR-34, have been used to inhibit tumor growth, while antagomiRs, such as anti-miR-10b, have been used to inhibit metastasis. The development of epi-drugs that target specific epigenetic changes may lead to more effective monotherapy options in the future.

Vorinostat Improves Myotonic Dystrophy Type 1 Splicing Abnormalities in DM1 Muscle Cell Lines and Skeletal Muscle from a DM1 Mouse Model

Abstract: Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by an abnormal expansion of CTG repeats in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The expanded repeats of the DMPK mRNA form hairpin structures in vitro, which cause misregulation and/or sequestration of proteins including the splicing regulator muscleblind-like 1 (MBNL1). In turn, misregulation and sequestration of such proteins result in the aberrant alternative splicing of diverse mRNAs and underlie, at least in part, DM1 pathogenesis. It has been previously shown that disaggregating RNA foci repletes free MBNL1, rescues DM1 spliceopathy, and alleviates associated symptoms such as myotonia. Using an FDA-approved drug library, we have screened for a reduction of CUG foci in patient muscle cells and identified the HDAC inhibitor, vorinostat, as an inhibitor of foci formation; SERCA1 (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) spliceopathy was also improved by vorinostat treatment. Vorinostat treatment in a mouse model of DM1 (human skeletal actin–long repeat; HSALR) improved several spliceopathies, reduced muscle central nucleation, and restored chloride channel levels at the sarcolemma. Our in vitro and in vivo evidence showing amelioration of several DM1 disease markers marks vorinostat as a promising novel DM1 therapy.

The screening of compounds regulating PD‐L1 transcriptional activity in a cell functional high‐throughput manner

Abstract: Immune checkpoints are protein molecules expressed on the immune cell membrane, which regulate the immune system to kill tumor cells. As an essential immune checkpoint, overexpressed PD‐1 on tumor cells could inhibit T‐cell activation after being bonded to PD‐1. Due to this inhibitory effect, T‐cell proliferation and cytokine secretion are suppressed, leading to immune escape of tumor cells. Here, we established a high‐throughput method based on cell function screening technology to screen drugs regulating PD‐L1 expression in tumor cells at the transcriptional level. After two screening rounds, 12 compounds that enhanced PD‐L1 transcription while seven weakened were sorted out among 1018 FDA‐approved drugs. Finally, a tumor cell line was used to verify the upregulation of endogenous PD‐L1 expression for a drug named “vorinostat,” a histone deacetylation inhibitor, after the two rounds of optional selection. Therefore, our research provides another perspective for using “vorinostat” in treating tumors and offers a convenient method to detect the transcriptional expression of other intracellular proteins besides PD‐L1.

Enabling Single‐Cell Drug Response Annotations from Bulk RNA‐Seq Using SCAD

Abstract: The single-cell RNA sequencing (scRNA-seq) quantifies the gene expression of individual cells, while the bulk RNA sequencing (bulk RNA-seq) characterizes the mixed transcriptome of cells. The inference of drug sensitivities for individual cells can provide new insights to understand the mechanism of anti-cancer response heterogeneity and drug resistance at the cellular resolution. However, pharmacogenomic information related to their corresponding scRNA-Seq is often limited. Therefore, a transfer learning model is proposed to infer the drug sensitivities at single-cell level. This framework learns bulk transcriptome profiles and pharmacogenomics information from population cell lines in a large public dataset and transfers the knowledge to infer drug efficacy of individual cells. The results suggest that it is suitable to learn knowledge from pre-clinical cell lines to infer pre-existing cell subpopulations with different drug sensitivities prior to drug exposure. In addition, the model offers a new perspective on drug combinations. It is observed that drug-resistant subpopulation can be sensitive to other drugs (e.g., a subset of JHU006 is Vorinostat-resistant while Gefitinib-sensitive); such finding corroborates the previously reported drug combination (Gefitinib + Vorinostat) strategy in several cancer types. The identified drug sensitivity biomarkers reveal insights into the tumor heterogeneity and treatment at cellular resolution.

Single Inhibitors versus Dual Inhibitors: Role of HDAC in Cancer

Abstract: Due to the multimodal character of cancer, inhibition of two targets simultaneously by a single molecule is a beneficial and effective approach against cancer. Histone deacetylase (HDAC) was widely investigated as a novel category of anticancer drug targets due to its crucial role in various biological processes like cell-proliferation, metastasis, and apoptosis. Numerous HDAC inhibitors such as vorinostat and panobinostat are clinically approved but have limited usage due to their low efficacy, nonselectivity, drug resistance, and toxicity. Therefore, HDACs with a dual targeting ability have attracted great attention. The strategy of combining a HDAC inhibitor with other antitumor agents has been proved advantageous for combating the nonselectivity and drug resistivity problems associated with single-target drugs. Henceforth, we have highlighted dual-targeting inhibitors to target HDAC along with topoisomerase, receptor tyrosine kinase inhibitors, and the zeste homolog 2 enzyme. Our Review mainly focuses on the impact of the substituent effect along with the linker variation of well-known HDAC-inhibitor-conjugated anticancer drugs.

Vorinostat decrease M2 macrophage polarization through ARID1A6488delG/HDAC6/IL-10 signaling pathway in endometriosis-associated ovarian carcinoma.

Abstract: Endometriosis is a common disease in women and may be one of the factors that induces malignant epithelial ovarian tumors. Previous studies suggested that endometriosis is related to ARID1A mutation mediating the expression of HDAC6, but the detailed pathogenic mechanism is still unclear. First, we collected endometriosis-associated ovarian carcinoma (EAOC) clinical samples and examined the expression of HDAC6. Our results found that the high HDAC6 expression group was positively correlated with EAOC histology (P = 0.015), stage (P < 0.000), and tumor size (P < 0.000) and inversely correlated with survival (P < 0.000). We also found that ARID1A6488delG/HDAC6 induced M2 polarization of macrophages through IL-10. In addition, the HDAC inhibitor (HDACi) vorinostat inhibited cell growth and blocked the effect of HDAC6. Tomographic microscopy was used to monitor the live cell morphology of these treated cells, and we found that vorinostat treatment resulted in substantial cell apoptosis by 3 h 42 min. Next, we established a transgenic mouse model of EAOC and found that vorinostat significantly reduced the size of ovarian tumors by inhibiting M2 macrophage polarization in mice. Together, these data demonstrate that the signaling pathway of E4F1/ARID1A6488delG/HDAC6/GATA3 mediates macrophage polarization and provides a novel immune cell-associated therapeutic strategy targeting IL-10 in EAOC.

Supplementary Table 1, Supplementary Table 2 from Safety and Efficacy of Vorinostat Plus Sirolimus or Everolimus in Patients with Relapsed Refractory Hodgkin Lymphoma

Abstract: <p>Supplementary Table 1. Durations of dose interruptions in vorinostat and sirolimus arm; Supplementary Table 2. Durations of dose interruptions in vorinostat and everolimus arm</p>

Supplementary Figures S1-S18 from Vorinostat and Sorafenib Synergistically Kill Tumor Cells via FLIP Suppression and CD95 Activation

Abstract: Supplementary Figures S1-S18 from Vorinostat and Sorafenib Synergistically Kill Tumor Cells via FLIP Suppression and CD95 Activation

Supplementary Figure 4 from Safety and Efficacy of Vorinostat Plus Sirolimus or Everolimus in Patients with Relapsed Refractory Hodgkin Lymphoma

Abstract: <p>In patients treated with vorinostat and sirolimus, there was a trend towards a longer median progression-free survival in patients with ECOG performance status 0 compared to ECOG 1 or 2 (not reached vs. 4.6 months, 95% CI 1.5-7.7; P = 0.06).</p>

Supplementary Figure 2 from Safety and Efficacy of Vorinostat Plus Sirolimus or Everolimus in Patients with Relapsed Refractory Hodgkin Lymphoma

Abstract: <p>Dose modifications: vorinostat and everolimus</p>

Supplemental Table 2 from The Novel IKK2 Inhibitor LY2409881 Potently Synergizes with Histone Deacetylase Inhibitors in Preclinical Models of Lymphoma through the Downregulation of NF-κB

Abstract: <p>Supplemental Table 2. Representative synergy index of LY2409881 with lymphoma active drugs.</p>

Combined treatment with osimertinib and vorinostat successively reduces the volumes of xenografts during the therapy. from Histone Deacetylase 3 Inhibition Overcomes &lt;i&gt;BIM&lt;/i&gt; Deletion Polymorphism–Mediated Osimertinib Resistance in &lt;i&gt;EGFR-&lt;/i&gt;Mutant Lung Cancer

Abstract: <p>All values are expressed as mean {plus minus} SE and assessed by one-way ANOVA. *, P < 0.05 osimertinib versus control in A, combination versus osimertinib in B.</p>

Supplementary Figures S1-S3 from Preclinical Studies of Vorinostat (Suberoylanilide Hydroxamic Acid) Combined with Cytosine Arabinoside and Etoposide for Treatment of Acute Leukemias

Abstract: Supplementary Figures S1-S3 from Preclinical Studies of Vorinostat (Suberoylanilide Hydroxamic Acid) Combined with Cytosine Arabinoside and Etoposide for Treatment of Acute Leukemias

Data Supplement from Synergistic Killing Effect between Vorinostat and Target of CD146 in Malignant Cells

Abstract: Data Supplement from Synergistic Killing Effect between Vorinostat and Target of CD146 in Malignant Cells

Supplementary File 2 from Safety and Efficacy of Vorinostat Plus Sirolimus or Everolimus in Patients with Relapsed Refractory Hodgkin Lymphoma

Abstract: <p>Protocol: Data Analysis of Patients Treated Off-protocol</p>

Data from Essential Role of DNA Methyltransferase 1–mediated Transcription of Insulin-like Growth Factor 2 in Resistance to Histone Deacetylase Inhibitors

Abstract: <div>Abstract<p><b>Purpose:</b> Histone deacetylase inhibitors (HDI) are promising anticancer therapies; however, drug resistance limits their efficacy. Here, we investigated the molecular mechanisms underlying HDI resistance, focusing on the mechanism of HDI-mediated induction of insulin-like growth factor 2 (IGF2) based on our previous study.</p><p><b>Experimental Design:</b> The methylation status of CCCTC-binding factor (CTCF)-binding sites in the <i>IGF2/H19</i> imprinting control region (ICR) were determined by methylation-specific PCR and bisulfite sequencing. The effectiveness of single or combinatorial blockade of DNA methyltransferase 1 (DNMT1) and histone deacetylase (HDAC) was evaluated using cell viability assay and patient-derived tumor xenograft (PDX) model.</p><p><b>Results:</b> HDAC inhibition by vorinostat increased acetylated STAT3 (K685), resulting in transcriptional upregulation of <i>DNMT1</i>. DNMT1-mediated hypermethylation of CTCF-binding sites in the <i>IGF2/H19</i> ICR decreased CTCF insulator activity, leading to a transcriptional upregulation of <i>IGF2</i> and activation of the insulin-like growth factor 1 receptor (IGF-1R) pathway in cells with acquired or <i>de novo</i> vorinostat resistance. Strategies targeting DNMT1 diminished the <i>IGF2</i> expression and potentiated vorinostat sensitivity in preclinical models of lung cancer with hypermethylation in the <i>H19/IGF2</i> ICR. The degree of ICR hypermethylation correlated with vorinostat resistance in patient-derived lung tumors and in patients with hematologic malignancies.</p><p><b>Conclusions:</b> DNMT1-mediated transcriptional upregulation of <i>IGF2</i> is a novel mechanism of resistance to HDIs, highlighting the role of epigenetic deregulation of IGF2 in HDI resistance and the potential value of the <i>H19/IGF2</i> ICR hypermethylation and DNMT1 expression as predictive biomarkers in HDI-based anticancer therapies. <i>Clin Cancer Res; 23(5); 1299–311. ©2016 AACR</i>.</p></div>

Supplementary Table S2 from Replication Stress Leading to Apoptosis within the S-phase Contributes to Synergism between Vorinostat and AZD1775 in HNSCC Harboring High-Risk &lt;i&gt;TP53&lt;/i&gt; Mutation

Abstract: <p>Genes that are significantly different between vorinostat and untreated cells with at least a four-fold difference in expression.</p>

Supplementary Figure 3 from Constitutive Activation of Signal Transducers and Activators of Transcription Predicts Vorinostat Resistance in Cutaneous T-Cell Lymphoma

Abstract: Supplementary Figure 3 from Constitutive Activation of Signal Transducers and Activators of Transcription Predicts Vorinostat Resistance in Cutaneous T-Cell Lymphoma

Data from Vorinostat Increases Expression of Functional Norepinephrine Transporter in Neuroblastoma &lt;i&gt;In Vitro&lt;/i&gt; and &lt;i&gt;In Vivo&lt;/i&gt; Model Systems

Abstract: <div>Abstract<p><b>Purpose:</b> Histone deacetylase (HDAC) inhibition causes transcriptional activation or repression of several genes that in turn can influence the biodistribution of other chemotherapeutic agents. Here, we hypothesize that the combination of vorinostat, a HDAC inhibitor, with ¹³¹I-<i>meta</i>-iodobenzylguanidine (MIBG) would lead to preferential accumulation of the latter in neuroblastoma (NB) tumors via increased expression of the human norepinephrine transporter (NET).</p><p><b>Experimental Design:</b><i>In vitro</i> and <i>in vivo</i> experiments examined the effect of vorinostat on the expression of NET, an uptake transporter for ¹³¹I-MIBG. Human NB cell lines (Kelly and SH-SY-5Y) and NB1691-luc mouse xenografts were employed. The upregulated NET protein was characterized for its effect on ¹²³I-MIBG biodistribution.</p><p><b>Results:</b> Preincubation of NB cell lines, Kelly, and SH-SY-5Y, with vorinostat caused dose-dependent increases in NET mRNA and protein levels. Accompanying this was a corresponding dose-dependent increase in MIBG uptake in NB cell lines. Four- and 2.5-fold increases were observed in Kelly and SH-SY-5Y cells, respectively, pretreated with vorinostat in comparison to untreated cells. Similarly, NB xenografts, created by intravenous tail vein injection of NB1691-luc, and harvested from nude mice livers treated with vorinostat (150 mg/kg i.p.) showed substantial increases in NET protein expression. Maximal effect of vorinostat pretreatment in NB xenografts on ¹²³I-MIBG biodistribution was observed in tumors that exhibited enhanced uptake in vorinostat-treated [0.062 ± 0.011 μCi/(mg tissue-dose injected)] vs. -untreated mice [0.022 ± 0.003 μCi/(mg tissue-dose injected); <i>P</i> < 0.05].</p><p><b>Conclusions:</b> The results of our study provide preclinical evidence that vorinostat treatment can enhance NB therapy with ¹³¹I-MIBG. <i>Clin Cancer Res; 17(8); 2339–49. ©2011 AACR</i>.</p></div>

Data from Proteostasis Modulation in Germline Missense von Hippel Lindau Disease

Abstract: <div>AbstractPurpose:<p>Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation and/or progression in VHL disease. Vorinostat can rescue missense mutated pVHL and arrest tumor growth in preclinical models. We asked whether short-term oral vorinostat could rescue pVHL in central nervous system hemangioblastomas in patients with germline missense VHL.</p>Patients and Methods:<p>We administered oral vorinostat to 7 subjects (ages 46.0 ± 14.5 years) and then removed symptomatic hemangioblastomas surgically (ClinicalTrials.gov identifier NCT02108002).</p>Results:<p>Vorinostat was tolerated without serious adverse events by all patients. pVHL expression was elevated in neoplastic stromal cells compared with untreated hemangioblastomas from same patients. We found transcriptional suppression of downstream hypoxia-inducible factor (HIF) effectors. Mechanistically, vorinostat prevented Hsp90 recruitment to mutated pVHL <i>in vitro</i>. The effects of vorinostat on the Hsp90–pVHL interaction, pVHL rescue, and transcriptional repression of downstream HIF effectors was independent of the location of the missense mutation on the <i>VHL</i> locus. We confirmed a neoplastic stromal cell–specific effect in suppression of protumorigenic pathways with single-nucleus transcriptomic profiling.</p>Conclusions:<p>We found that oral vorinostat treatment in patients with germline missense VHL mutations has a potent biologic effect that warrants further clinical study. These results provide biologic evidence to support the use of proteostasis modulation for the treatment of syndromic solid tumors involving protein misfolding. Proteostasis modulation with vorinostat rescues missense mutated VHL protein. Further clinical trials are needed to demonstrate tumor growth arrest.</p></div>

Abstract 1601: Potentiation of arsenic trioxide in glioblastoma

Abstract: Glioblastoma (GBM) is the most prevalent type of malignant tumor within the central nervous system. Possessing a five-year survival rate of 6.8%, new therapeutic options are a necessity in order to increase patient quality of life and survival outcomes. Arsenic trioxide (ATO) is an FDA approved drug for the treatment of relapsed or refractory acute promyelocytic leukemia. Clinical trials of ATO in combination with radiation and temozolomide show therapeutic effects in a modest subset of glioblastoma patients. ATO resistance in GBM cell lines is associated with MNK1-eIF4E upregulation. Additionally, diminished response to ATO is linked to resistance to oxidative stress via increased glutathione levels and NrF2 pathway expression. We sought to target each of these proposed mechanisms of resistance in order to develop a suite of compounds for use in combination therapies, with the goal of sensitizing GBM models to ATO. Six GBM PDX models were dosed with ATO at varying concentrations and monitored for the IC50 value of treatment. The cell lines exhibited a 20-fold difference in sensitivity, indicative of an underlying innate resistance to ATO. We performed drug dose response studies of patient-derived glioma cells treated with ATO in combination with the nutraceutical compounds Chrysin and Silibinin. Combination treatments using Chrysin and Silibinin showed potentiation of the cytotoxic effects of ATO. Confirmation of the mechanism for induced sensitivity to ATO will be explored by measuring shifts in glutathione content and susceptibility to oxidative stress in response to treatment using nutraceutical compounds. In addition, drug dosing with combination therapies utilizing the MAPK interacting serine/threonine kinase 1 (MNK1) inhibitors eFT-508 and EFT-206 also show synergistic effects in GBM cell lines. The eIF4E phosphorylation response to treatment of both ATO alone ATO MNK1i combination therapies will be monitored and analyzed for potential translational effects. Each of these compounds were selected based on safe use determined in clinical trials (MNK1 inhibitors) or over-the-counter availability (nutraceuticals). All four companion approaches show low pharmacological liabilities in crossing the blood brain barrier. Future studies involving these compounds will consist of testing these suggested combination therapies in vivo by observing their effectiveness in orthotopic, GBM tumor bearing mice. Identification and development of sensitization targets for ATO will allow for greater effectiveness of treatment and a greater potency of the drug in combating resistance which arises in response to treatment. Discovery of a predictive molecular signature of synergy from ATO and other targeted agents may pave the way for a successful clinical trial of these combinations in an identifiable subpopulation of GBM patients. Citation Format: Charles Shaffer, Nanyun Tang, Yue Hao, Karen Fink, George Snipes, Bruce Mickey, Michael Berens. Potentiation of arsenic trioxide in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1601.

Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients

Abstract: Androgen Receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase II clinical trial, we epigenetically profiled enhancer/promoter activities with H3K27ac chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identified a distinct subset of H3K27ac-differentially marked regions that associated with treatment responsiveness. These data were successfully validated in mCRPC patient-derived xenograft models (PDX). In silico analyses revealed HDAC3 as a critical factor that can drive resistance to hormonal interventions, which we validated in vitro. Using cell lines and mCRPC PDX tumors in vitro, we identified drug-drug synergy between enzalutamide and the pan-HDAC inhibitor vorinostat, providing therapeutic proof-of-concept. These findings demonstrate rationale for new therapeutic strategies using a combination of AR and HDAC inhibitors to improve patient outcome in advanced stages of mCRPC.

Supplementary Figures S1-S6 from Vorinostat Increases Expression of Functional Norepinephrine Transporter in Neuroblastoma &lt;i&gt;In Vitro&lt;/i&gt; and &lt;i&gt;In Vivo&lt;/i&gt; Model Systems

Abstract: <p>Supplementary Figures S1-S6.</p>

Data from HDAC Inhibitor Entinostat Restores Responsiveness of Letrozole-Resistant MCF-7Ca Xenografts to Aromatase Inhibitors through Modulation of Her-2

Abstract: <div>Abstract<p>We previously showed that in innately resistant tumors, silencing of the estrogen receptor (ER) could be reversed by treatment with a histone deacetylase (HDAC) inhibitor, entinostat. Tumors were then responsive to aromatase inhibitor (AI) letrozole. Here, we investigated whether ER in the acquired letrozole-resistant tumors could be restored with entinostat. Ovariectomized athymic mice were inoculated with MCF-7Ca cells, supplemented with androstenedione (Δ⁴A), the aromatizable substrate. When the tumors reached about 300 mm³, the mice were treated with letrozole. After initial response to letrozole, the tumors eventually became resistant (doubled their initial volume). The mice then were grouped to receive letrozole, exemestane (250 μg/d), entinostat (50 μg/d), or the combination of entinostat with letrozole or exemestane for 26 weeks. The growth rates of tumors of mice treated with the combination of entinostat with letrozole or exemestane were significantly slower than with the single agent (<i>P</i> < 0.05). Analysis of the letrozole-resistant tumors showed entinostat increased ERα expression and aromatase activity but downregulated Her-2, p-Her-2, p-MAPK, and p-Akt. However, the mechanism of action of entinostat in reversing acquired resistance did not involve epigenetic silencing but rather included posttranslational as well as transcriptional modulation of Her-2. Entinostat treatment reduced the association of the Her-2 protein with HSP-90, possibly by reducing the stability of Her-2 protein. In addition, entinostat also reduced Her-2 mRNA levels and its stability. Our results suggest that the HDAC inhibitor may reverse letrozole resistance in cells and tumors by modulating Her-2 expression and activity. <i>Mol Cancer Ther; 12(12); 2804–16. ©2013 AACR</i>.</p></div>

Supplementary Data from A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

Abstract: Supplementary Data from A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

Supplemental Table 3 from Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature

Abstract: <p>Table S3. Variants detected by NGS targeted re-sequencing</p>

Data Supplement from Synergistic Killing Effect between Vorinostat and Target of CD146 in Malignant Cells

Abstract: Data Supplement from Synergistic Killing Effect between Vorinostat and Target of CD146 in Malignant Cells