bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3182: Cytoskeletal modulation results in increased tumor survival and drug resistance through attenuation of p53 dependent apoptosis
Authors: Wang Victoria E. , Doench John , Root David , Bernards Rene , Settleman Jeffrey , McCormick Frank 
Published: July 2017

Abstract
One of the major challenges to eradicating cancer involves the evolution of drug resistant clones and persistence of residual disease that escapes our current limit of detection but may proliferate upon cessation of therapy. These microscopic foci of residual diseases often exhibit stem-cell like properties and are intrinsically more resistant to drug therapy. A better understanding of the mechanisms underlying the innate drug resistance of these cellular populations may lead to improved treatment strategies, resulting in more durable remissions and ultimately improved patient survival.
We utilize functional genomic platforms to identify mechanisms responsible for the persistence of drug tolerant cells. A genome wide shRNA enrichment screen was performed using the c-Met addicted cell line GTL-16 to identify genes whose knockdown conferred DTP survival. Inhibition of the RhoA-ROCK-myosin pathway promotes drug resistance in a variety of tumor models, including those treated with either targeted therapy or conventional chemotherapy. Furthermore, pharmacological validation using multiple small molecule inhibitors of ROCK1 phenocopied both myosin heavy chain (MYH9) and light chain (MYL12) shRNA knockdown. More recently, utilizing a combination of gene expression and biochemical approaches, we have identified attenuation of p53 induced apoptosis to be a key event in mediating survival of these drug tolerant persisters. Reactivation of p53 using nutlin results in increased cell death.
These findings demonstrate that modulation of cytoskeleton is an important, but underappreciated, mechanism of drug resistance across many tumor types. These downstream effectors may serve as novel therapeutic targets for intervention and also biomarkers to stratify patients and their response to treatment.
Citation Format: Victoria E. Wang, John Doench, David Root, Rene Bernards, Jeffrey Settleman, Frank McCormick. Cytoskeletal modulation results in increased tumor survival and drug resistance through attenuation of p53 dependent apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3182. doi:10.1158/1538-7445.AM2017-3182
Abstract 3186: Taxane resistance in prostate cancer: A role for miRNA 181a
Authors: Armstrong Cameron M. , Liu Chengfei , Lou Wei , Gao Allen C. 
Published: July 2017

Abstract
Introduction: Docetaxel (DTX) is one of the primary drugs used for treating castration resistant prostate cancer (CRPC). Unfortunately, over time patients invariably develop resistance to DTX therapy and their disease will continue to progress. The mechanisms by which resistance develops are still incompletely understood. This study seeks to determine the involvement of miRNAs, specifically miR-181a, in DTX resistance in CRPC.
Methods: Total RNA from parental C4-2B prostate cancer cells and DTX resistant C4-2B cells (C4-2B TaxR) was submitted for small RNA deep sequencing. Data was analyzed to ascertain which miRNAs expressions were most altered in C4-2B TaxR cells compared to parental cells. Having identified an increase in miR-181a in resistant cells, its expression was modulated in C4-2B and C4-2B TaxR cells by transfecting them with miR-181a mimics or antisense, respectively. Following transfection, cell number was determined after 48 h with or without DTX. Cross resistance to cabazitaxel induced by miR-181a was also determined. Western blots were used to determine ABCB1 protein expression and rhodamine assays used to assess activity. Phospho-p53 expression was assessed by western blot and apoptosis was measured by ELISA in C4-2B TaxR cells with inhibited miR-181a expression with or without DTX.
Results: miR-181a is significantly upregulated in C4-2B TaxR cells compared to parental C4-2B cells as analyzed by small RNA sequencing. Overexpression of miR-181a in C4-2B cells confers DTX and cabazitaxel resistance. Knockdown of miR-181a in C4-2B TaxR cells re-sensitizes them to treatment with both DTX and cabazitaxel. miR-181a knockdown alone induced apoptosis in C4-2B TaxR cells which is further enhanced by DTX. We next assessed if miR-181a altered expression or activity of ABCB1, which is overexpressed/active in C4-2B TaxR cells and promotes resistance to DTX by pumping the drug out of cells. We found that miR-181a does not impact ABCB1 expression or activity. Since we previously demonstrated that phospho-p53 can modulate DTX sensitivity, we determined if miR-181a can alter p53 expression in C4-2B TaxR cells. Knockdown of miR-181a in C4-2B TaxR cells induced phospho-p53 expression, suggesting that miR-181a induced resistance to DTX is mediated by inhibition of phospho-p53 expression.
Conclusions: Overexpression of miR-181a in C4-2B TaxR cells contributes to their resistance to DTX and inhibition of miR-181a expression can restore treatment response. This is due, in part, to modulation of p53 phosphorylation and induction of apoptosis.
Note: This abstract was not presented at the meeting.
Citation Format: Cameron M. Armstrong, Chengfei Liu, Wei Lou, Allen C. Gao. Taxane resistance in prostate cancer: A role for miRNA 181a [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3186. doi:10.1158/1538-7445.AM2017-3186
Abstract 3196: Genetic and pharmacologic approaches to overcome epithelial to mesenchymal mediated chemoresistance in breast cancer
Authors: Crowley Michael J. , Altorki Nasser , Mittal Vivek , Gao Dingcheng 
Published: July 2017

Abstract
Development of resistance to conventional chemotherapy remains a major barrier to effective treatment of breast cancer. We and others have recently demonstrated in breast and pancreatic cancer models that epithelial-mesenchymal transition (EMT) may not be a critical mediator of cancer metastasis, however, it contributes to cancer drug resistance (Fischer et al. Nature 2015; Zeng et al Nature 2015). Importantly, blocking EMT through miR-200 family abrogated chemoresistance, indicating potentials for clinical translation. Using our novel EMT lineage tracing system, we have performed both genetic (CRISPR/Cas9 mediated genome-wide targeted mutagenesis) and pharmacological (high-throughput small molecule libraries) screens, to identify potential candidates to overcome EMT-mediated chemoresistance in breast cancer metastasis. The identified molecules provide not only novel mechanistic insights but also attractive anti-metastatic strategies for breast cancer treatment and the design of future clinical trials.
Citation Format: Michael J. Crowley, Nasser Altorki, Vivek Mittal, Dingcheng Gao. Genetic and pharmacologic approaches to overcome epithelial to mesenchymal mediated chemoresistance in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3196. doi:10.1158/1538-7445.AM2017-3196
Abstract 3197: Splicing factors and the role of Navitoclax in drug-resistant ovarian cancer
Authors: Coley Helen M. , Lattanzio Laura , Garrone Ornella , Merlano Marco , Vivenza Daniela , Nigro Cristiana Lo , Syed Nelofer , Thompson Alistair , Rao Bhavya , Crook Tim 
Published: July 2017

Abstract
Alternative RNA splicing allows processing of a pre-mRNA into various mature mRNAs. In this way multiple protein products can be derived from a single gene. In cancer it is known that specific splice variants may facilitate malignant transformation and therapeutic resistance. Our current studies focus on the problem of drug resistance in ovarian cancer and we have approached this in a variety of ways. Following sequencing analysis of a panel of ovarian cancer cell lines we identified the RNA splicing factors TCERG and SRSF2 as being reduced in drug resistant ovarian cancer cell lines, compared with their drug sensitive counterpart. TCERG is important in regulating the splicing of variant forms of the BClx gene: BClxL (long form) and BClxs (short form). There are clear implications for drug resistance whereby low TCERG results in reduced BClx splicing to yield the pro-apoptotic BClxs form. In the SKOV-3 human ovarian cancer cell line panel both paclitaxel resistant SKOV-3TaxR and SKOV-3CR carboplatin resistant cells showed reduced levels of TCERG mRNA using qPCR analysis. In addition, qPCR analysis for BClxl and BClxs levels indicated increased ratio of long:short form with drug resistance: SKOV-3 parent line ratio 1.0; SKOV-3TaxR 1.8; SKOV-3CR 1.65. Western immunoblotting showed relatively decreased levels of Bax protein in drug resistant versus drug sensitive cell line in line with a reduced apoptotic reduced. We then explored the use of Navitoclax (ABT0263), the small-molecule Bcl-2 family protein inhibitor for Bcl-xL, Bcl-2 and Bcl-w in our cell line panel. Navitoclax in combination with paclitaxel for 48h gave rise to significantly increased apoptotic response in drug-resistant versus drug sensitive ovarian cancer cell line counterparts, using the Annexin V assay with PI, indicative of re-sensitisation to paclitaxel. Synergistic effects were also seen for the parental cell line but the effects were more marked for the resistant cell lines. Our future work will also involve the use of clinical biopsies of ovarian cancer cases.
Citation Format: Helen M. Coley, Laura Lattanzio, Ornella Garrone, Marco Merlano, Daniela Vivenza, Cristiana Lo Nigro, Nelofer Syed, Alistair Thompson, Bhavya Rao, Tim Crook. Splicing factors and the role of Navitoclax in drug-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3197. doi:10.1158/1538-7445.AM2017-3197
Abstract 320: Potential of targeting of MYC-driven cancers via CIP2A without detrimental physiological effects
Authors: Qiao Xi 
Published: July 2017

Abstract
Transcription factor MYC is a driver of many human cancers due to its widespread effects on gene expression. An understanding of the mechanisms determining MYC’s transcriptional and proliferation-promoting activities in vivo could facilitate approaches for MYC targeting. However, post-translational mechanisms that control MYC function in vivo are poorly understood. Here, we demonstrate that MYC phosphorylation at serine 62 enhances MYC accumulation on Lamin A/C-associated nuclear structures and that the protein phosphatase 2A (PP2A) inhibitor protein CIP2A is required for this process. CIP2A is also critical for serum-induced MYC phosphorylation and for MYC-elicited proliferation induction in vitro. Complementary transgenic approaches and an intestinal regeneration model further demonstrated the in vivo importance of CIP2A and serine 62 phosphorylation for MYC activity upon DNA damage-induced proliferation. However, targeting of CIP2A did not influence the normal function of intestinal crypt cells or general well-being of the mice. Meanwhile, in breast cancer cells, CIP2A depletion was shown to inhibit the MYC serine 62 phosphorylation, MYC-mediated gene expression, and anchorage-independent growth. Furthermore, CIP2A supports MDA-MB-231 xenograft growth in nude mice. Therefore, results of these studies collectively suggest for a novel opportunity to target MYC’s function in MYC- driven cancers via CIP2A, and without detrimental physiological effects.
Citation Format: Xi Qiao. Potential of targeting of MYC-driven cancers via CIP2A without detrimental physiological effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 320. doi:10.1158/1538-7445.AM2017-320
Abstract 3206: A potent and selective CSF-1R inhibitor, DCR-0064, inhibits colony stimulating factor 1 signaling in vitro and in vivo
Authors: Liao Chu-Bin , Peng Shao-Zheng , Ho Chen-Hsuan , Lee Chao-Pin , Chang Jia-Ming , Huang Hung-Jyun , Ciou Sian-Yi , Pan Yu-Chih , Chen Yu-Kai 
Published: July 2017

Abstract
Tumor-associated macrophages (TAMs) are major components of leukocytic infiltrate of tumors. It has been reported that high TAMs density is associated with poor clinical prognosis. Within the tumor microenvironment, TAMs rely on signaling through CSF-1/CSF-1 Receptor kinase axis to promote tumor growth, angiogenesis, and metastasis. Therefore, decrease of TAMs density in tumors through inhibition of CSF-1R kinase is considered a potential target for drug development. In this study, we report that a novel small molecule DCR-0064 inhibits CSF-1R kinase with IC50 value below 10 nM and possesses specificity for CSF-1R over other tyrosine or serine/threonine kinases. DCR-0064 selectively inhibits CSF-1 induced growth of M-NFS-60 myeloid cells and effectively suppresses intracellular CSF-1R activation with IC50 value less than 100 nM. The potency and selectivity of DCR-0064 is superior to the current lead CSF-1R inhibitor, PLX3397, which is in phase III clinical development for treating tenosynovial giant cell tumor. The selectively growth inhibitory activity of DCR-0064 is consistent with inhibition of CSF-1R signaling. Oral administration of DCR-0064 reduces TAMs density in vivo in mice. DCR-0064 is being developed as a candidate for preclinical development.
Citation Format: Chu-Bin Liao, Shao-Zheng Peng, Chen-Hsuan Ho, Chao-Pin Lee, Jia-Ming Chang, Hung-Jyun Huang, Sian-Yi Ciou, Yu-Chih Pan, Yu-Kai Chen. A potent and selective CSF-1R inhibitor, DCR-0064, inhibits colony stimulating factor 1 signaling in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3206. doi:10.1158/1538-7445.AM2017-3206
Abstract 3210: Targeting PTP4A3 phosphatase in ovarian cancer with the potent noncompetitive inhibitor JMS-631-053
Authors: Lazo John S. , Pekic Paula , Cheung Alex , McQueeney Kelley , Salamoun Joseph , Wipf Peter , Landen Charles N. , Sharlow Elizabeth R. 
Published: July 2017

Abstract
PTP4A3 is a highly attractive molecular target for ovarian cancer (OvCa). Elevated levels of PTP4A3 mRNA and protein in human ovarian tumors correlate with disease progression, poor prognosis and poor survival. Genetic depletion of PTP4A3 in OvCa cell lines diminishes their ability to migrate and reduces their in vivo tumorigenicity while PTP4A3 overexpression increases tumor cell migration, invasion, and dissemination. Together, these data suggest PTP4A3 is a novel molecular target for OvCa; however, the lack of potent and selective PTP4A3 small molecule inhibitors has hindered PTP4A3’s definitive validation in OvCa and in other cancers. To drive the pharmacological validation of PTP4A3, we developed JMS-631-053 (7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione), a potent (Ki=3 nM in vitro), specific, noncompetitive, PTP4A3 inhibitor. JMS-631-053 inhibited cellular migration, invasion, and colony formation in soft agar. Potent OvCa cell-based effects were observed by profiling JMS-631-053 against a panel of 8 OvCa cell lines using a 2D drug susceptibility assay, with EC50 values as low as 600 nM. Likewise, JMS-631-053 killed OvCa 3D spheroids, including those derived from high grade serous OvCa cell lines, with EC50 values as low as 300 nM. The OvCa drug resistant cell lines (i.e., A2780CP20 and HeyA8MDR) retained responsiveness to JMS-631-053 (using 2D and 3D culturing conditions) suggesting that inhibition of PTP4A3 may be a viable therapeutic strategy for chemoresistant OvCa. Preliminary data also suggests that JMS-631-053 synergizes with cisplatin when used in combination studies. Hence, JMS-631-053 will be a valuable chemical tool for further validation of PTP4A3 as an OvCa target as well as provide potential leads for future drug discovery.
Citation Format: John S. Lazo, Paula Pekic, Alex Cheung, Kelley McQueeney, Joseph Salamoun, Peter Wipf, Charles N. Landen, Elizabeth R. Sharlow. Targeting PTP4A3 phosphatase in ovarian cancer with the potent noncompetitive inhibitor JMS-631-053 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3210. doi:10.1158/1538-7445.AM2017-3210
Abstract 3215: Therapeutic potential of dual-function small molecules for breast cancers
Authors: Nicholas Nicole , Velena Alfredo , Grindrod Scott , Jung Mira 
Published: July 2017

Abstract
Epigenetic silencing of tumor suppressors is an important mechanism in tumor initiation and progression. A tumor suppressor gene, BRCA1, is part of complex molecules in the repair of DNA double-strand breaks (DSBs), and loss of BRCA1 contributes to both sporadic and inherited breast tumor progression. Furthermore, recent studies have shown that the ataxia-telangiectasia mutated (ATM) activity is abnormal in breast cancer. Therefore, we tested the hypothesis that the dual-functional drug that fused the HDAC inhibitor with an ATM activator may enhance killing of breast cancer (BC) cells by increasing ATM activation. In addition, the expression of ATM may enhance the synergistic antitumor effects of HDAC inhibitors in combination with radiotherapy. To determine the HDAC inhibitory potency, SP-1-303 was screened against a panel of Class I and Class II HDAC enzymes in vitro and identified as a pan-HDAC inhibitor (IC50=120 nM). Western blot confirmed that SP-1-303 increased acetylated histone H3/H4, α-tubulin, and phosphorylation of ATM within 30 min - 4 h in a time-dependent manner. Using two ER positive BC cell lines (MCF7 and T-47D), two triple negative breast cancer (TNBC) cell lines (MDA-MB-231 and HCC 1937), and one normal breast epithelial cell line as a control (MCF10A), the effects of SP-1-303 on cell growth and cell death were examined by performing cytotoxicity assays and flow cytometry. SAHA and Tamoxifen were used as controls. SP-1-303 conferred the values of cytotoxicity (IC50) for the ER positive BC cells in a range of 0.25-0.4 μM, while the values are in a range of 1-3 μM for TNBC and 12 μM for normal breast epithelial cells, respectively. Flow cytometry (FACS) analyses demonstrated significant increases in G1 arrest (81%) in MCF7 cells and a further enhancement in the G1 phase (91%) in combination with radiation. The data implies the mechanism of action from this drug—cancer cells are being arrested in the G1 phase of the cell cycle, a radiation sensitive phase, suggesting that SP-1-303 may have a synergistic effect with radiation on cell killing. Taken together, SP-1-303 had the largest impact on ER positive breast cancer over TNBC. These data imply that an increased cell death is occurring in ER positive breast cancers from these dual-action molecules through HDAC inhibition and increased ATM activation, suggesting that SP-1-303 alone or its combination with radiotherapy may improve clinical efficacy.
Citation Format: Nicole Nicholas, Alfredo Velena, Scott Grindrod, Mira Jung. Therapeutic potential of dual-function small molecules for breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3215. doi:10.1158/1538-7445.AM2017-3215
Abstract 3226: The apoptotic mechanism of MT-6, a mitotic inducer, in human ovarian cancer cells
Authors: Mei-Chuan Chen 
Published: July 2017

Abstract
Patients with ovarian cancer are typically diagnosed at an advanced stage, resulting in poor prognosis since there are currently no effective early-detection screening tests for women at average-risk for ovarian cancer. Here, we investigated the effects of MT-6, a derivative of moscatilin, in ovarian cancer cells. Our investigation showed that MT-6 inhibited the proliferation and viability of SKOV3 ovarian cancer cells with submicromolar IC50 values. MT-6-treated SKOV3 cells showed significant cell cycle arrest at G2/M phase, followed by an increase in the proportion of cells in a sub-G1 phase. In addition, MT-6 induced a concentration-dependent increase in mitotic markers, mitotic kinases, cell cycle regulators of G2/M transition, and apoptosis-related markers in SKOV3 cells. MT-6 treatment also induced mitochondrial membrane potential loss, JNK activation, and DR5 expression. Cotreatment of cells with the JNK inhibitor SP600125 considerably attenuated MT-6-induced apoptosis, mitochondria membrane potential loss, DR5 upregulation, and suppression of cell viability. MT-6 also inhibited tumor growth in an SKOV3 xenograft model without significant body weight loss. Together, our findings suggest that MT-6 is a potent anticancer agent with tumor-suppressive activity in vitro and in vivo that could be further investigated for ovarian cancer therapy in the future.
Citation Format: Chen Mei-Chuan. The apoptotic mechanism of MT-6, a mitotic inducer, in human ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3226. doi:10.1158/1538-7445.AM2017-3226