bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1687: A BRCA2-targeting antisense oligodeoxynucleotide enhances cisplatin effectiveness by decreasing human tumor cell proliferation, metastatic frequency, and metabolic response
Authors: Rytelewski Mateusz , Tong Jessica , Buensuceso Adrian , Leong Hon , Ferguson Peter , Vareki Saman Maleki , Cresce Christine Di , Romanow Larissa , Shepherd Trevor , Deroo Bonnie , Chambers Ann , Vincent Mark , Koropatnick James 
Published: May 2015

Abstract
BRCA2 is involved in homologous recombination repair of double-stranded DNA breaks in human cells. Inactivating mutations in BRCA2 predispose to early onset cancer of the breast, ovary and other tissues. However, patients with tumors that harbor BRCA2 mutations respond better to cancer therapy. Therefore, reducing BRCA2 in cancer cells capable of homologous recombination repair may sensitize otherwise resistant tumors to DNA-damaging anti-cancer treatment. We developed a second generation antisense oligodeoxynucleotide (BR-1) that specifically targets BRCA2. BR-1 decreased BRCA2 mRNA and protein and inhibited BRCA2-mediated RAD51 repair focus formation. BR-1 potently sensitized A549 (lung), SKOV-3 (ovarian), and MDA-MB-231 (breast) cells to cisplatin as evidenced by decreased cell proliferation. However, non-cancerous HK-2 kidney cells were not sensitized to cisplatin by BR-1. In A549 cells BR-1 enhanced cisplatin or ionizing radiation-induced inhibition of in vitro colony formation. Cisplatin-resistant head and neck squamous cancer cells (HN-15a) were rendered as sensitive to cisplatin following BR-1 treatment as the parent population. In addition, BR-1 plus cisplatin treatment decreased A549 cell metastatic frequency in an in vivo chicken chorio-allantoic membrane (CAM) model by over 70% when compared with drug treatment alone. Treatment with BR-1 and cisplatin decreased cellular respiration (decreased oxygen consumption) compared to control oligonucleotide plus cisplatin treatment, suggesting that downregulation of BRCA2 in the context of platinating drug treatment alters cellular metabolism. This change in respiration occurred independently of changes in mitochondrial number. We are continuing to develop and test BR-1 with the aim of applying it in an adjuvant setting with cisplatin in human clinical trials in the future. Supported by grants from the Ontario Centres of Excellence (OCE)
Citation Format: Mateusz Rytelewski, Jessica Tong, Adrian Buensuceso, Hon Leong, Peter Ferguson, Saman Maleki Vareki, Christine Di Cresce, Larissa Romanow, Trevor Shepherd, Bonnie Deroo, Ann Chambers, Mark Vincent, James Koropatnick. A BRCA2-targeting antisense oligodeoxynucleotide enhances cisplatin effectiveness by decreasing human tumor cell proliferation, metastatic frequency, and metabolic response. [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 1687. doi:10.1158/1538-7445.AM2014-1687
Abstract 1692: Dalantercept, an ALK1 inhibitor of angiogenesis, in combination with cisplatin inhibits tumor growth in a xenograft model of squamous cell carcinoma of the head and neck
Authors: Alimzhanov Marat , Lee Michael , Solban Nicolas , Pearsall Scott , Pandya Susan , Sherman Matthew L. , Kumar Ravindra 
Published: May 2015

Abstract
Activin receptor-like kinase 1 (ALK1) is a key regulator of angiogenesis and vascular morphogenesis. ALK1 and its co-receptor endoglin are selectively expressed on the surface of activated endothelial cells during angiogenesis. Bone morphogenetic proteins (BMP) 9 and 10 are ligands that bind to ALK1 and induce activation of the heteromeric receptor complex, phosphorylation of SMAD1/5/8, and upregulation of specific genes involved in the maturation stage of angiogenesis, such as Id-1 and TMEM100. In particular, BMP9 expression is upregulated in a majority of squamous cell carcinomas of the head and neck (SCCHN).
Dalantercept is an ALK1 extracellular domain-Fc fusion protein that binds BMP9 and BMP10 with high affinity and antagonizes ALK1 signaling in vivo resulting in defective vascular maturation and inhibition of tumor growth in preclinical models. In a completed Phase 1 trial in patients with advanced, refractory solid tumors dalantercept demonstrated signs of clinical activity in a variety of patients, including two of three patients with SCCHN who achieved either an objective response or prolonged stable disease. A Phase 2 trial of dalantercept as monotherapy in recurrent/metastatic SCCHN patients who have had prior platinum-based chemotherapy is currently ongoing.
Based upon the single agent activity of both dalantercept and cisplatin in SCCHN, we tested the feasibility of the combination of cisplatin plus dalantercept in a mouse model of SCCHN. Combination treatment of dalantercept plus cisplatin showed significant tumor growth inhibition (TGI) in the RPMI2650 xenograft model (59% TGI on day 30) which was significantly better than either cisplatin (35% TGI, p= 0.0077) or dalantercept (32% TGI, p=0.0002) alone. No additional toxicity was observed in the combination treatment group compared to cisplatin monotherapy group.
These data suggest that combination of dalantercept plus cisplatin may result in enhanced clinical activity and supports prospective evaluation in patients with SCCHN.
Citation Format: Marat Alimzhanov, Michael Lee, Nicolas Solban, Scott Pearsall, Susan Pandya, Matthew L. Sherman, Ravindra Kumar. Dalantercept, an ALK1 inhibitor of angiogenesis, in combination with cisplatin inhibits tumor growth in a xenograft model of squamous cell carcinoma of the head and neck. [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 1692. doi:10.1158/1538-7445.AM2014-1692
Abstract 1695: CKD-581, a novel histone deacetylase inhibitor, synergistically enhances Bortezomib cytotoxicity in multiple myeloma cells
Authors: Lee Chansu , Ahn Kwang-Sung , Jung Woo June , Koh Youngil , Kim Hyo Jung , Lee Hyun Jung , Yoon Hwi-Joong , Yoon Sung-Soo 
Published: May 2015

Abstract
For Multiple Myeloma (MM), better anti-MM therapies need to be developed in order to treat refractory, relapsed, and newly diagnosed MM. Recently, Histone deacetylase inhibitors (HDACIs) as a combined drug with bortezomib have been evaluated for the treatment of MM. In this study, we examined to determine the anti-MM effects of a novel HDACI, CKD-581, in MM cells. We treated MM cells with CKD-581 either alone or in combination with Bortezomib. Treatments of 9 different MM cell lines with CKD-581 resulted in dose-and time-dependent growth arrest accompanied by the induction of p21 expression and the reduction of cMYC. CKD-581 enhanced Bortezomib-induced cell growth arrest and apoptosis by further reduction of NF-kB mediated cell signaling pathway, which resulted in functional blockage of ubiquitination-related genes. CKD-581, alone or combined with bortezomib, also abrogated the G2/M cell cycle checkpoint, potentially through the suppression of CHK1 expression as well as synergic growth arrest via induction/reduction of CHKs and cMYC, as revealed in combined treatment of CDK-581 and bortezomib. CKD-581-induced sensitization of Bortezomib resistant MM cells to cytotoxic treatment resulted in an increased number of apoptotic cells as judged by annexin V-positivity and the presence of cleaved caspase-3. In addition, CKD-581 effectively induced the apoptosis of MM cells, which were co-cultured with BMSCs obtained from MM patients' BM. CKD-581 effectively inhibited the secretion of IL-6/sIL-6 and HGF, involved in bone lesion, from MM patients' BMSCs. In animal model, CKD-581 was well tolerated, and resulted in tumor growth inhibition and prolonged survival. In summary, the HDAC inhibitor, CKD-581, is a promising therapeutic agent for MM patients, especially when used in combination with Bortezomib.
Citation Format: Chansu Lee, Kwang-Sung Ahn, Woo June Jung, Youngil Koh, Hyo Jung Kim, Hyun Jung Lee, Hwi-Joong Yoon, Sung-Soo Yoon. CKD-581, a novel histone deacetylase inhibitor, synergistically enhances Bortezomib cytotoxicity in multiple myeloma 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 1695. doi:10.1158/1538-7445.AM2014-1695
Abstract 170: Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells
Authors: Park Sae-Ra 
Published: May 2015

Abstract
Exosomes are small membrane vesicles released by a variety of cell types. Exosomes contain genetic materials, such as mRNAs and microRNAs (miRNAs), implying that they may play a pivotal role in cell-to-cell communication. Mesenchymal stem cells (MSCs), which potentially differentiate into multiple cell types, can migrate to the tumor sites and have been reported to exert complex effects on tumor progression. To elucidate the role of MSCs within the tumor microenvironment, previous studies have suggested various mechanisms such as immune modulation and secreted factors of MSCs. However, the paracrine effects of MSC-derived exosomes on the tumor microenvironment remain to be explored. The hypothesis of this study was that MSC-derived exosomes might reprogram tumor behavior by transferring their molecular contents. To test this hypothesis, exosomes from MSCs were isolated and characterized. MSC-derived exosomes exhibited different protein and RNA profiles compared with their donor cells and these vesicles could be internalized by breast cancer cells. The results demonstrated that MSC-derived exosomes significantly down-regulated the expression of vascular endothelial growth factor (VEGF) in tumor cells, which lead to inhibition of angiogenesis in vitro and in vivo. Additionally, miR-16, a miRNA known to target VEGF, was enriched in MSC-derived exosomes and it was partially responsible for the anti-angiogenic effect of MSC-derived exosomes. The collective results suggest that MSC-derived exosomes may serve as a significant mediator of cell-to-cell communication within the tumor microenvironment and suppress angiogenesis by transferring anti-angiogenic molecules.
Citation Format: Sae-Ra Park. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast 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 170. doi:10.1158/1538-7445.AM2014-170
Abstract 1712: Sunitinib-resistant ccRCC cell lines subjected to TKI/mTOR inhibitors as a model for sequence therapy
Authors: Unteregger Gerhard , Schendel Darja , Heinzelmann Joana , Weiland Anne , Ernst Simone , Stoeckle Michael , Junker Kerstin 
Published: May 2015

Abstract
Introduction: Treatment of advanced renal cell carcinoma (RCC) by tyrosine kinase inhibitors like Sunitinib (SUN) is hampered by the appearance of drug resistance. Sequence therapy using different TKIs as well as inhibitors attacking the mTOR pathway offers a promising tool to overcome this lack in ccRCC therapy.
Material and Methods: CAKI-1/2, A-498 and 786-O cell lines were treated with different SUN-concentrations to obtain the corresponding IC50-values. Using sub-lethal SUNI-concentrations they were cultivated for up to 20 passages. At defined intervals total RNA was isolated. Microarray analysis was performed for a global miRNA expression profiling, SUN-resistant cell lines were subjected to an ongoing sequence therapy using TKI 258 (Novartis) and RAD001 as a mTOR inhibitor. Resistance-development as well as drug efficacy during sequence therapy was monitored by sequential quantification of the growth behavior and changes in drug-sensitivity by proliferation-assays.
Results: Growth behavior of all ccRCC cell lines during SUN-application is reduced down to 10-60% depending on cell number and cell type. Long term application (10-20 passages) of SUN at concentrations near the IC50 value results in a constantly increasing drug resistance and the cells acquire a growth rate of 60-90% compared to the untreated long term control. Accordingly to these phenomenon we observed characteristic changes in miRNA expression. Starting sequence therapy SUN-resistant cell lines (CAKI-1 and 786-0) offer initially an increase in drug resistance to TKI 258 in pretreated CAKI-1 cells. In contrast long term SUN-application had no influence in the sensitivity to RAD001 as compared to untreated controls in both cell lines.
Conclusion: Understanding the molecular changes during drug resistance in ccRCC provides an indispensable prerequisite to create new therapeutic strategies in the treatment of metastatic renal cell carcinoma. The results indicate a complex mechanism in drug resistance depending on therapeutic protocol and cell type. However, drug-resistant cell lines offer a promising tool to elucidate the molecular mechanism responsible for drug-resistance as well as to simulate the benefit of a sequence therapy. Since miRNAs represent an important tool in gene regulation the observed patterns may help to elucidate new genes involved in drug resistance in ccRCC.
Citation Format: Gerhard Unteregger, Darja Schendel, Joana Heinzelmann, Anne Weiland, Simone Ernst, Michael Stoeckle, Kerstin Junker. Sunitinib-resistant ccRCC cell lines subjected to TKI/mTOR inhibitors as a model for sequence therapy. [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 1712. doi:10.1158/1538-7445.AM2014-1712
Abstract 1713: PDK1 and hexokinase 2 are downstream effectors of PTEN loss and regulate response to targeted therapies in multiple tumor types
Authors: Pazarentzos Evangelos , Bivona Trever G. 
Published: May 2015

Abstract
Recent advances in molecular profiling of many human tumor types has enabled the development and clinical use of molecularly-targeted therapies in patients. Many tumors exhibit inactivation of PTEN which is predicted to sensitize tumor cells to PI3 kinase or AKT inhibitor therapy. However, clinical responses to PI3 kinase or AKT inhibitors are variable and not curative. Furthermore, these responses in patients do not correlate uniformly with PTEN inactivation. Therefore, we investigated whether PTEN inactivation could lead to dependence on signaling pathways and components that function independently of PI3K or AKT and that could serve as novel therapeutic targets in PTEN deficient tumors. Using multiple human tumor models including lung adenocarcinoma, lung squamous, renal cell carcinoma, and prostate adenocarcinoma that express or lack PTEN and Gene Set Enrichment Analysis, we identified alterations in numerous metabolic regulatory genes in response to PTEN inactivation, including hexokinase 2 (HK2) and pyruvate dehydrogenase kinase 1 (PDK1). We found that in PTEN-deficient tumor cells HK2 is upregulated and selectively localizes to the mitochondria, where it enhances glycolytic flux and inhibits apoptosis. Furthermore, we found that PDK1 is also upregulated upon PTEN inactivation and suppresses oxidative phosphorylation, upregulating glycolysis and the production of lactate. Thus, we uncovered a novel role for HK2 and PDK1 in the metabolic reprogramming that occurs as a consequence of PTEN inactivation in tumor cells. Furthermore, we found that overexpression of either HK2 or PDK1 confers resistance to targeted therapies against PI3K and other oncogenic drivers more broadly. Conversely, genetic or pharmacological suppression of HK2 or PDK1 enhances response to targeted therapy in multiple tumor cell types. Together, our data identify HK2 and PDK1 as novel molecular biomarkers and promising therapeutic targets in multiple PTEN deficient tumor types.
Citation Format: Evangelos Pazarentzos, Trever G. Bivona. PDK1 and hexokinase 2 are downstream effectors of PTEN loss and regulate response to targeted therapies in multiple tumor types. [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 1713. doi:10.1158/1538-7445.AM2014-1713
Abstract 1714: Erk inhibitor overcomes type II interleukin 1 receptor, a decoy receptor, associated Regorafenib resistance in colorectal carcinoma
Authors: Mar Ai-Chung , Chu Chun-Ho , Lee Te-Chang 
Published: May 2015

Abstract
We have previously demonstrated that type II interleukin 1 receptor (IL1R2), which is an IL-1 decoy receptor and inhibits exogenous IL-1 signaling, activates the expression of several proinflammatory cytokines. We also found that enhanced expression of IL1R2 promotes tumor growth and increases tumor angiogenesis through activated IL-6/VEGF-A signalings. Recently, we observed a close association of enhanced expression of IL1R2 and Regorafenib resistance in colorectal cancer (CRC) cell lines. Regorafenib is the newly approved multi-kinase inhibitor used for treatment of late-stage metastatic CRC by US FDA. To have a better use of Regorafenib against CRC, we conducted experiments to understand the mechanism underlying which IL1R2 is involved in Regorafenib resistance. In the present study, we demonstrated that silencing of IL1R2 in HT29 cell overcame its resistance to Regorafenib whereas ectopic expression of IL1R2 decreased the sensitivity of HCT116 cell to Regorafenib in in vitro and in vivo systems. IL1R2 silencing also enhanced the apoptotic proteins expression in Regorafenib-treated cells. In addition, we have established Regorafenib-resistant DLD-1 colon cancer cells by growing them in the presence of Regorafenib. Consistently, higher IL1R2 expression was found in Regorafenib-resistant cells than the parental cells. Mechanistically, we observed that Regorafenib treatment significantly resulted in enhanced expression of extracellular-signal-regulated kinase (Erk), which functions as a survival factor, in IL1R2-overexpressing cells. Therefore, pretreatment of IL1R2-overepressing CRC cells with Erk inhibitor, U0126, reversed their Regorafenib resistance, suggesting that Erk signaling cascade is crucial in Regorafenib resistance resulted from IL1R2 overexpression. Taken together, our present study suggested that combination of Regorafenib and Erk inhibitor is a rationale regime to overcome IL1R2 overexpression-induced Regorafenib resistance in CRC patients, but also IL1R2 is a potential biomarker for colon cancer therapy.
Citation Format: Ai-Chung Mar, Chun-Ho Chu, Te-Chang Lee. Erk inhibitor overcomes type II interleukin 1 receptor, a decoy receptor, associated Regorafenib resistance in colorectal carcinoma. [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 1714. doi:10.1158/1538-7445.AM2014-1714
Abstract 1715: Elucidating mechanisms of resistance to FGFR inhibitors in endometrial cancer
Authors: Packer Leisl M. , Byron Sara , Loch David , Dehkhoda Farhad , Wortmann Andreas , Geng Xinyan , Nones Katia , Grimmond Sean , Pearson John , Waddell Nic , Pollock Pamela 
Published: May 2015

Abstract
Preclinical studies by our lab and others have demonstrated Fibroblast Growth Factor Receptor (FGFR) inhibition is a viable therapeutic strategy in FGFR2-mutant endometrial cancer (EC). A significant clinical issue that we aim to address is that of intrinsic and acquired resistance to anti-FGFR therapeutics in the context of EC.
Using mutagenesis screens, we have identified mutations in the FGFR2 kinase domain that cause resistance to the FGFR inhibitors dovitinib and NVP-BGJ398 and explore the mechanism of action of the drug-resistant mutations. We previously reported the N550K and V565I mutations caused resistance to dovitinib. The sensitivity/resistance of these FGFR2 mutants to emerging FGFR inhibitors including AZD4547, NVP-BGJ398 and LY2874455 has now been tested.
To gain insights into potential mechanisms of acquired resistance to FGFR inhibitors in EC cells we generated subclones of FGFR2mutant AN3CA, MFE280 and JHUEM-2 EC cells resistant to FGFR inhibitors PD173074, Dovitinib and NVP-BGJ398, respectively. Phospho- protein arrays, gene expression profiling, exome sequencing and SNP analysis were performed to identify genes and signalling pathways that mediate resistance to FGFR inhibitors. Sequencing of AN3CAresistant and MFE280resistant subclones excluded secondary FGFR2 mutations as the resistance mechanisms. Upregulation of downstream survival pathways such as pERK and pAKT was observed in some of the JHUEM-2resistant and AN3CAresistant subclones. To further characterise these subclones we are currently analysing data from exome sequencing and copy number analysis, to determine the molecular mechanisms of resistance in these cell lines. In the MFE280resistant cells resistance to FGFR inhibition is associated with an EMT phenotype. Signaling through pERK and pAKT is downregulated in these cells, suggesting that resistance is not mediated by activation of kinase-driven survival pathways. Analysis of expression data is underway to understand how these cells have become resistant to FGFR inhibitors. This research will provide insight into possible combination therapies that may combat drug resistance in FGFR-mutant endometrial cancer.
Citation Format: Leisl M. Packer, Sara Byron, David Loch, Farhad Dehkhoda, Andreas Wortmann, Xinyan Geng, Katia Nones, Sean Grimmond, John Pearson, Nic Waddell, Pamela Pollock. Elucidating mechanisms of resistance to FGFR inhibitors in endometrial 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 1715. doi:10.1158/1538-7445.AM2014-1715