bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3544: Clinical applicable human adipose tissue-derived mesenchymal stem cells delivering therapeutic genes to brainstem glioma
Authors: Choi Seung Ah , Lee Young Eun , Kwak Phil Ae , Moon Youn Joo , Phi Ji Hoon , Wang Kyu-Chang , Kim Sung Su , Wang Kyu-Chang , Joo Kyeung Min , Kim Seung-Ki 
Published: August 2015

Abstract
Brainstem glioma is one of incurable malignancies in children due to its unique inoperable location. Regarding the extensive migratory ability toward cancer and the possible autologous transplantation, human adipose-derived mesenchymal stem cells (hAT-MSC) are attractive vehicles to deliver therapeutic genes to brainstem glioma. In this study, we established clinically applicable hAT-MSCs expressing therapeutic genes in a GMP facility and investigated the therapeutic efficacy against brainstem glioma preclinically. For the feasible clinical application, 1) hAT-MSCs were primarily cultured from the human subcutaneous adipose tissue for making autologous transplantation possible, 2) hAT-MSCs were genetically engineered to express two therapeutic genes, carboxyl esterase (CE) and a secreted form of the TNF-related apoptosis-inducing ligand (sTRAIL) for synergistic effects, 3) human CE and sTRAIL sequences were utilized to avoid immunological side effects, and 4) sTRAIL expression vector was delivered by non-gDNA integrating gene transfer technology. hAT-MSCs expressing sTRAIL ± CE showed significant therapeutic effects against brainstem gliomas in vitro and in vivo. However, simultaneous sTRAIL and CE expression failed to show synergistic effects in vivo. The results indicate that non-viral transient sTRAIL gene transfer to autologous hAT-MSCs is a clinically applicable stem cell-based gene therapy for brainstem gliomas in terms of therapeutic effects and safety.
Citation Format: Seung Ah Choi, Young Eun Lee, Phil Ae Kwak, Youn Joo Moon, Ji Hoon Phi, Kyu-Chang Wang, Sung Su Kim, Kyu-Chang Wang, Kyeung Min Joo, Seung-Ki Kim. Clinical applicable human adipose tissue-derived mesenchymal stem cells delivering therapeutic genes to brainstem glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3544. doi:10.1158/1538-7445.AM2015-3544
Abstract 3583: Drug-resistant NPM/ALK mutants show different sensitivity to second generation tyrosine kinase inhibitors
Authors: Mologni Luca , Ceccon Monica , Fontana Diletta , Pirola Alessandra , Piazza Rocco , Gambacorti-Passerini Carlo 
Published: August 2015

Abstract
Rearranged or mutated forms of the Anaplastic Lymphoma Kinase (ALK) are involved in the pathogenesis of various cancers, in particular anaplastic large cell lymphoma (ALCL), non-small-cell lung cancer (NSCLC) and neuroblastoma. ALK-positive tumors are currently treated with crizotinib (XalkoriTM, Pfizer) or ceritinib (ZykadiaTM, Novartis), two oral ALK inhibitors (ALKi). Additional inhibitors are in clinical trial. Despite high response rates, drug-resistant disease often develops in patients. In order to study the mechanisms that underlie resistance, we generated several ALKi-resistant cell lines in vitro. Here we present the selection of novel NPM/ALK-positive ALCL cells resistant to ASP3026 (Astellas) that grow in the presence of up to 2 μM ASP3026 and show 10 to 60 fold shift in IC50. The established ASP3026-resistant cell lines carry several point mutations in the ALK kinase domain (G1128S, C1156F, I1171N/T, F1174I, N1178H, E1210K, and C1156F/D1203N) that confer resistance to ASP3026 when reintroduced in a Ba/F3 cell model. Furthermore, the activity profile of ASP3026, crizotinib, ceritinib, alectinib, AP26113 and PF-06463922 against a panel of 20 NPM/ALK drug-resistant mutants will be presented. We report for each ALKi the IC50 value against the mutants, the IC50 fold increase over wild-type NPM/ALK (relative resistance, RR) and the IC50 ratio between parental Ba/F3 cells and mutants (therapeutic index, TI). From our screen, the G1202R and C1156F/D1203N mutations appear to be highly resistant to all tested inhibitors, therefore they are predicted to be the most challenging mutants for ALKi therapy.
Citation Format: Luca Mologni, Monica Ceccon, Diletta Fontana, Alessandra Pirola, Rocco Piazza, Carlo Gambacorti-Passerini. Drug-resistant NPM/ALK mutants show different sensitivity to second generation tyrosine kinase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3583. doi:10.1158/1538-7445.AM2015-3583
Abstract 3586: The use of kinome profiling to determine potential resistance pathways in pancreatic cancer cells treated with PIM kinase inhibitors
Authors: Singh Vandana , Nixon Brittany , Gilbert T.S. Karim , Warner Steve , Bearss David , Graves Lee M. , Baines Antonio T. 
Published: August 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent cancer of the pancreas with a 5-year survival rate of 6%, making it the 4th most common cause of cancer deaths in the United States. One of the challenges related to this cancer is the issue of chemoresistance. Chemoresistance renders most drugs ineffective in the treatment of PDAC, including kinase inhibitors and the chemotherapeutic drug gemcitabine. PIM (Proviral Integration site for the Moloney murine leukemia virus) kinases are a family of proteins shown to play an important role in the chemoresistance of many cancers, including pancreatic cancer. PIMs act downstream of the JAK-STAT cytokine signaling pathway and phosphorylate substrates involved in numerous cell functions including cell cycle progression and apoptosis. One objective of our research was to determine the role of PIM kinases on transformed phenotypes of PDAC cells. We were able to demonstrate that the PIM kinase inhibitor SGI-1776 and TP-3654, a second generation PIM kinase inhibitor, were able to inhibit growth in cell viability assay. Also, the PIM inhibitors were able to decrease various phenotypes such as anchorage-dependent and anchorage-independent growth in MIA PaCa-2 and PANC-1 cells. A second objective was to determine if PIM kinase inhibitors could reduce chemoresistance in PDAC cells. PIM inhibitors in combination with gemcitabine decreased cell viability in PDAC cells significantly more than when administered separately. To investigate resistance pathways activated in PDAC cells after treatment with PIM kinase inhibitors, we applied multiplexed inhibitor beads (MIBs) mass spectrometry (MS) to profile the kinome. We observed numerous kinases that were downregulated or upregulated after treatment. One of the kinases upregulated was IKKα, a key kinase in the anti-apoptotic NF-κB signaling pathway. Our results suggest that PIM kinases are an important target for cell growth and chemoresistance in pancreatic cancer. Also, these results suggest that treating PDAC cells with a PIM inhibitor simultaneously with an IKK inhibitor might prevent the effects of resistance pathways. Overall, our studies demonstrate that kinome profiling is an effective strategy to identify cellular responses to PIM kinase inhibitors as well as other drugs for treating pancreatic and other cancers.
Citation Format: Vandana Singh, Brittany Nixon, T.S. Karim Gilbert, Steve Warner, David Bearss, Lee M. Graves, Antonio T. Baines. The use of kinome profiling to determine potential resistance pathways in pancreatic cancer cells treated with PIM kinase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3586. doi:10.1158/1538-7445.AM2015-3586
Abstract 3587: Developing targeted therapy for the treatment of drug-resistant ovarian cancer
Authors: Kreitzburg Kelly M. , Dobbins Zacchary , Katre Ashwini , Anwer Tooba , Alvarez Ronald , Landen Charles N. , Yoon Karina J. 
Published: August 2015

Abstract
Despite therapeutic approaches that combine surgical cytoreduction with chemotherapy, ovarian cancer remains the principal cause of death among women with gynecological malignancies. Virtually all patients relapse with drug-resistant disease. To elucidate the biological mechanisms that contribute to this resistance, we established a repository of patient-derived xenograft (PDX) models of ovarian cancer in mice. We used RNA-seq and Ingenuity Canonical Pathway software to analyze chemotherapy induced changes in expression patterns of six of these models. We found that the sphingosine-1-phosphate (S1P) signaling pathway is one of the pathways most affected by paclitaxel and cisplatin treatment, with altered expression in seven genes associated with the S1P pathway (p&lt;0.05). The biologically active lipid S1P contributes to cell growth, survival/apoptosis, angiogenesis, migration and metastasis in normal and tumor tissue. The S1P pathway has also been reported to be involved in chemoresistance in several types of solid tumors.
The S1P pathway depends predominately on three core lipids: ceramide, sphingosine, and S1P. These molecules are termed the ceramide-sphingosine-S1P rheostat, and their expression is tightly regulated both intra- and extra-cellularly. Recent studies suggest a correlation between aberrations in the S1P pathway and poor prognosis, advanced stage, and resistance to chemotherapy and radiation.
Preliminary data using the sphingosine analog FTY-720 is consistent with the hypothesis that the S1P pathway regulates cell survival by effecting changes in the relative levels of ceramide, sphingosine, and S1P, as a cytoprotective autophagic mechanism to evade chemotherapy-induced cytotoxic effects. Cell proliferation assays, immunoblots, and fluorescence microscopy results of ovarian cancer cells exposed to FTY-720 in combination with carboplatin or paclitaxel treatment provide evidence that the S1P pathway may evade cell death through the induction of cytoprotective autophagy. Our data suggest that the S1P pathway contributes to the chemoresistance of ovarian cancer cells to conventional chemotherapeutic agents.
Citation Format: Kelly M. Kreitzburg, Zacchary Dobbins, Ashwini Katre, Tooba Anwer, Ronald Alvarez, Charles N. Landen, Karina J. Yoon. Developing targeted therapy for the treatment of drug-resistant ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3587. doi:10.1158/1538-7445.AM2015-3587
Abstract 3599: Resistance mechanisms to HER2-targeting treatment in HER2-positive gastric cancer
Authors: Kang Kyo Hwa , Nam Ah-Rong , Park Ji Eun , Bang Ju-Hee , Ling Jin , Jin Mei Hua , Kim Tae Yong , Han Sae-Won , Song Sang-Hyun , Im Seock-Ah , Kim Tae-You , Oh Do-Youn , Bang Yung-Jue 
Published: August 2015

Abstract
Background: HER2 is the first validated therapeutic target in advanced gastric cancer (GC). Trastuzumab in combination with chemotherapy is used as a first-line treatment of GC. The resistance mechanisms to trastuzumab have not been widely known in GC. We investigated the resistance mechanisms to HER2-targeting agents in HER2-positive gastric cancer cells.
Methods: SNU216 and NCI-N87 are HER2 amplified gastric cancer cells. Using these cells, we established trastuzumab-resistant cells (SNU216-HR, N87-HR) and dacomitinib (panHER inhibitor)-resistant cells (SNU216-PR). Acquired resistance of the established cell lines was verified by MTT assay and western blotting. We compared various receptor tyrosine kinase activities and protein expression levels between parental and resistant cells by RTK arrays and western blotting. We used many targeted agents (HER family inhibitor, PI3K inhibitor, mTOR inhibitor, MEK inhibitor, Src inhibitor, HSP90 inhibitor, etc) to overcome the resistance.
Results: Resistant cells displayed more rapid growth rate and different morphology compared with parent cells. Resistant cells showed increased levels of pEGFR, pHER2, pHER3, pMET, pIGF1R, pAXL, pSTAT3, pAKT, pFAK, and TS compared with the parental cells in western blot. With the treatment of trastuzumab, HR cells showed elevated levels of EGFR, pHER2, AXL, pAXL, pMEK, pSRC, pSTAT3, pAKT, pERK and TS compared with the parental cells. With the treatment of dacominitib, PR cells showed elevated levels of pEGFR, pAXL, pIGF1R, pMEK, pSRC, pERK and TS compared with the parental cells in western blot. The RTK arrays also showed the similar findings. These resistant cells were more sensitive to Src inhibitor and PI3K inhibitor than parent cells.
Conclusion: Resistance mechanisms to HER2-targeting strategy in gastric cancer include activation of HER, MET, FAK and Src pathway. Targeting these pathways is needed to overcome resistance.
Citation Format: Kyo Hwa Kang, Ah-Rong Nam, Ji Eun Park, Ju-Hee Bang, Jin Ling, Mei Hua Jin, Tae Yong Kim, Sae-Won Han, Sang-Hyun Song, Seock-Ah Im, Tae-You Kim, Do-Youn Oh, Yung-Jue Bang. Resistance mechanisms to HER2-targeting treatment in HER2-positive gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3599. doi:10.1158/1538-7445.AM2015-3599
Abstract 3602: Cross-resistance to 1st, 2nd, and 3rd generation EGFR tyrosine kinase inhibitors in vitro is characterized by MET amplification and PTEN loss
Authors: Paul Sarah M. , Nickles Dorothee , Ye Xioafen , Yauch Robert L. , Shames David S. 
Published: August 2015

Abstract
Reversible EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib offer significant clinical benefit to patients with EGFR mutation positive non-small cell lung cancer (NSCLC) compared to chemotherapy alone, but high rates of resistance especially at EGFR T790M (50-60% of resistant cases) underscore the need for better targeted treatments for NSCLC patients. Third generation irreversible TKIs–AZD9291 and CO-1686–were developed for efficacy in the T790M setting. However, resistance to the new class of EGFR TKIs is inevitable, prompting us to investigate the relationship between erlotinib and AZD9291 resistance mechanisms and explore novel ones. NSCLC cell lines harboring activating EGFR mutations with (NCI-H1975) or without T790M (HCC4006, HCC827, and PC-9) were exposed to erlotinib, dacomitnib, or AZD9291 at IC 75 or greater for three months to generate resistance. We observed cross-resistance to other EGFR TKIs in nearly all resistant lines, suggesting that T790M was not the main driver of resistance in the erlotinib-treated lines and that a common mechanism might account for resistance in each cell line set. An epithelial to mesenchymal transition (EMT) was observed and a corresponding increase in vimentin staining was seen in resistant lines, consistent with cross-resistance. Previous studies showed that MET amplification caused erlotinib resistance in HCC827; our data suggest MET amplification also accounted for the AZD9291 and dacomitnib resistance in HCC827. In AZD9291-resistant HCC4006 and H1975 lines, PTEN levels were substantially reduced compared to the parental line, with a corresponding increase in PIK3 pathway markers. Whole exome sequencing data support homozygous deletion of PTEN loss as a mechanism of acquired resistance to AZD9291 in NCI-H1975. The PTEN null line NCI-H1650 was found to be resistant to all three TKIs without long-term drug exposure, implicating PTEN loss as a mechanism of de novo resistance. An analysis of EGFR mutation status, PTEN status, MET expression, and the kinetics of acquired resistance will be presented and clinical implications will be discussed.
Citation Format: Sarah M. Paul, Dorothee Nickles, Xioafen Ye, Robert L. Yauch, David S. Shames. Cross-resistance to 1st, 2nd, and 3rd generation EGFR tyrosine kinase inhibitors in vitro is characterized by MET amplification and PTEN loss. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3602. doi:10.1158/1538-7445.AM2015-3602
Abstract 3606: Increase of MET gene copy number confers resistance to a monovalent MET antibody and establishes drug dependence
Authors: Martin Valentina , Corso Simona , Comoglio Paolo Maria , Giordano Silvia 
Published: August 2015

Abstract
The tyrosine kinase receptor encoded by the MET oncogene is one of the most frequently altered oncogenes in human cancer. The relevant role played by the MET oncogene in cancer progression led to the development of specific inhibitors targeting MET, some of which are now in advanced phases of clinical trials.
Previous experience has shown that the main limit to the efficacy of most targeted treatments is the advent of resistance. Mechanisms underlying resistance to MET-specific small tyrosine kinase inhibitors (TKIs) have been already described, while nothing is known about resistance to MET monoclonal antibodies, nor about bypassing resistance to chemical TKIs by antibodies or vice-versa.
A monovalent form of an anti-MET monoclonal antibody (MV-DN30) was previously generated to target MET by promoting receptor “shedding”, inactivation and by inhibiting the MET-mediated invasive growth program both in vitro and in vivo cancer models. In our study EBC1 lung cancer cells that are MET-addicted as a consequence of gene amplification and thus sensitive to MET inhibitors, including the MV-DN30 were used as cell model. Upon prolonged treatment of these cells with the MV-DN30 we generated EBC1 cells resistant to this antibody and found that resistance was due to a further increase of MET gene copy number and a dramatic over-expression of the MET receptor. Such an excess of expression saturated the ‘shedding’ activity of MV-DN30, and prevented both the efficient down-regulation of the MET receptor from the surface and the inhibition of the ensuing constitutive activation.
Notably, antibody-resistant cells became ‘drug-dependent’, since the removal of MV-DN30 led them to death due to an excess of MET signal and a concomitant p38MAPK activation. Moreover, antibody-resistant cells remained MET-’addicted’ and were still sensitive to MET TKIs.
Finally, cells made resistant to MET specific TKIs were still sensitive to treatment with the antibody MV-DN30.
These findings suggest that a discontinuous or combined treatment by antibodies and chemical kinase inhibitors may increase the clinical response and bypass resistance to anti-MET targeted therapies.
Citation Format: Valentina Martin, Simona Corso, Paolo Maria Comoglio, Silvia Giordano. Increase of MET gene copy number confers resistance to a monovalent MET antibody and establishes drug dependence. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3606. doi:10.1158/1538-7445.AM2015-3606
Abstract 3624: A novel, selective DNA-PK inhibitor sensitizes poor prognosis chronic lymphocytic leukemia (CLL) cells to mitoxantrone
Authors: Junge Gesa 
Published: August 2015

Abstract
Approximately 20% of Chronic Lymphocytic Leukaemia (CLL) cases carry 11q deletions and 10% carry 17p deletions (associated with loss of p53 function), both of which are poor prognostic markers. Ataxia telangiectasia mutated kinase (ATM) is located on chromosome 11q23 and 30% of del11q patients lack ATM function. Previous work has shown that the DNA-PK inhibitor NU7441 chemosensitises CLL cells to fludarabine ex vivo (Willmore E et al 2008), and monotherapy with KU60648, a dual inhibitor of PI3kδ and DNA-PK has been shown to be effective in ATM deficient cells (Riabinska A et al 2013). Furthermore, a dual DNA-PK/mTOR inhibitor, CC-115, is now in clinical trials (NCT01353625).
Here, we aimed to validate the selective inhibition of DNA-PK over related kinases as a therapeutic approach in CLL, using a novel, more selective compound (NDD0004, cell-free IC50 10nM). Both primary CLL cells and an isogenic pair of DNA-PK-deficient and proficient HCT116 cells were used as models.
Primary CLL cells were cultured ex vivo and treated with the topoisomerase II poison mitoxantrone in the presence and absence of NU7441 and NDD0004. Cell viability was determined after 48h by XTT assay. Apoptosis and DNA damage (yH2AX foci) were measured by caspase 3/7GloAssay and immunofluorescence, respectively. ATM function was determined by the cells ability to autophosphorylate ATM on serine 1981 after ionising radiation.
Chemosensitisation to mitoxantrone in primary CLL cells was substantial and it was higher with NDD0004 than with NU7441 (mean 202- vs. 69-fold, ranges 1-1000 vs. 1-543-fold). Intriguingly, cells lacking ATM or p53 function were also sensitised by DNA-PK inhibition (mean 15- and 21-fold, respectively). HCT116 cells lacking DNA-PK were not chemosensitised by NDD0004 but DNA-PK proficient cells were sensitised 5-fold. Mitoxantrone-induced DSBs (as measured by yH2AX foci) were repaired by 24h, but persisted in the presence of DNA-PK inhibitors. In keeping with this observation, apoptosis as measured by caspase 3/7 activity was potentiated by DNA-PK inhibitors.
NDD0004 and KU60648 were also evaluated in a panel of ATM deficient (HT144, H1395) and ATM proficient (A549, A375) cell lines. ATM status had no impact on (a) the level of chemosensitisation to mitoxantrone by both inhibitors and (b) single agent activity for NDD0004 and KU60648.
In conclusion, our data show that selective inhibition of DNA-PK chemosensitises primary CLL cells even when p53 is mutated or ATM function is lost. Current work is focused on identifying biomarkers which predict good response to DNA-PK inhibitors.
Citation Format: Gesa Junge. A novel, selective DNA-PK inhibitor sensitizes poor prognosis chronic lymphocytic leukemia (CLL) cells to mitoxantrone. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3624. doi:10.1158/1538-7445.AM2015-3624