bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 715: Vivo-Morpholino antisense oligomers decrease tumor growth in mice by altering mVEGF mRNA splicing to knock down mVEGF expression
Authors: Jiang Shan 
Published: May 2015

Abstract
Vivo-Morpholino antisense oligomers can knock down gene expression by altering splicing of the pre-mRNA and generating a translational frameshift. VEGF overexpression is crucial for tumor growth and anti-VEGF therapies are promising in the treatment of certain cancers. Decreasing VEGF gene expression by exon deletion using Vivo-Morpholinos could suppress tumor growth. We examine the efficiency of mVEGF exon 2 deletion and tumor growth inhibition in mice injected with a Vivo-Morpholino oligomer (VMO-e2i2), which is designed to specifically delete the mVEGF exon 2 and cause downstream frameshifting in mVEGF protein. Mice bearing s.c. Lewis lung carcinoma tumors are I.V. injected with the VMO-e2i2 oligomers at 15mg/kg twice weekly for 2 weeks. VEGF exon 2 deletions are detected by RT-PCR in various tissues tested: approximately 100% exon 2 deletion in kidney, 80% in liver, 70% in skeletal muscles and 40% in s.c. tumors. The tumor volumes decrease by 6 fold over 16 days in mice injected with the VMO-e2i2 oligomers. Exon deletions are detected in various tissues including liver, small intestine, colon, skeletal and cardiac muscles, lung, stomach and kidney. The exon deletion mediated by Vivo-Morpholinos is target specific, dose-dependent and is detectable for more than 15 weeks after a single IV injection in mice. No significant toxicity is observed in mice injected with the effective dosage. Vivo-Morpholinos therefore represent a useful tool for cancer target identification and validation in rodent models and a possible therapeutic treatment.
Citation Format: Shan Jiang. Vivo-Morpholino antisense oligomers decrease tumor growth in mice by altering mVEGF mRNA splicing to knock down mVEGF expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 715. doi:10.1158/1538-7445.AM2014-715
Abstract 736: DJ4, a novel ROCK and MRCK inhibitor, potently inhibits migration and invasion of cancer cells
Authors: Kale Vijaykumar P. , Desai Dhimant , Dick Taryn , Choe Katherine , Colledge Ashley , Amin Shantu , Hengst Jeremy , Yun Jong 
Published: May 2015

Abstract
Rho-associated coiled-coil containing protein kinase (Rho kinase/ROCK) and myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK) are involved in the aggressive migration of cancer cells. These are the key proteins involved in the formation of stress fibers that confer contractility to cancer cells during migration and invasion. ROCK and MRCK are primarily involved in amoeboid and mesenchymal type of migration of cancer cells respectively. Earlier studies reported that combined inhibition/silencing of ROCK and MRCK has more pronounced effect than inhibition of the individual kinases suggesting a more effective therapeutic strategy to combat metastatic cancers. With this hypothesis in mind, we developed a series of novel multikinase inhibitors and identified DJ4 as a potent ATP competitive inhibitor of ROCK1, ROCK2 and MRCKβ. DJ4 effectively inhibits the kinase activity of ROCK (ROCK1 and ROCK2) and MRCK in a cell-free system and multiple human non-small cell lung cancer cell lines. In cellular functional assays DJ4 inhibited migration of human melanoma, lung, pancreatic and breast cancer cells in a concentration-dependent manner. In live cell imaging over 20h by time-lapse microscopy, DJ4 (2.5µM ) reduced the migration rate of lung-and breast-cancer cells by 2.7 and 5.5 times compared to control cells respectively. DJ4 (5µM) also inhibited invasion of MDA-MB-231 breast cancer cells by ∼70%. Fluorescent microscopic observation also revealed that inhibition of activity of these kinases, by DJ4, causes reduction in stress fibers which leads to inhibition of cell contractility and migration.
In summary, our studies demonstrate that DJ4 is a potent ATP competitive inhibitor of ROCK and MRCK, and effectively inhibits migration and invasion of multiple cancers in vitro. Together these results indicate that DJ4 has a strong potential to be an anti-metastatic drug against multiple cancer types.
Citation Format: Vijaykumar P. Kale, Dhimant Desai, Taryn Dick, Katherine Choe, Ashley Colledge, Shantu Amin, Jeremy Hengst, Jong Yun. DJ4, a novel ROCK and MRCK inhibitor, potently inhibits migration and invasion of cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 736. doi:10.1158/1538-7445.AM2014-736
Abstract 752: Genetic and pharmacological FAK inhibition disrupt a β5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth
Authors: Tancioni Isabelle , Uryu Sean , Sulzmaier Florian , Shah Nina , Lawson Christine , Miller Nichol L.G. , Jean Christine , Chen Xiao Lei , Ward Kristy K. , Schlaepfer David D. 
Published: May 2015

Abstract
Ovarian cancer spreads via cell shedding and growth within malignant ascites. Effective targeted therapies have not been developed for ovarian cancer. Ascites contains an abundance of matrix proteins, and spheroids maintain integrin receptor expression. Through databases analyses we find that elevated osteopontin (OPN), β5 integrin, and focal adhesion kinase (FAK) mRNA levels are associated with decreased overall survival of serous ovarian cancer patients treated with platinum and taxol. In ovarian tumor tissue arrays, increased FAK activation (FAK Y397 phosphorylation) correlated with elevated tumor grade in parallel with increased in β5 integin and OPN levels. FAK is a cytoplasmic tyrosine kinase that remains active in spheroids, and treatment of seven ovarian carcinoma cell lines with sub-micromolar levels of FAK inhibitor (PND-1186) identified sensitive (HEY and OVCAR8), intermediate (OVCAR3, ID8-IP, and IGROV1-IP), and resistant (SKOV3-IP and OVCAR10) cells to blockage of growth under anchorage-independent conditions. Genetic or pharmacological FAK inhibition within ID8-IP or HEY cells selectively prevents anchorage-independent growth in culture and tumor growth in mice with corresponding reductions in β5 integrin and OPN expression. β5 knockdown reduced HEY growth in soft agar, tumor growth in mice, FAK Y397 phosphorylation, and OPN expression in spheroids. Although FAK inhibitor resistant ovarian carcinoma cells (SKOV3-IP and OVCAR10) were associated with anchorage-independent Akt S473 phosphorylation, membrane-targeted and activated Akt expression in sensitive cells (HEY and OVCAR8) resulted in only a partial rescue of FAK inhibitor-associated growth block. These results support the hypothesis that OPN, αvβ5 integrins, and FAK may function as a signaling axis promoting ovarian tumor progression. Although Akt signaling pathway activation is a common event in serous ovarian cancer, our results suggest that this may not impart complete resistance to FAK inhibitor treatment.
Supported by NIH CA102310
Citation Format: Isabelle Tancioni, Sean Uryu, Florian Sulzmaier, Nina Shah, Christine Lawson, Nichol L.G. Miller, Christine Jean, Xiao Lei Chen, Kristy K. Ward, David D. Schlaepfer. Genetic and pharmacological FAK inhibition disrupt a β5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 752. doi:10.1158/1538-7445.AM2014-752
Abstract 754: Selective ALK inhibitor alectinib (CH5424802/RO5424802) with potent antitumor activity in models of crizotinib resistance, including intracranial metastases
Authors: Kodama Tatsushi , Tsukaguchi Toshiyuki , Hasegawa Masami , Yoshida Miyuki , Takanashi Kenji , Kondoh Osamu , Sakamoto Hiroshi 
Published: May 2015

Abstract
Purpose: EML4-ALK has been implicated as a driver oncogene and a therapeutic target in non-small cell lung cancer (NSCLC). The clinical efficacy of the ALK inhibitor crizotinib has been demonstrated in ALK fusion-positive NSCLC; however, resistance to crizotinib certainly occurs through ALK secondary mutations in clinical use. In addition, brain metastases are frequent sites of initial failure in patients because crizotinib has poor penetration of the central nervous system. This study aimed to clarify the efficacy of ALK inhibitor alectinib (CH5424802/RO5424802) in models of crizotinib-resistant ALK mutant tumors and intracranial tumors.
Experimental Design: The antitumor activity of alectinib was evaluated in subcutaneous xenograft tumor models of Ba/F3 cells expressing mutated EML4-ALK, and in intracranial tumor implantation models of EML4-ALK-positive NSCLC NCI-H2228.
Results: Alectinib had kinase inhibitory activity against some ALK mutations, including G1269A, and blocked tumor growth driven by a mutant of EML4-ALK in vitro and in vivo. In intracranial tumor implantation mouse models, alectinib resulted in regression of NCI-H2228 tumor in brain and provided a survival benefit. Alectinib is not a substrate for P-glycoprotein efflux transporter in vitro and showed a high brain-to-plasma ratio in rat. Additionally, alectinib led to tumor size reduction in the subcutaneous NCI-H2228 xenograft tumor that had failed to regress fully during treatment with crizotinib.
Conclusions: Alectinib was effective against most EML4-ALK mutations and showed potent efficacy against intracranial ALK-positive tumor. Thus, alectinib might provide therapeutic opportunities for crizotinib-treated patients with ALK secondary mutations and brain metastases.
Citation Format: Tatsushi Kodama, Toshiyuki Tsukaguchi, Masami Hasegawa, Miyuki Yoshida, Kenji Takanashi, Osamu Kondoh, Hiroshi Sakamoto. Selective ALK inhibitor alectinib (CH5424802/RO5424802) with potent antitumor activity in models of crizotinib resistance, including intracranial metastases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 754. doi:10.1158/1538-7445.AM2014-754
Abstract 757: ET-D5, first-in-class synthetic selective Protein Phosphatase 1 (PP1) inhibitor with anti-proliferative and anti-vascular activity
Authors: Juhem Aurelie , Lecercle Delphine , Deverchère Julie , Gazel Arnaud , Florent Jean-Claude , Popov Andrei 
Published: May 2015

Abstract
In this work we describe ET-D5, a synthetic small molecule serine-threonine protein phosphatase inhibitor with proven in vivo anti-mitotic and anti-vascular properties.
The potential anti-cancer properties of serine-threonine protein phosphatase inhibitors have been identified since ancient times (extract from blister beetle mylabris was used in China for cancer treatment as early as in 1264), and several, mostly natural, inhibitors were evaluated in clinical trials. Their development was, however, discontinued due to the toxic effects of these non-selective (PP2A&gt;&gt;PP1) serine-threonine protein phosphatase inhibitors.
ET-D5 is a remarkably specific (PP1 versus PP2A) inhibitor with potent anti-mitotic and anti-vascular activities. In vitro, ET-D5 display high efficacy against a wide range of human cancer cells (GI50 values determined were in low nM range for certain cell lines). In addition, ET-D5 disrupts the in vitro preformed capillary tubes (endothelial cells HMEC-1). In vivo experiments confirmed these activities in numerous animal models of human cancer, such as cancer of lung, brain, thyroid, kidney and ovaries.
ET-D5 presents interesting pharmacological properties, good toxicology profile and is also active when administered per os. Contrary to many vascular-disrupting agents (VDA) which target tubulin, ET-D5 exerts its activity by selectively inhibiting in vivo protein-phosphatase I (PP1). We confirmed this activity in classical pharmacodynamics experiments, showing PP1 inhibition in xenografted tumors after oral administration of ET-D5.
Based on all these results, ET-D5 is scheduled to enter clinical trials in early 2015.
Citation Format: Aurelie Juhem, Delphine Lecercle, Julie Deverchère, Arnaud Gazel, Jean-Claude Florent, Andrei Popov. ET-D5, first-in-class synthetic selective Protein Phosphatase 1 (PP1) inhibitor with anti-proliferative and anti-vascular activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 757. doi:10.1158/1538-7445.AM2014-757
Abstract 764: A role for GLI1 in the development of multidrug resistance in rhabdomyosarcoma (RMS) cells
Authors: Yoon Joon Won , Lamm Marilyn , Leong King-Fu , Iannaccone Stephen , Iannaccone Philip , Walterhouse David 
Published: May 2015

Abstract
RMS is the most common sarcoma of childhood. About 30% of patients with localized tumors will recur following treatment. The outcome for patients with recurrent RMS remains poor. Therefore, development of chemotherapy resistance during RMS therapy represents an important problem and novel approaches to prevent or reverse drug resistance are essential. Activation of multidrug transporter genes, including MDR1, MRP1, LRP and TAP1 represents an important mechanism for drug resistance in RMS. However, the mechanism of expression of multidrug resistance genes in RMS is incompletely understood. Recent reports have suggested a role for the Hedgehog (HH) signaling pathway and its downstream mediator GLI1 in acquisition of a multidrug resistance phenotype in esophageal adenocarcinoma, glioblastoma, and myeloid leukemia. Since approximately 60% of embryonal RMS (ERMS) and more rarely alveolar RMS (ARMS) express HH pathway components, we hypothesized that HH pathway activation may up-regulate the expression of multidrug resistance genes in RMS. We demonstrated expression of HH pathway components, including GLI1, in ERMS (RD, Rh18 and Ruch-2) and ARMS (Rh30 and Rh41) cell lines by qRT PCR and/or Western blot. We found variable expression of MDR1, MRP1, LRP and TAP1 by qRT PCR in these cell lines. Treatment of RMS cells with GLI1 siRNA (RD, Rh18 and Rh41) or the GLI1 antagonist GANT61 (Rh18 and Rh30) caused down-regulation LRP and TAP1 expression. In addition, GLI1, MDR1, LRP and TAP1 expression was increased in vincristine resistant UKF Rhb-1 RMS cells compared with parental cells (obtained from Dr. Cinatl) by qRT PCR. Treatment of vincristine resistant UKF Rhb-1 cells with vincristine together with either GANT61 or Cpd#33 (GLI1 inhibitors), each at a dose, which did not reduce cell viability individually, significantly decreased cell viability by MTT assay. Our results suggest that GLI1 up-regulates a subset of multidrug resistance genes in RMS cells and that GLI1-inhibitors may reduce multidrug resistance.
Citation Format: Joon Won Yoon, Marilyn Lamm, King-Fu Leong, Stephen Iannaccone, Philip Iannaccone, David Walterhouse. A role for GLI1 in the development of multidrug resistance in rhabdomyosarcoma (RMS) cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 764. doi:10.1158/1538-7445.AM2014-764
Abstract 779: Osteopontin gene expression is associated with 5-fluorouracil drug resistance in colon cancer
Authors: Nakajima Go , Kuramochi Hidekazu , Yamamoto Masakazu , Hayashi Kazuhiko 
Published: May 2015

Abstract
Background: Resistance to chemotherapeutic drugs complicates the treatment of cancer patients. The extracellular matrix protein osteopontin (OPN) plays multiple roles in the proliferation and metastasis of cancer cells. We therefore attempted to determine whether OPN expression correlated with drug resistance. Methods: OPN expression in the HCT 116 colon cancer cell line was inhibited by an OPN-short interfering RNA (siRNA). We determined the cytotoxic effect (IC50) of 5-fluorouracil (5FU) on these cells. Patients with recurrence or colorectal cancer or harbored residual tumor cells were treated with S-1-based chemotherapy. The levels of OPN mRNA expression in the tumors were determined and compared with the patients’ responses to chemotherapy. Results: The IC50 of 5FU for HCT 116 cells transfected with the OPN-siRNA was 32.9 μM. In contrast, the IC50 values for cells transfected with a negative control siRNA, mock-transfected cells, or untreated cells were 6.58 μM, 7.08 μM, and 6.76 μM, respectively (P&lt;0.001). The level of OPN mRNA expression in the S-1 non-responder group was significantly lower than that of the responder group (P = 0.0387). Survival analysis revealed no significant difference between the responder and non-responder groups (P = 0.8737). Conclusions: The level of OPN expression plays a role in the resistance of colorectal tumor cells to 5FU.
Citation Format: Go Nakajima, Hidekazu Kuramochi, Masakazu Yamamoto, Kazuhiko Hayashi. Osteopontin gene expression is associated with 5-fluorouracil drug resistance in colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 779. doi:10.1158/1538-7445.AM2014-779
Abstract 780: Metformin induces apoptotic cell death and inhibits CD133+ cancer stem cells in 5-Fu-resistant colorectal cancer cells
Authors: Kim Sunghee , Ku Ja-Lok 
Published: May 2015

Abstract
Colorectal cancer (CRC) is the third most common cancer and estimated cancer related death is high in worldwide. 5-Fluorouracil (5-Fu) is common used chemotherapeutic agent for colorectal cancer. Nevertheless the use frequency, the resistance to 5-Fu is still a critical problem. To improvement of therapeutic effects of 5-Fu, there are the new chemotherapeutic strategies like FOLFOX and FORFIRI, combination treatment 5-Fu with oxaliplatin or irinotecan. However, it is arguable that the side effects and efficiency of these strategies.
Metformin is widely used therapeutic agent for type II diabetics, obesity, and polycystic ovarian syndrome with limited side effects. Recently, there are some evidence that metformin has anticancer effects for some types of cancers e.g. breast, pancreases, prostate, and colon. Recently, correlation of metformin and cancer stem cell population was proved.
Here, we examined that metformin effects on parental colorectal cancer cells and their 5-Fu-resistant colorectal cancer cells. Metformin has the anticancer effects in parental cells and their 5-Fu-resistant cells in both cell lines. As treated with metformin, wound healing ability is decreased in both cell lines. Cell proliferation was 41.7% decreased in parental cells and 30.6% in 5-Fu-resistant cells. Also, expression of PARP and caspase-3 were induced by metformin dose dependent manner in both cell lines. It is suggested that metformin induces inhibition of cell proliferation and increased apoptosis. In addition, metformin treatment affects cell cycle; subG1 stage was increased to 1.7 fold and G2/M stage was increased to 1.6 fold in both cell lines. It means that metformin induces cell death and leads cell cycle arrest. However, there are no significant synergistic effect in cell proliferation, apoptosis, and cell cycle change with combination treatment of 5-Fu and metformin. CD133+ cancer stem cell population was decreased in 20 to 40 % as treated with 5-Fu and low dose of metformin to parental cells. On the other hand, CD133+ population in 5-Fu-resistant cells was affected in only low dose of metformin not 5-Fu.
In sum, metformin has anticancer effects via inhibition of cell proliferation, cell cycle changes and metformin decreases CD133+ cancer stem cell population. Further studies will be necessary to verify the mechanisms that metformin decreases CD133+ cancer stem cell population in colorectal cancer cell lines.
Citation Format: Sunghee Kim, Ja-Lok Ku. Metformin induces apoptotic cell death and inhibits CD133+ cancer stem cells in 5-Fu-resistant colorectal cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 780. doi:10.1158/1538-7445.AM2014-780
Abstract 802: Synergistic effect of curcumin on FL118 efficacy in colon cancer
Authors: Ling Xiang , Gandhi Nishant , Jiao Boyang , Chandra Dhyan , Li Fengzhi 
Published: May 2015

Abstract
Colorectal cancer is the third most commonly diagnosed cancer in the United States and may cause about 50,830 deaths in 2013. Therefore, there is an unmet need for new therapeutic strategies. Combination of natural compounds with pharmacological small molecular inhibitors to increase anticancer efficacy while minimizing toxicity is an attractive approach for management of cancer. Curcumin, a natural dietary compound, has been shown to inhibit multiple cancer cell signaling pathways involved in survival, proliferation, apoptosis, angiogenesis and metastasis. FL118, a novel camptothecin derivative and an IAP (inhibitor of apoptosis) inhibitor, significantly attenuates colon cancer cell growth in vitro and tumor growth in vivo. In the current study, we report that curcumin enhances FL118 anti-cancer efficiency in colon cancer cell models. MTT and cell death detection ELISA assays were used for quantification of cell viability and apoptosis, respectively, in colon cancer HCT8 and SW620 cells. The synergistic effect of curcumin in combination with FL118 treatment on colon cancer growth inhibition was further analyzed by the Combination Index (CI) equation developed by Chou-Talalay using a CalcuSyn program (Biosoft, Cambridge, UK). Our data demonstrated that curcumin shows a synergistic growth inhibitory effect with FL118 in multiple colon cancer cells (p&lt;0.05). Furthermore, combinational treatment can significantly enhance apoptotic cell death induced in comparison with either FL118 or curcumin treatment alone (p&lt;0.05). In HCT8 colon cancer cells, a combination of 10µM curcumin with 0.3-20 nM FL118 treatment for 72 h showed a strong synergistic effect (CI &lt; 0.5) in cell growth inhibition. Mechanistically, the combination treatment-enhanced cell growth inhibition and apoptosis are associated with alteration of the expression of cell death and cell cycle related genes. In conclusion, we propose that combination of curcumin with FL118 might provide a novel therapeutic strategy in colon cancer treatment.
Citation Format: Xiang Ling, Nishant Gandhi, Boyang Jiao, Dhyan Chandra, Fengzhi Li. Synergistic effect of curcumin on FL118 efficacy in colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 802. doi:10.1158/1538-7445.AM2014-802