bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2559: Preclinical evaluation of dual PI3K-mTOR inhibitors and histone deacetylase inhibitors in head and neck squamous cell carcinoma
Authors: Saunders Nicholas A. , Erlich Rafael , Kherrouche Zoulika , Hazar-Rethinam Mehlika , de Long Lilia Merida , Guminski Alexander 
Published: June 2012

Abstract
In this study we have examined the potential value of a series of clinically relevant PI3K-mTOR inhibitors alone, or in combination with histone deacetylase inhibitors, in a model of head and neck squamous cell carcinoma (HNSCC). We present data relating to in vitro and in vivo pharmacological effects and efficacy for both these classes of drugs.
HNSCC cell lines, human keratinocyte and HNSCC xenograft models were treated with histone deacetylase inhibitors (HDACIs) and new generation PI3K and dual PI3K-mTOR inhibitors either alone or in combination. Cell and tumour tissue viability and proliferation were determined in vitro and in vivo following treatments. Effect upon activation status of signalling pathways was also investigated.
We report that PI3K, AKT, and dual PI3K-mTOR inhibitors (LY294002, Wortmannin, AKT VIII, BEZ235, BKM120 and BGT226) caused a marked in vitro enhancement of cytotoxicity induced by HDACIs (vorinostat, depsipeptide, valproic acid and LBH589) in HNSCC cancer cells (SCC25, Cal27, Detroit 562). This effect correlates with intense and duration of AKT inhibition, reactive oxygen species (ROS) accumulation, and is attenuated by expression of constitutively active AKT. LBH589, BEZ235, BGT226 and BKM120 inhibited tumour growth alone and in combination in a xenograft model of HNSCC. However, we saw no evidence of improved efficacy with an HDACI / PI3KI combination. Importantly, we observed intratumoural HDAC inhibition and PI3K inhibition as assessed by histone H3 acetylation status and phospho-AKT staining respectively. Finally, further studies indicated that the PI3KI/mTOR inhibitor, BGT226, could significantly enhance cisplatin or taxane-induced cytotoxicity in HNSCC cell lines in vitro.This study indicates, for the first time, that new generation clinically relevant PI3K and dual PI3K-mTOR inhibitors possess antitumour effect against SCC in vivo. These findings provide a rational basis for pursuing clinical trials of PI3KIs in HNSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2559. doi:10.1158/1538-7445.AM2011-2559
Abstract 2575: Differentiation of NUT midline carcinoma by epigenomic reprogramming
Authors: Schwartz Brian , Hofer Matthias , Lemieux Madeleine , Bauer Daniel , Cameron Michael , West Nathan , Agoston Elin , Ince Tan , Christie Amanda , Aster Jon , Sallan Stephen , Kung Andrew , Bradner James , French Chris A. 
Published: June 2012

Abstract
NUT midline carcinoma (NMC) is a lethal tumor defined by the presence of BRD-NUT fusion proteins that act by arresting differentiation. Here, we explore the mechanisms underlying the ability of BRD4-NUT to prevent squamous differentiation. We find that overexpression of the twin bromodomains of BRD4 or a portion of NUT that binds the histone acetyltransferase (HAT) p300 induces NMC cells to differentiate, suggesting a model in which BRD4-NUT sequesters HATs in areas of acetylated chromatin. Consistent with this idea, knockdown of BRD4-NUT caused global increases in histone acetylation, whereas enforced expression of BRD4-NUT had the opposite effect. Sequestration of HATs appears to occur in nuclear BRD4-NUT foci, which correspond to specific genomic regions that are rich in acetylated histones but transcriptionally inactive. Of therapeutic interest, treatment of NMC cells with histone deacetylase inhibitors (HDACi) dispersed nuclear foci, restored histone acetylation, induced NMC cells to differentiate in vitro, and had anti-tumor effects in NMC xenograft models. The data suggest that this rational therapeutic approach merits further evaluation in patients with NMC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2575. doi:10.1158/1538-7445.AM2011-2575
Abstract 2600: HMGB1, a potential new target for mesothelioma therapy
Authors: Jube Sandro , Rivera Zeyana , Gaudino Giovanni , Pass Harvey I. , Bianchi Marco E. , Carbone Michele , Yang Haining 
Published: June 2012

Abstract
Malignant mesothelioma (MM) is a very aggressive cancer that causes 2000-3000 deaths annually in the U.S. and is resistant to current therapies. Diagnosis frequently occurs at a late stage of disease progression and median survival from time of diagnosis is about 1 year. Therefore, novel therapeutic strategies are urgently needed. We found previously that High-Mobility Group Box 1 protein (HMGB1), a known pro-inflammatory cytokine, induces tumor necrosis factor-alpha (TNF-α) secretion, potentiates survival of asbestos-exposed primary human mesothelial cells (HM) and enables HM malignant transformation, which leads to the initiation of MM. We show here that HMGB1 is also critical in the maintenance and progression of established MM. We found that HMGB1 is highly expressed in MM tissues and its levels in MM patients’ sera are significantly higher than in those of healthy individuals (P &lt; 0.0001). MM tumor cells over-express HMGB1 in both the nucleus and cytoplasm. Instead, normal HM only express nuclear HMGB1 at significantly lower level than MM cells. The main receptor of HMGB1, receptor for advanced glycation end products (RAGE), is also upregulated in MM cells compared to HM. MM cells release biologically active HMGB1 into extra-cellular space, and the interaction with its receptors induces cell proliferation and chemo-attractant activity on MM cells. Moreover, the interference with HMGB1 activity by using specific HMGB1 inhibitors, such as BoxA and HMGB1 neutralizing monoclonal antibodies, leads to MM cell death. HMGB1 inhibitors impair MM cells migration, invasion, wound healing and also colony formation in soft agar. Our results strongly suggest that HMGB1 can be a novel target for mesothelioma therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2600. doi:10.1158/1538-7445.AM2011-2600
Abstract 2608: HDAC-C1A: An irreversible HDAC inhibitor with significant anti-tumor activity
Authors: Kaliszczak Maciej , Perumal Meg , Aboagye Eric 
Published: June 2012

Abstract
Histone deacetylase (HDAC) enzymes exert control over gene transcription and cell cycle progression and their inhibition has recently emerged as an efficacious strategy to treat cancer. However, current HDAC inhibitors have been linked to a shared undesirable toxicological profile that prompts the development of new entities. The present study evaluates the in vitro and in vivo PK/PD of a newly developed HDAC inhibitor, HDAC-C1A.
HDAC-C1A inhibited class I, II and sirtuins, with highest affinity for HDAC6 (IC50 = 63 ng/mL), an HDAC subtype thought to be associated with low toxicity; HDAC6 knockout does not lead to embryonic lethality. The drug irreversibly inhibited HDAC from HeLa cell extract; in HCT116 cells inhibition of enzyme activity as assessed by levels of acetyl-histone H3, H4 and acetyl-tubulin was maintained after washout demonstrating an irreversible mechanism. HDAC-C1A treatment was associated with a dose and time dependent increase of histone and non-histone targets that was maintained at 4 hours after washout; acetylation was lost by 4 h with clinically licensed HDAC inhibitor SAHA. HDAC-C1A inhibited the growth of a panel of 7 cancer cell lines with a mean GI50 of 1.6 ± 0.6 µg/mL. The drug was relatively stable after parenteral administration for 4 h. The Cmax and AUC0-4h following i.p. injection (160 mg/kg) were 20.4 µg/mL and 50 µg/mL*h, respectively.
Regarding efficacy, HDAC-C1A treatment was associated with a Tumor Growth Delay (TGD2x) of 5.7 ± 1.4 days and a Tumor Growth Inhibition (TGI) of 78% compared with vehicle when given i.p. at 20 mg/kg b.i.d. in a HCT116 human colon cancer xenograft model. This dose was non-toxic (no reduction in body weight). We also assessed the potential of [18F]fluorothymidine positron emission tomography ([18F]FLT-PET) to measure early response to HDAC-C1A treatment in HCT116 xenograft bearing mice. There was a 2-fold decrease in tumor [18F]FLT uptake compared to vehicle treated animals at 48 h post-treatment; the area under the normalized [18F]FLT time versus activity curve was 117 ± 6.9 at before treatment and decreased to 106 ± 5.5 (P = 0.02) at 24 hours and 54 ± 5 (P = 0.0001) at 48 h after initiating treatment.
In summary, HDAC-C1A combines irreversible HDAC inhibition with a favourable pharmacokinetic profile leading to significant anti-tumor activity in the HCT116 tumor model. Early response to the drug was detectable by [18F]FLT-PET. These preclinical data support further development of HDAC-C1A. This work was supported in part by Cancer Research U.K.-Engineering and Physical Sciences Research Council Grant C2536/A10337.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2608. doi:10.1158/1538-7445.AM2011-2608
Abstract 2614: Inhibition of class I histone deacetylases attenuates anthracycline induced activation of the ATM pathway
Authors: Thurn Kenneth (Ted) , Thomas Scott , Raha Paromita , Qureshi Ian , Munster Pamela N. 
Published: June 2012

Abstract
Breast cancer is one of the most common cancers to afflict women in the world. Anthracycline-based regimens, including doxorubicin and epirubicin (epidoxorubicin), are common therapies for patients with breast cancer. Doxorubicin and epirubicin are inhibitors of topoisomerase II, which cause double strand DNA breaks. Following anthracycline-induced damage, DNA damage response pathways are activated in order to initiate cell cycle arrest, DNA repair, and/or cell death. The recent introduction of PARP inhibitors highlights the clinical relevance of targeting DNA repair pathways in treating this disease.
Recently, two histone deacetylase (HDAC) inhibitors have been approved by the Federal Drug Administration for the treatment of cutaneous T-cell lymphoma: vorinostat and romidepsin. HDAC inhibitors reduce the repair of DNA, and are being used in combination with DNA damaging chemotherapeutic agents. The mechanisms regulating the HDAC inhibitor-mediated reduction of DNA repair in breast cancer cells are not well established. Understanding these mechanisms will identify key therapeutic targets for reducing DNA repair, define the role of HDACs in DNA repair, and allow for the enrichment of patients most susceptible to HDAC inhibitor-chemotherapy combined treatment.
Previously, our group has demonstrated an increase in DNA decondensation which permits greater access of anthracyclines to DNA after therapeutic inhibition of HDACs. New results demonstrate that phosphorylation of p53 at Serine 15 is decreased in the presence of epirubicin after pre-treatment with vorinostat in a time- and concentration-dependent manner. Total p53 protein levels are also decreased, while mRNA levels remain unchanged after combined treatment. Treatment of breast cancer cells with valproic acid or entinostat also attenuates phosphorylation of p53 after epirubicin treatment, suggesting the involvement of Class I HDACs in the activation of p53. Phosphorylation of DNA repair kinase ATM is also decreased following DNA damage in the presence of clinically relevant concentrations of vorinostat, and corresponds with a decrease in activation of downstream factors including CHK1, CHK2, and BRCA1. These results demonstrate that inhibition of Class I HDACs in breast cancer cells delays DNA damaging response signaling through p53 modification after anthracycline administration; suggesting a possible mechanism for synergy between HDAC inhibitors and DNA damaging agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2614. doi:10.1158/1538-7445.AM2011-2614
Abstract 2619: Potential advantages of CUDC-101, a multi-targeted HDAC, EGFR and HER2 inhibitor, on preventing drug resistance and tumor metastasis
Authors: Wang Jing , Selmi Kader , Samson Maria , Forrester Jeffrey , Atoyan Ruzanna , Qu Hui , Yin Ling , Wang Da-Gong , Zifcak Brian , Borek Mylissa , DellaRocca Steven , Bao Rudi , Zhai Hai-Xiao , Cai Xiong , Qian Changgeng , Savagner Pierre , Lai Cheng-Jung 
Published: June 2012

Abstract
CUDC-101 is a novel small-molecule multi-target anti-cancer agent currently in Phase Ib clinical trial, which targets histone deacetylase (HDAC), epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor2 (HER2). Previously, we reported that CUDC-101 has potent anti-proliferative and pro-apoptotic activities in cultured tumor cells and in vitro xenograft models when compared to other single-target agents. Additionally, we demonstrated that CUDC-101 reduces the levels of phosphorylated and total MET. MET amplification and secondary EGFR mutation are two validated mechanisms responsible for EGFR tyrosine kinase inhibitor (TKI) drug resistance in patients. In an effort to expand on our previous findings, we further substantiate here that cancer cells harboring MET amplification are sensitive to CUDC-101. This result, together with the finding that cancer cells containing the EGFR-T790M mutation are sensitive to CUDC-101, suggests that RTK inhibitor-resistant tumor cells are sensitive to treatment with CUDC-101. Additionally, erlotinib-resistant HCC827 cells, which lost their EGFR dependence, are still sensitive to treatment with CUDC-101. Interestingly, this drug-resistant cell line shows neither secondary EGFR mutation nor c-Met amplification, suggesting that CUDC-101 has the potential to overcome drug resistance through other mechanisms. Because c-Met plays an important role in metastasis, we further investigated the effect of CUDC-101 in regulating cell motility, and demonstrate that CUDC-101 can induce E-cadherin accumulation in MDA-MB-231 cells and inhibit EGF induced epithelial-mesenchymal transition (EMT) in in vitro cultured cell and in vivo animal models. In vitro functional study also shows that CUDC-101 reduces tumor cell migration and invasion. Together, our findings suggest that CUDC-101, an investigational anti-cancer drug, may provide great potential for simultaneously overcoming tumor growth, metastasis, and drug resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2619. doi:10.1158/1538-7445.AM2011-2619
Abstract 2623: ST3595, a new histone deacetylase (HDAC) inhibitor endowed with a peculiar mechanism of action
Authors: Pisano Claudio , Vesci Loredana , Milazzo Ferdinando M. , Guglielmi Mario B. , Barbarino Marcella , Foderà Rosanna , Zuco Valentina , Zunino Franco 
Published: June 2012

Abstract
The novel hydroxamic acid-based compound ST3595, was identified within an in vitro screening for its inhibitory activity on histone deacetylase's (HDAC's) (Pisano C. et al., Clin Cancer Res 2010, 16 (15): 3944-53; Dalla Valle S et al., Eur J Med Chem 2009, 44 (5): 1900-12). With aim to define its antitumor potential, we investigated the in vivo activity of ST3595 in a variety of tumor models. In addition, we performed a comparative study of ST3595 and vorinostat (SAHA) to better understand the cellular/molecular basis of the antiproliferative activity. In in vivo experiments, ST3595, delivered orally or i.p. at well-tolerated doses (100 mg/kg) induced a significant tumor growth inhibition (ranging from 57 to 87%) in a variety of human tumor xenografts (H460 non-small cell lung, HCT116 colon and A2780 ovarian carcinoma). In in vitro studies, ST3595 exhibited arrest of H460 cells (wt p53) in S phase associated with a large extent of apoptosis. Under conditions producing comparable antiproliferative effects, treatment with vorinostat resulted in a G2/M arrest with a marginal induction of apoptosis. In HT29 cells (mutant p53) ST3595 caused arrest in S and G2/M phases with apoptosis induction, whereas vorinostat induced G1 accumulation without evidence of apoptosis, thus suggesting only antiproliferative effects. To explore the basis of the different cellular effects, we investigated the modulation of various factors implicated in DNA damage response and repair, cell cycle control and regulation of apoptosis. In H460 cells, we found that, in contrast to vorinostat, ST3595 was an effective inducer of p53 acetylation, supporting a role of this p53 modification in the proapoptotic activity of ST3595. In addition, in contrast to vorinostat, ST3595 strongly affected the expression of critical proteins involved in cell cycle control and DNA damage response. In particular, ST3595 induced activation and phosphorylation of H2AX, and of the checkpoint kinases chk1 and chk2, thus supporting an interference of the HDAC inhibitor in the processes controlling DNA integrity. In the light of the use of broad-specificity HDAC inhibitors in cancer therapy and in combination with other antitumor agents, the ability of ST3595 to modulate DNA damage response and it proapoptotic efficacy may have relevant implications in enhancing antitumor activity of well-established cytotoxic agents. Preclinical studies of ST3595 with genotoxic agents support this interpretation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2623. doi:10.1158/1538-7445.AM2011-2623
Abstract 2626: Thiazole antibiotic/proteasome inhibitor thiostrepton against cancer
Authors: Pandit Bulbul , Wang Ming , Halasi Marianna , Gartel Andrei L. 
Published: June 2012

Abstract
Thiazole antibiotic, thiostrepton was identified as an inhibitor of oncogenic transcription factor FoxM1, later demonstrated to exhibit proteasome inhibitory activity. We found that polymeric micelle-encapsulated thiostrepton reduced tumor growth rate in MDA-MB-231-luc breast cancer xenografts. Encapsulation of thiostrepton into polymeric micelles can aid its solubilization and increase its accumulation into tumor sites. Furthermore, its anti-cancer effects on breast cancer xenografts were found to be through reducing cell proliferation and inducing cell death. Thiostrepton is sulfur containing highly modified macrocyclic antibiotic with a central pyridine/tetrapyridine/dehydropiperidine ring with up to three thiazole substituents on positions 2, 3 and 6, which has macrocyclic loop connecting thiazole rings at position 2 and 3 described as ring A. In addition, it has a quinaldic acid macrocycle also connected to thiazole on position 2 described as ring B. Structural modification of thiostrepton to thiostrepton methyl ester (with open B ring) did not demonstrate proteasome inhibitory activity. These data suggest that B ring of thiostrepton and similar thiazole antibiotic Siomycin A that is absent in other thiazole antibiotics determines the proteasome inhibitory activity of these drugs. We investigated the therapeutic potential of the combination of thiostrepton and proteasome inhibitor bortezomib (Velcade) on various human tumor cell lines. Combination of sublethal concentrations of thiostrepton and bortezomib induced potent apoptosis and inhibition of long-term colony formation in a wide variety of human cancer cell lines. The synergistic realtionship between thiostrepton and bortezomib combination was also quantitatively demonstrated by low combination index between 0.1 and 0.8. The synergy between these drugs was based on their proteasome inhibitory activities of both drugs, because structurally similar thiostrepton modification, thiostrepton methyl ester that did not have proteasome inhibitory activity failed to increase apoptosis in combination with bortezomib
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2626. doi:10.1158/1538-7445.AM2011-2626
Abstract 263: MYC enforces overexpression of EZH2 in early prostatic neoplasia via transcriptional and posttranscriptional mechanisms
Authors: Koh Cheryl M. , Iwata Tsuyoshi , Zheng Qizhi , Bethel Carlise , Yegnasubramanian Srinivasan , De Marzo Angelo M. 
Published: June 2012

Abstract
EZH2 is part of the PRC2 polycomb repressive complex that is overexpressed in multiple cancer types and has been implicated in prostate cancer initiation and progression. Here we identify EZH2 as a target of the MYC oncogene in prostate cancer and show that MYC coordinately regulates EZH2 through transcriptional and post-transcriptional means. Although prior studies in prostate cancer revealed a number of possible mechanisms of EZH2 upregulation, these changes cannot account for the overexpression of EZH2 in many primary prostate cancers, nor in most cases of high grade PIN. We report that upregulation of MYC in the mouse prostate results in overexpression of EZH2 mRNA and protein which coincides with reductions in miR-26a and miR-26b, known regulators of EZH2 in some non-prostate cell types, albeit not in others. Further, in human prostate cancer cells, MYC negatively regulates miR-26a and miR-26b via direct binding to their parental Pol II gene promoters, and forced overexpression of miR-26a and miR-26b in prostate cancer cells results in decreased EZH2 levels and suppressed proliferation. In human clinical samples, miR-26a and miR-26b are downregulated in most prostate cancers. In a novel mechanism of EZH2 mRNA upregulation, we find that MYC binds directly to and activates the transcription of the EZH2 promoter. These results link two major pathways in prostate cancer by providing two additional and complementary MYC-regulated mechanisms by which EZH2 upregulation occurs and is enforced during prostatic carcinogenesis. Further, the results implicate EZH2-driven mechanisms by which MYC may stimulate prostate tumor initiation and disease progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 263. doi:10.1158/1538-7445.AM2011-263