bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3733: Augmentation of response to therapeutic agents by (-)-gallocatechin gallate through inhibition of RAD51 nuclear translocation
Authors: Wu Ming-Hsi , Lin Lie-Chwen , Lee Te-Chang 
Published: July 2016

Abstract
Lung cancer is the most common cancer worldwide. Platinum-based combination chemotherapy is one of first line treatments for patients with lung cancer. Most of the cytotoxic drugs are targeting DNA, interfere with DNA synthesis, and triggering DNA damage response (DDR). Since DDR usually activates important defensive pathways to repair damaged DNA, DDR is known as a key factor determining the outcome of chemotherapy. Among them, RAD51, playing a central role in homologous recombination (HR) DNA repair, has been shown to interfere with the prognosis of patients treated with chemoradiotherapy. Since we have demonstrated that inhibition of RAD51 nuclear focus formation synergistically enhances the anticancer activity of cisplatin, we further screened purified natural products in order to find products with activity to inhibit RAD51 nuclear focus formation. In the present study, we found that a green tea catechin derivative, the (-)-Gallocatechin gallate (GCG) has potent inhibitory activity against RAD51 nuclear focus formation in cisplatin-treated H460 cells. The in vitro cytotoxicity assay showed that the combination of cisplatin or irinotecan with GCG significantly increases the sensitivity of H460 cells to these DNA damage agents. We also evaluated the anti-tumor growth activity of cisplatin or irinotecan in combination with GCG using H460 xenografts. Our results showed that cisplatin and irinotecan suppresses tumor growth by 17.6% and 33.8%, while in combination with GCG suppresses tumor growth by 52.2% and 68.9%, respectively. We further demonstrated that GCG is able to inhibit cisplatin-induced ATM and Chk2 phosphorylation. Together, our results suggest that GCG may interfere with ATM-Chk2 pathway and hence suppress RAD51 nuclear focus formation and DNA repair activities.
Citation Format: Ming-Hsi Wu, Lie-Chwen Lin, Te-Chang Lee. Augmentation of response to therapeutic agents by (-)-gallocatechin gallate through inhibition of RAD51 nuclear translocation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3733.
Abstract 3737: Inhibition of O-GlcNAc transferase in tamoxifen resistant breast cancer cells
Authors: Barkovskaya Anna , Prasmickaite Lina , Mills Ian G. , Mælandsmo Gunhild M. , Moestue Siver A. , Itkonen Harri M. 
Published: July 2016

Abstract
O-linked N-acetyl-glucosamine transferase (OGT) is an enzyme that catalyzes addition of the O-GlcNAc modification to a wide range of intracellular proteins. The O-GlcNAc modification is a product of the hexosamine biosynthetic pathway, which requires glucose and glutamine as substrates. Uptake of both of these nutrients is often up-regulated in cancer, which in turn leads to an increase in the total protein O-GlcNAcylation. Increased OGT expression has also been reported in most cancer types, including the most frequently diagnosed cancer in women, breast cancer. Many of the breast cancers rely on estrogen receptor alpha (ERα) for proliferation and have shown a strong response to the ERα inhibition, most commonly achieved by treatment with tamoxifen. However, while efficient, prolonged exposure to tamoxifen commonly causes resistance and relapse of the disease. It is therefore vital to uncover mechanisms which contribute to the resistance in order to develop adequate treatment strategy for these patients.
Here, we have investigated the effect of targeting OGT in an isogenic pair of ERα-positive tamoxifen-sensitive MCF7 and tamoxifen-resistant TAMR breast cancer cell lines. OGT inhibition decreased viability and triggered cell death in both cell lines. These responses were associated with over 50% reduction in ERα expression in both MCF7 and TAMR cells. Reduced O-GlcNAcylation has previously been reported to induce endoplasmic reticulum stress and activation of transcription factor C/EBP homologous protein (CHOP), which promotes cell death. Targeting OGT resulted in a strong increase of CHOP expression, which appeared more prominent in the TAMR cells. Finally, targeting OGT induced a very pronounced cell cycle arrest in the G2/M phase in the TAMR cells, while the MCF7 cell lined showed a very modest response.
Taken together, these results indicate that targeting OGT leads to a differential response in the tamoxifen-sensitive and resistant breast cancer cells. Currently, we are using an expanded panel of tamoxifen-resistant cell lines to perform expression microarrays, metabolic flux assays and DNA damage response analysis in order to uncover the cause of the differential response to OGT targeting. This may help us identify potential therapeutic combinations that might be suitable for treatment of tamoxifen-resistant cancers.
Citation Format: Anna Barkovskaya, Lina Prasmickaite, Ian G. Mills, Gunhild M. Mælandsmo, Siver A. Moestue, Harri M. Itkonen. Inhibition of O-GlcNAc transferase in tamoxifen resistant breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3737.
Abstract 3750: CD133-targeted oncolytic adenovirus shows therapeutic effect by attacking colon cancer stem cells
Authors: Sato Mizuho , Miura Yoshiaki , Yamamoto Masato 
Published: July 2016

Abstract
Colorectal cancer is the third most common cancer in the world and about 50% of patients relapse after treatment. Cancer stem cells (CSCs) have contribution to recurrence, metastasis and and chemotherapy resistant of colorectal cancers. CD133 (Prominin-1), a member of the transmembrane glycoprotein family, is a marker of CSCs in several cancers and is also generally accepted as a colorectal cancer stem cell marker. CD133 expression was correlated with recurrence, metastases and chemotherapy resistance, as well as poor prognosis in colorectal cancer. It is therefore reasonable to develop CSCs-directed therapeutic strategies by employing CD133 as a target molecule. Recently, we have established a method for isolating transductionally-targeted adenovirus by high-throughput screening. In this study, using this adenovirus library screening system, we isolated the CD133-specific Oncolytic Adenovirus (OAd) and tested the oncolytic activity of CD133-targeted Ad in both in vitro and in vivo. CD133-targeted OAd (AdML-TYML) showed strong binding to CD133-positive cells (293-CD133 and LoVo (CD133 (+) human colon carcinoma)), not to CD133-negative cells (parental 293 and LS174T (CD133 (-) human colon carcinoma)) and this virus also showed strong oncolysis selectively in LoVo cells, whereas there was no effect on LS174T cells.
In order to assess the effect of AdML-TYML on stemness, tumor establishment assay was performed. AdML-TYML treatment leads to inhibition of tumor establishment of CD133-positive colorectal cancer cell lines in nude mice. 100% of the mice inoculated with non-infected LoVo cells had developed tumors, while 0% of the mice inoculated with AdML-TYML infected LoVo cells had done so. In addition, when the anti-tumor effect of the CD133-targeted OAd was analyzed in established tumors of CD133(+) colorectal cancer subcutaneous xenografts, intra-tumor (i.t.) administration of AdML-TYML exhibited significantly stronger antitumor effect compared to its equivalent Ad5-WT (wild type Ad5 fiber).
We focused on the CD133 as a target molecule of CSCs in colon cancer and successfully identified potent CD133-targeting OAd using high-throughput screening system. The CD133-targeted OAd exhibited selective infectivity and oncolysis to CD133-positive cells and anti-tumor effect against established colon cancer cells. Our results suggest that CD133-targeted oncolytic adenovirus selectively eliminate CD133 (+) colorectal cancer stem cells from the tumor and also this virus could be a key tool for the prevention of metastases and relapses in a variety of cancers.
Citation Format: Mizuho Sato, Yoshiaki Miura, Masato Yamamoto. CD133-targeted oncolytic adenovirus shows therapeutic effect by attacking colon cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3750.
Abstract 3754: Pre-clinical studies of a highly potent folate receptor targeted DNA crosslinking agent
Authors: Reddy Joseph A. , Nelson Melissa , Johnson Theresa , Dirksen Christina , Vetzel Marilynn , Hahn Spencer , Qi LongWu , Vlahov Iontcho , Leamon Christopher 
Published: July 2016

Abstract
Folate receptor (FR) targeted small molecule drug conjugates (SMDC) have shown promising results in early stage clinical trials with Vintafolide and EC1456. In our effort to develop FR targeted SMDCs with varying mechanisms of action, we have now built a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ∼ 100 x lower than any other folate SMDC we have created to date. Treatment of nude mice bearing FR positive human xenografts led to cures in 100% of the mice at very low doses (&gt; 500 nmol/kg) and a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing) or major organ tissue degeneration. In contrast, no significant anti-tumor activity (0% CR’s) was observed in treated animals that were co-dosed with an excess of a benign folate ligand, thus demonstrating its target-specific activity. Complete responses were also observed in other FR positive drug resistant (paclitaxel and cisplatin) models. Taken together, these studies demonstrated that this SMDC with a distinct DNA reacting mechanism has significant anti-tumor growth activity and tolerability, thus lending support to future clinical development of this novel FR-targeted agent.
Citation Format: Joseph A. Reddy, Melissa Nelson, Theresa Johnson, Christina Dirksen, Marilynn Vetzel, Spencer Hahn, LongWu Qi, Iontcho Vlahov, Christopher Leamon. Pre-clinical studies of a highly potent folate receptor targeted DNA crosslinking agent. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3754.
Abstract 3759: Inhibition of heat shock protein 27 (Hsp27) expression by apatorsen as a therapeutic strategy in breast cancer
Authors: Komulainen Emilia , Shia Alice , Bansal Jasmin , Cavicchioli Francessa , O’Leary Karen , Foster John , Schmid Peter 
Published: July 2016

Abstract
Background: Heat shock protein 27 (Hsp27) is over-expressed in a number of cancers, including breast cancer, and interacts with apoptotic proteins inhibiting the apoptotic process and promoting tumourgenesis. Clinically, Hsp27 expression has been associated with a more aggressive phenotype and resistance to chemotherapy. Apatorsen (OGX-427) is a therapeutic antisense oligonucleotide designed to specifically target Hsp27. Apatorsen has shown single agent clinical activity, and randomised trials in combination with chemotherapy are underway. Here we present pre-clinical validation of inhibition of Hsp27 expression by apatorsen as a novel therapeutic strategy in breast cancer.
Results: Basal expression analysis of Hsp27 by qPCR and western blot in a panel of &gt;20 breast cancer cell lines demonstrated a wide variation with up to 3-log difference in expression between cell lines and good correlation of RNA and protein expression levels. Hsp27 expression increased after treatment with chemotherapy agents. Treatment with apatorsen caused rapid reduction of cellular Hsp27 levels within 24-48 hours; effects on Hsp27 levels were sustained for 5 and 7 days. Knockdown of Hsp27 was associated with significant reduction of cell survival with 38-93% loss of cell viability across the cell line panel (compared to mismatched oligonucleotide). There was no association between response to apatorsen and basal Hsp27 expression or molecular breast cancer subtype. Using whole genome mRNA (Illumina Human HT-12 v4 Expression BeadChip Kit) and methylation analysis (Illumina Human 450K Methylation BeadChip), we were unable to define a predictive signature of response to apatorsen. Co-treatment of breast cancer cell lines with apatorsen and Doxorubicin, Paclitaxel and Vinorelbine chemotherapy showed an additive cytotoxic effect. In vivo validation of the effects of apatorsen is ongoing.
Conclusions: Therapeutic silencing of Hsp27 expression in breast cancer cell lines with apatorsen presents a novel strategy for the treatment of disease. Here we present data to support the use of apatorsen in combination with conventional chemotherapy for the treatment of breast cancer.
Citation Format: Emilia Komulainen, Alice Shia, Jasmin Bansal, Francessa Cavicchioli, Karen O’Leary, John Foster, Peter Schmid. Inhibition of heat shock protein 27 (Hsp27) expression by apatorsen as a therapeutic strategy in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3759.
Abstract 3778: In vitro and in vivo characterization of E7090, a novel and selective FGFR inhibitor, for the treatment of endometrial cancer
Authors: Miyano Saori Watanabe , Yamamoto Yuji , Kodama Kotaro , Sugi Naoko Hata , Minoshima Yukinori , Matsui Junji , Iwata Masao 
Published: July 2016

Abstract
Genetic abnormalities (gene fusion, mutation and amplification) of Fibroblast Growth Factor Receptor (FGFR) family members are known to cause constitutive activation of their signaling pathways, which play an important role in proliferation, survival and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR2 is mutated in about 10% of endometrial cancer patients and is associated with a higher risk of recurrence. E7090, an oral available FGFR1, 2, and 3 inhibitor that the chemical-structure and basic kinase inhibitory activity of this compound have been presented at AACR2015, is currently under a first-in-human study (NCT02275910) in Japan. In this presentation, the efficacy of E7090 against human endometrial cancer was examined.
E7090 exhibited selective potent antiproliferative activity against 3 human endometrial cancer cell lines harboring FGFR2 mutation with IC50 values of approximately 10 nM among 8 endometrial cancer cell lines. These cell lines harbor S252W mutation (extracellular domain mutation; MFE280) or N549K mutation (kinase domain mutation; AN3CA and MFE296), that are the most common mutations of FGFR2 in endometrial cancer. E7090 also showed antiproliferative activity against Ba/F3 cells expressing mutated type of FGFR2, confirming the inhibitory activity of E7090 against mutated FGFR2. The antiproliferative activity of E7090 against these cell lines was based on inhibition of phosphorylated FRS2α and ERK1/2 as downstream molecules of FGF/FGFR signaling. Especially, the antiproliferative activities of E7090 against AN3CA and MFE296 harboring N550K mutation were more potent compared to these of other FGFR specific inhibitors. In addition, oral administration of E7090 resulted in significant tumor growth inhibition in MFE280, AN3CA and MFE296 xenograft models in mice. Especially, E7090 showed tumor regression in AN3CA xenograft model with a delta T/C value of -66% at a dose of 50 mg/kg.
These results indicated that E7090 showed potent inhibitory activity against mutated type of FGFR2 both in vitro and in vivo, and suggest that E7090 may provide therapeutic opportunities for endometrial cancer harboring FGFR2 mutations.
Citation Format: Saori Watanabe Miyano, Yuji Yamamoto, Kotaro Kodama, Naoko Hata Sugi, Yukinori Minoshima, Junji Matsui, Masao Iwata. In vitro and in vivo characterization of E7090, a novel and selective FGFR inhibitor, for the treatment of endometrial cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3778.
Abstract 3797: Validation of a novel antibody against fibulin-3 for targeted therapy of glioblastoma
Authors: Nandhu Mohan Sobhana , Behera Prajna , Bhaskaran Vivek , Chiocca Ennio Antonio , Viapiano Mariano S. 
Published: July 2016

Abstract
Glioblastomas (GBM) are highly invasive brain tumors that resist cytotoxic and antiangiogenic therapies, resulting in a high rate of recurrence. Fibulin-3 is an extracellular matrix protein secreted by GBM cells but absent from normal brain. This protein activates Notch signaling to promote tumor invasion and resistance to apoptosis. Conditional knockdown of fibulin-3 reduces GBM growth, invasion and vascularization, thus extending survival. Here we report the initial validation of a function-blocking antibody against this unique GBM target. We first identified the Notch-activating motif of fibulin-3 and developed an immunizing peptide against a key sequence within this motif. A monoclonal antibody generated against this peptide (mAb428.2) showed high affinity for fibulin-3 (Kd 5 nM) and no cross-reactivity against highly homologous fibulin-4 or -5. Antibody mAb428.2 detected fibulin-3 in the stroma and capillaries of human GBM without cross-reactivity against normal brain. The antibody (50-250 μg/ml) blocked the activation of Notch induced by fibulin-3 in GBM cells and caused GBM cell cytotoxicity but had no effects on astrocytes or HEK293 cells. Treatment of mice carrying subcutaneous GBM stem-cell (GSC) derived tumors with mAb428.2 (30 mg/kg IV, q24h x 8 days) resulted in tumor slowdown and extended median survival (47% and 64% in two different GSC models). mAb428.2-treated tumors showed decreased BrdU uptake and increased inflammatory reaction in the tumor stroma (macrophage infiltration and cytokine levels). Mice bearing intracranial tumors did not respond to mAb428.2 when delivered by IV or IP routes, likely due to the inability of the antibody to cross the blood brain barrier. This deficiency was overcome by direct intraparenchymal delivery of the mAb428.2 using chronic infusion (0.3 mg of mAb in 200 μl delivered at 1 μl/h over 7d), which resulted in a 26% increase in median survival. These encouraging results suggest that targeted reagents against fibulin-3 may be of clinical importance for novel combination therapies against GBM.
Citation Format: Mohan Sobhana Nandhu, Prajna Behera, Vivek Bhaskaran, Ennio Antonio Chiocca, Mariano S. Viapiano. Validation of a novel antibody against fibulin-3 for targeted therapy of glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3797.
Abstract 3807: Histone deacetylase inhibitors repress hypoxia signaling through affecting Hsp90
Authors: Yang Chunzhang , Zhuang Zhengping 
Published: July 2016

Abstract
Histone deacetylase inhibitors (HDACis) are among the most promising recently developed anti-cancer agents. Recent work suggests that HDACis suppress both malignant cell metabolism and progression by interfering with the hypoxia-inducible factor (HIF) signaling, which plays a key role in tumor progression in both actual and falsely perceived cellular hypoxia (pseudohypoxia). However, the precise biochemical mechanism of HDACis repression of HIFs function remains unclear. In this study, we demonstrated that the class-2 histone deacetylase inhibitor SAHA potently inhibits hypoxia signaling via interfering with heat shock protein 90 (Hsp90). HDACis increase in the acetylation of Hsp90, resulting in less HIF-α recognition and nuclear translocation. Accumulated cytoplasmic HIF-α is not transcriptionally active and degradaded through proteosomal pathway. Finally, we demonstrated that SAHA remarkably reduces hypoxia signaling and decreases tumor growth in vivo. These findings provide insight into new possible therapeutic strategies for using HDACis in tumors with known HIF pathway aberrations.
Citation Format: Chunzhang Yang, Zhengping Zhuang. Histone deacetylase inhibitors repress hypoxia signaling through affecting Hsp90. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3807.
Abstract 3811: The mechanobiome of pancreatic ductal adenocarcinoma: a new, targetable drug space
Authors: Surcel Alexandra , Zhu Qingfeng , Schiffhauer Eric , Anders Robert A. , Robinson Douglas N. 
Published: July 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality, with 37,000 people dying annually in the US. Existing strategies for treating cancer primarily mainly focus on inhibiting cell growth through specific genetic pathways, which typically either fail to completely abolish the disease or which lead to compensatory regulatory changes, and hence, drug resistance. Targeting cell mechanics remains an under-used approach for drug development.
The direct driver of cell shape change events intrinsic to cellular functions, such migration and invasion, is the mechanobiome - a collection of cytoskeletal proteins which are the final determinants of a cell's mechanical attributes and which lie downstream of KRAS and other regulatory molecules. Targeting, and ultimately, inhibiting these processes is less likely to be subject to compensatory regulation by cancer cells. We determined via western blot analysis and immunohistochemistry of patient-derived samples that key players involved in mechanosensation-myosin IIA, IIC, α-actin-4, and filamin B -show increased expression in cancerous ductal epithelial over normal tissue, while non-mechanosensory, or variable mechanosensory, paralogs (myosin IIB, α-actin-1, and filamin A) show decreased expression. This upregulation of highly mechanosensory proteins has initiated an investigation into the necessity and sufficiency of the myosin II paralogs in PDAC metastasis through overexpression and knockdown of expression, coupled with mechanical assays. In addition to resolving the mechanobiome of PDAC, we have previously shown that targeting of myosin IIC by 4-hydroxyacetophenone affects PDAC mechanics. We are testing the in vivo efficacy of 4-HAP by conducting a murine multi-arm study of metastatically human derived pancreatic cancer cells. Preliminary results suggest a protective effect against the metastasis of human pancreatic cancer cells among mice treated with 4-HAP every other day.
Citation Format: Alexandra Surcel, Qingfeng Zhu, Eric Schiffhauer, Robert A. Anders, Douglas N. Robinson. The mechanobiome of pancreatic ductal adenocarcinoma: a new, targetable drug space. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3811.