bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5849: Valproic acid reverses trastuzumab resistance in erbB2-positive breast cancer cells via downregulation of ErbB2/ErbB3 signaling through induction of ErbB family members-targeting miRNAs
Authors: Lin Tingting , Ren Qun , Zuo Weimin , Lin Rong , Zhao Hu , Wang Ping , Tan Jianming , Lyu Hui , Liu Bolin , Wang Shuiliang 
Published: August 2018

Abstract
Amplification and/or overexpression of erbB2 occur in approximately 25% of invasive breast cancer and are significantly associated with a worse prognosis for breast cancer patients. Trastuzumab, a humanized monoclonal antibody against erbB2 receptor, has been successfully used in early-stage and metastatic breast cancer therapy of patients with erbB2-overexpressing tumors as monotherapy and in combination with other agents; however, both primary and acquired resistances to trastuzumab are common and currently represent a significant clinical problem. Thus, seeking of novel therapeutic strategies/agents to overcome trastuzumab resistance is vital to improve the survival of breast cancer patients whose tumors overexpress erbB2. In our current study, we explored whether valproic acid (VPA), a clinically used anticonvulsant drug with reported HDACi activity, reverses trastuzumab resistance in erbB2-positive breast cancer cells. We have found that VPA inhibits proliferation of both trastuzumab-sensitive SKBR3 and BT474 cell lines as well as their corresponding trastuzumab-resistant SKBR3-pool2 and BT474-HR20 cell lines in a dose- and time-dependent manner, which is accompanied by significant reduction of cyclin D1 as well as induction of P21. Meanwhile, VPA also induces caspase-dependent apoptosis in all aforementioned four cell lines. More interestingly, VPA not only significantly enhances the anti-proliferative effects of trastuzumab, but also potentiates trastuzumab-induced apoptosis in trastuzumab-sensitive and resistant cells. Our further mechanistic studies revealed that VPA treatment results in significant inactivation of PI3K/Akt signaling via simultaneous down-regulation of ErbB2 and ErbB3 in erbB2-positive breast cancer cancer cells, an effect which could be mainly arrtibuted to induction of ErbB family members-targeting microRNAs including miR-125a, miR-125b and miR-205 by VPA. Taken together, we presented here that VPA reverses trastuzumab resistance in erbB2-positive breast cance cells via downregulation of ErbB2/ErbB3 signaling in a miRNAs-inducing-dependent manner. Our data suggested that further investigation regarding the in vivo therapeutic effect of VAP against trastuzumab-resistant breast cancer should be of especial interest.
Citation Format: Tingting Lin, Qun Ren, Weimin Zuo, Rong Lin, Hu Zhao, Ping Wang, Jianming Tan, Hui Lyu, Bolin Liu, Shuiliang Wang. Valproic acid reverses trastuzumab resistance in erbB2-positive breast cancer cells via downregulation of ErbB2/ErbB3 signaling through induction of ErbB family members-targeting miRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5849.
Abstract 5861: RX-3117 promotes epigenetic effects in cancer cells through enhanced degradation of DNMT1
Authors: Sarkisjan Dzjemma , Pronk Ferry , Kuin Rosan , Hassouni Btissame el , Lee Young B. , Kim Deog J. , Dijk Marc , Geerke Daan P. , Peters G. J. 
Published: August 2018

Abstract
RX-3117 is a novel, investigational, oral, small molecule nucleoside compound that shows promising antitumor activity in xenografts including patient-derived xenografts resistant to gemcitabine. RX-3117 is currently being evaluated in a Phase IIa multi-center, open-label clinical study in patients with relapsed or refractory pancreatic cancer and advanced bladder cancer. RX-3117 can downregulate DNMT1 and activate genes controlled by methylation, such as E-cadherin and p16. We aimed to elucidate the mechanism of RX-3117 mediated downregulation of DNMT1.
Expression of DNMT1 was evaluated by western blotting. Binding of DNMT1 to DNA was measured after DNA isolation, DNAse treatment and gel electrophoresis. DNMT1 trapping in the nucleus was also studied with ImageStream FACS analysis. DNMT1 ubiquitination was measured by immunoprecipitation and quantification of the ubiquitin tag K48. Translocation of DNMT1 was studied by confocal microscopy. Modeling studies were performed with Quantum Mechanics (QM) and Molecular Dynamics (MD).
DNMT1 acts on the DNA during the so-called base flipping necessary for methyl transfer. To determine whether RX-3117 treatment would lead to trapping of DNMT1, NSCLC A549 and PDAC SUIT-028 cells were treated for 24 hr with 1 µM RX-3117. Immunostaining of DNMT1-DNA and ImageStream FACS analysis demonstrated binding of DNMT1 to DNA. Treatment with RX-3117 also resulted in DNMT1 ubiquitination, as shown by an increase in the ubiquitin tag K48, reaching the highest level after 48 hr. Incubation of A549 and SUIT-028 cells with 80 nM of the specific proteasome inhibitor bortezomib prevented RX-3117 mediated degradation of DNMT1 (at 24 and 24 hr exposure to 1 µM RX-3117). This underlines the role of the proteasome in DNMT1 degradation. With confocal microscopy it was demonstrated that DNMT1 and the proteasome co-localized and translocated to the cytosol of A549 and SUIT-028 cells treated for 48 hours with 1 µM RX-3117. With molecular modelling using QM and MD, changes in nucleophilicity of C4-C5 double bound were observed indicating that DNMT1 would initiate methyl transfer but cannot proceed.
In summary we conclude that RX-3117 induces epigenetic changes in cancer cells by trapping DNMT1 in the nucleus followed by translocation of the protein to the proteasome for degradation.
Citation Format: Dzjemma Sarkisjan, Ferry Pronk, Rosan Kuin, Btissame el Hassouni, Young B. Lee, Deog J. Kim, Marc Dijk, Daan P. Geerke, G. J. Peters. RX-3117 promotes epigenetic effects in cancer cells through enhanced degradation of DNMT1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5861.
Abstract 5874: Targeting DDX3 in medulloblastoma by RK-33
Authors: Tantravedi Saritha , Vesuna Farhad , Martin Allison , Lim Michael , Eberhart Charles G. Eberhart G. , Diest Paul J. van , Raman Venu 
Published: August 2018

Abstract
Introduction: Medulloblastoma is the most common form of pediatric brain cancer. Current treatments of surgical resection, craniospinal irradiation, and chemotherapy increase survival but around 40% of patients experience disease recurrence. Classically, four molecular subgroups of medulloblastoma have been identified: Wnt; Sonic hedgehog (SHH); Group 3; and Group 4. More recent work has subtyped up to seven molecular subgroups. The RNA helicase DDX3 is involved in many biological activities such as transcription, mRNA translation, splicing, and nuclear export. About 8% of medulloblastoma cases involve mutations in DDX3, of which 11% involve the pediatric Wnt and SHH subtypes. In addition, coinciding DDX3 and CTNNB1 mutations associated with dysregulated Wnt /β-catenin signaling in Wnt-type medulloblastomas have also been reported.
Aims and Methods: The goal of this work was to study whether RK-33, a small molecule inhibitor of DDX3, would be effective against medulloblastoma as a single agent and in combination with radiotherapy. We studied DDX3 expression in medulloblastoma cell lines DAOY and UW228 and human tissue microarrays by immunohistochemistry, western blotting, and qRT-PCR. We targeted DDX3 by siRNA and by RK-33 and observed proliferation and viability changes by MTS assays. Flow cytometric analysis was used to determine effect of RK-33 on cell cycle and apoptosis. TOP/FOP promoter assay was utilized to study effect on TCF promoter activity. We used colony formation assays to study effect of combining radiation and RK-33 treatment on cells. DAOY tumors were generated in nude mice and treated with combination therapy to study effects in vivo.
Results: High DDX3 expression was observed in 55% of pediatric and 66% of adult medulloblastomas. DDX3 knockdown resulted in reduced cellular proliferation. Both the medulloblastoma cell lines were sensitive to RK-33, with IC50 values of 2.5 µM and 3.5 µM, respectively and resulted in decreased levels of DDX3 expression, with no observable toxicity. RK-33 resulted in a G1 phase cell cycle arrest before the onset of apoptosis. DDX3 knockdown resulted in a significant decrease of TCF activity and reduced transcription of Axin2, CCND1, MYC, and Survivin. A combination of RK-33 and radiation resulted in a significantly higher inhibitory effect than using single treatment of either RK-33 or radiation. We conclude that inhibiting DDX3 via the small molecule inhibitor RK-33 is effective in reducing medulloblastoma tumors and that the effect is synergistic with radiation treatment.
Citation Format: Saritha Tantravedi, Farhad Vesuna, Allison Martin, Michael Lim, Charles G. Eberhart G. Eberhart, Paul J. van Diest, Venu Raman. Targeting DDX3 in medulloblastoma by RK-33 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5874.
Abstract 5881: Novel inhibitors of the epigenetic reader protein MBD2
Authors: Giovinazzo Hugh , Reichert Zachary R. , Bergman Andries , Lin Xiaohui , Wyhs Nicolas , Esopi David , Vaghasia Ajay , Liu Jianyong , Jain Yash , Bhamidipati Akshay , Steinberg Ruchama , Speed Traci , Vaughn Matthew , Zhang Yonggang , Brennen Nate , Deweese Theodore , Yegnasubramanian Srinivasan , Nelson William G. 
Published: August 2018

Abstract
DNA hypermethylation can trigger silencing of tumor suppressor genes during cancer development and progression, partly through binding by methylated-DNA binding proteins (MBD), such as MBD2, that function as “epigenetic readers” and recruit co-repressor complexes to promote gene repression. Inhibiting MBD2-mediated repression represents an attractive cancer therapeutic strategy. Here, we used a cell-based screen to identify small molecules capable of reactivating hypermethylated promoter sequences. We used biochemical, molecular biologic, and pharmacologic approaches to characterize mechanism of action of identified MBD2 inhibitors. A subset of these compounds represent a new class of inhibitors capable of selectively antagonizing interactions between MBD2 and methylated DNA, leading to reactivation of the hypermethylated gene GSTP1 and the epigenetically silenced retinoic acid signaling pathway. Combinations of one of the newly identified MBD2 inhibitors, KCC-08, with the retinoic acid receptor agonist, isotretinoin, significantly reduced cancer cell growth/survival in vitro and in vivo. These novel MBD2 inhibitors are thus positioned for further pharmacologic lead development for use as probes to interrogate epigenetic gene silencing mechanisms and as cancer therapeutics.
Citation Format: Hugh Giovinazzo, Zachary R. Reichert, Andries Bergman, Xiaohui Lin, Nicolas Wyhs, David Esopi, Ajay Vaghasia, Jianyong Liu, Yash Jain, Akshay Bhamidipati, Ruchama Steinberg, Traci Speed, Matthew Vaughn, Yonggang Zhang, Nate Brennen, Theodore Deweese, Srinivasan Yegnasubramanian, William G. Nelson. Novel inhibitors of the epigenetic reader protein MBD2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5881.
Abstract 5888: Disruption of FOXO3a-miRNAs mediated feedback inhibition of IGF2-IRS1 signaling contributes to Herceptin resistance in HER2 positive breast cancer cells
Authors: He Zhimin 
Published: August 2018

Abstract
Resistance to HER2-target therapy remains a clinical challenge for HER2+ breast cancer subtype. The molecular mechanisms for Herceptin resistance remain elusive. Here, we demonstrated that the IGF2 and IRS1 protein levels were increased in Herceptin resistant breast cancer cells and that the IGF2/IGF1R/IRS1/Akt/mTOR signaling was involved in Herceptin resistance. In Herceptin sensitive HER2+ breast cancer cells, IRS1 protein level resulted from mTOR2 mediated FOXO3a status determined the feedback regulation of IGF2. Upon high dose rhIGF2 treatment, the mTOR1 translationally upregulated PPP3CB protein level that recovered the function of FOXO3a inactivated by mTOR2. FOXO3a positively transcriptionally regulated miR-128-3p and miR-30-5p expression that targeted IRS1 mRNA to control the feedback regulation of IGF2 signaling. In agreement, in Herceptin resistant cells, the decrease of miR-128-3p and miR-30-5p resulted from constitutively inactivation of FOXO3a by mTOR2, led to increase of IRS1 protein level, even in response to high endogenous IGF2 protein level in culture medium. High IGF2 protein level was resulted from decrease of miR-193a-5p that was also regulated by FOXO3a. Unexpectedly, in Herceptin resistant cells, Src/p-STAT5 signaling cooperating with HDAC1 transcriptionally repressed PPP3CB expression resulting into FOXO3a inactivation. Moreover, we confirmed that IRS1 knockdown reversed the Herceptin resistance in vivo using a xenograft mouse model. Serums form patients with poor response to Herceptin, had higher IGF2 protein level. Tissues from patients with poor response had higher IRS1, p-Akts473, p-FOXO3a and p-Src levels, but had lower PPP3CB, miR-128-3p, miR-30-5p and miR-193a-5p levels. In conclusions, disruption of PPP3CB-FOXO3a-miRNAs mediated feedback inhibition of IGF2-IRS1 signaling plays pivotal role in Herceptin resistance of HER2+ breast cancer. Related molecules in this signaling may represent potential biomarkers and therapeutic targets for HER2+ breast cancer treatment.
Keywords: Breast cancer, Herceptin resistance, IGF2, IRS1, FOXO3a
This study was supported by grants from the National Natural Science Foundation of China: No.81672616, No.81402196 and No.81272450, supported by grants from Guangdong Natural Science Funds for Distinguished Young Scholars No.2016A030306003 (G Zheng).
Citation Format: Zhimin He. Disruption of FOXO3a-miRNAs mediated feedback inhibition of IGF2-IRS1 signaling contributes to Herceptin resistance in HER2 positive breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5888.
Abstract 589: A systematic review of randomized clinical trials for therapeutic outcomes of anti-EGFR agents used in combination with other targeted therapies
Authors: Kurup Sonali , Liskova Pavlina , Jungsuwadee Paiboon , Sakharkar Prashant , Tambe Soniya 
Published: August 2018

Abstract
Introduction: The epidermal growth factor receptor (EGFR) plays a prominent role in cancer cell proliferation and metastasis in non-small-cell lung cancer (NSCLC). Targeted cancer therapies include agents that block tumor-specific molecular targets and thereby interfere with tumor growth, progression and metastasis. This study focuses on a systematic review of outcomes from phase II and III clinical trials for standard anti-EGFR therapy plus a targeted therapy to EGFR monotherapy.
Methods: Studies were identified through a thorough literature search using, EMBASE, Pubmed, Scifinder Scholar, clinicaltrials.gov and the Cochrane library using the following terms: “epidermal growth factor receptor kinase”, “combination therapy”, “non small cell lung cancer”. Eligible studies included patients of any stage and mutation status. Data abstraction included patient demographic characteristics; sample size, patient inclusion and exclusion criteria, overall response rate (ORR), median progression free survival (PFS), median overall survival (OS), and adverse effects (AE).
Results: Literature search resulted in the identification of 1543 studies of which 153 were found to be relevant for this review and 31 fit the inclusion criteria. Of the 31 studies, 28 included erlotinib and 3 studies included gefitinib as the control. Twenty-five of the studies focused on kinase inhibitors targeting VEGFR, EGFR, MET, IGF-1R, AKT, mTOR and HER3 as the combination agent. The remaining six studies focused on alternate pathways of targeted inhibition including hormonal agents and histone deacetylase inhibitors. The identified studies included patients (N=7552) of mean age (63 ± 2), female (22-80%), smokers in combination therapy (12-96%) versus monotherapy (8-95%). Median OS (months) for patients on the EGFR-based combination regimen (range 5.7-24.7) vs monotherapy (range 4.5-21.8). Median PFS (months) for patients on the EGFR-based combination regimen (range 1.3-16.0) vs monotherapy (1.5-9.7). A greater incidence of AE was observed for EGFR-based combination therapy compared to EGFR monotherapy.
Conclusions: Several different targeted therapies have been evaluated as part of clinical trials for NSCLC in combination with EGFR-based therapies, and compared to EGFR-based monotherapy. For patients with NSCLC, a higher range for median OS and median PFS was observed for EGFR-based combination regimens compared to EGFR monotherapy.
Citation Format: Sonali Kurup, Pavlina Liskova, Paiboon Jungsuwadee, Prashant Sakharkar, Soniya Tambe. A systematic review of randomized clinical trials for therapeutic outcomes of anti-EGFR agents used in combination with other targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 589.
Abstract 5893: Expression and role of autophagy-associated p62 (SQSTM1) in multidrug-resistant ovarian cancer
Authors: Wang Jinglu , Garbutt Cassandra , Hornicek Francis J , Duan Zhenfeng 
Published: August 2018

Abstract
Multidrug resistance is the major cause of treatment failure in ovarian cancer. p62 (SQSTM1) is a multifunctional protein involved in multiple cellular processes including proliferation, drug sensitivity and autophagy-associated cancer cell growth. p62 is a critical indicator of autophagic flux, which is inversely associated with autophagy activity. However, the role of p62 remains controversial in drug resistance in human ovarian cancer. In this study, we examined p62 expression by immunohistochemistry in a unique ovarian cancer tissue microarray (TMA), which was constructed with paired primary, metastatic, and recurrent tumor tissues from 26 individual patients. Results showed that both the metastatic and recurrent tumor tissues expressed less p62 than the patient-matched primary tumor. A significant inverse correlation has been found between p62 expression and both the disease free survival and overall survival. In addition, multidrug resistant cancer cell lines expressed lower levels of p62 as compared with their parental drug sensitive cell lines. Importantly, cell viabilities determined by MTT assay after exposure to different concentrations of paclitaxel showed inhibition of autophagy or accumulation of p62 enhances paclitaxel sensitivity in ovarian cancer drug resistant cells. Furthermore, the wound healing assay exhibited that inhibition of autophagy significantly decreased multidrug resistant ovarian cancer cell migration in vitro. Collectively, these data highlight that autophagy pathway may be a promising therapeutic target to prevent metastasis, recurrence and to reverse drug resistance in ovarian cancer.
Citation Format: Jinglu Wang, Cassandra Garbutt, Francis J Hornicek, Zhenfeng Duan. Expression and role of autophagy-associated p62 (SQSTM1) in multidrug-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5893.
Abstract 5902: RNA sequencing analysis of taxane-resistant prostate cancer cells reveals potential candidate genes for therapeutic targeting
Authors: Ross Christina K. Cajigas-Du , Woods-Burnham Leanne , Ramirez Joshua , Chen Xin , Wang Charles , Casiano Carlos A. 
Published: August 2018

Abstract
There is no cure for metastatic prostate cancer (PCa), the most commonly diagnosed cancer and third leading cause of cancer mortality among U.S. men. Patients with advanced PCa often develop resistance to conventional therapies resulting in metastatic castration-resistant PCa (mCRPC). Docetaxel (DTX) chemotherapy is the standard-of-care for mCRPC, followed by secondary chemotherapy with cabazitaxel (CBZ), yet chemoresistance and death inevitably occurs. While pharmacological agents targeting single survival pathways have shown promise at the bench side, clinical trials have failed. This is mostly due to the presence of redundant pathways utilized by PCa tumor cells to maintain chemoresistance. Therefore, we are interested in further defining molecular pathways associated with DTX-resistance in order to identify novel therapeutic targets to overcome this resistance. We hypothesized that RNA sequencing (RNAseq) analysis comparing the transcriptomes of chemosensitive and chemoresistant mCRPC cells will reveal potential targets for combinatorial therapies. RNAseq analysis of DTX-sensitive and -resistant PC3 and DU145 cells revealed a number of differentially regulated genes that were either unique to each cell line or common to both. We found that dipeptidyl peptidase 4 (DPP4), fatty acid binding protein 5 (FABP5), nestin (NES), and tetraspanin 8 (TSPAN8) were among the top most robustly and significantly upregulated genes in both DTX-resistant PC3 and DU145 cell lines. In-house qPCR studies validated the RNAseq results for these genes, and Western blotting analysis showed increased expression of these proteins in DTX-resistant cells, which correlated with increased mRNA expression. Interestingly, NES, TSPAN8, DPP4 are genes associated with development of the cancer stem-cell (CSC) phenotype. Other genes associated with CSCs were also upregulated in the DTX-resistant cells, suggesting that in vitro selection of mCRPC cells for DTX resistance may enrich for CSCs. This novel finding is consistent with recent studies implicating CSCs in PCa chemoresistance. Further analysis and validation of our RNAseq data will increase our understanding of DTX-resistance mechanisms in PCa cells, including the yet undefined functional role of CSC-related genes. These studies also reveal potential therapeutic targets to circumvent DTX resistance in PCa.
Citation Format: Christina K. Cajigas-Du Ross, Leanne Woods-Burnham, Joshua Ramirez, Xin Chen, Charles Wang, Carlos A. Casiano. RNA sequencing analysis of taxane-resistant prostate cancer cells reveals potential candidate genes for therapeutic targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5902.