bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5388: High throughput toxicity assay for three-dimensional cell cultures
Authors: Trumpi Kari , Egan David A. , Vellinga Thomas T. , Rinkes Inne H.M Borel , Kranenburg Onno W. 
Published: May 2015

Abstract
Introduction:
Three-dimensional cell culture methods are currently not widely used for cancer drug discovery due to the specific imaging demands of the systems. In particular there is a need for well validated robust high throughput methods for image-based assays that can be used for high content screening.
Methods:
Therefore we have developed an image-based three-dimensional high throughput toxicity assay. We used two platforms, the Thermo Scientific ArrayScan VTi and BD FACSCanto™, to characterize antiproliferative potency, cell death and cell cycle distribution. Cultures of uniform spheroids were treated with Irinotecan either alone or in combination with the ABC transporter inhibitor Valspodar, which blocks irinotecan efflux. All drugs were dispensed using a Tecan HP-D300 digital dispenser. Treatment-induced effects were analyzed after 48, 72 or 96 hours with both platforms using dihydro derivatives of fluorescent live cell dyes such as dihydrocalcein, AM and DNA-binding dyes such as DRAQ5™ and Propidium Iodide.
Results:
All cell lines tested on the two platforms showed the expected effects of Irinotecan alone or in combination with Valspodar and correlations between the Thermo Scientific ArrayScan VTi and BD FACSCanto™ were high, with Pearson tests varying from 0.76 to 0.95, p &lt; 0.05, depending on the cell line used. All results were reproducible and showed minor variation.
Conclusion:
The demonstrated approach provides an easy-to-handle, low-cost, accurate and reproducible high content method for measuring drug efficacy in three-dimensional cell cultures. This method can be used for high throughput drug discovery screens and personalized cancer care.
Citation Format: Kari Trumpi, David A. Egan, Thomas T. Vellinga, Inne H.M Borel Rinkes, Onno W. Kranenburg. High throughput toxicity assay for three-dimensional cell cultures. [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 5388. doi:10.1158/1538-7445.AM2014-5388
Abstract 5439: Metabolomic study of EGFR drug resistance mechanisms
Authors: Zhao Yang , Tan Bo , Kuo Ming-Shang , Liu Ling , Breyer Matthew D. 
Published: May 2015

Abstract
Therapies targeting EGFR often fail after certain period of treatment due to development of resistance. There are many causes of resistance such as genetic mutations of KRAS, BRAF, etc.. Overexpression of other receptor tyrosine kinases can also lead to resistance of EGFR therapies. A therapeutic targeting metabolic phenotypes that can overcome multiple resistance mechanisms is highly desired. In order to identify the Achilles heel of resistant cell metabolism, we investigated the metabolic effects of the current EGFR targeting agents as well as the metabolic differences between sensitive and resistant cancer cells.
Citation Format: Yang Zhao, Bo Tan, Ming-Shang Kuo, Ling Liu, Matthew D. Breyer. Metabolomic study of EGFR drug resistance mechanisms. [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 5439. doi:10.1158/1538-7445.AM2014-5439
Abstract 5474: The formin, DIAPH3, regulates response to MT stabilizing drugs in prostate and breast cancer
Authors: Morley Samantha , Pollan Sara G. , You Sungyong , Knudsen Beatrice S. , Freeman Michael 
Published: May 2015

Abstract
Diaphanous-related formin-3 (DIAPH3), a cytoskeletal regulator of the formin family, is lost at high frequency in metastatic breast and prostate cancers and has characteristics of a non-canonical metastasis suppressor. We previously showed that DIAPH3 silencing evokes a transition to an “amoeboid” phenotype, characterized by rapid motility, RhoA/ROCK and ERK pathway activation, dynamic membrane blebbing and increased shedding of microvesicles. Here we demonstrate that DIAPH3 loss reduces microtubule (MT) stability in prostate and breast cancer cell lines, and increases the cells' sensitivity to the taxanes, paclitaxel and docetaxel and the non-taxane, epothilone B. DIAPH3 silencing reduces membrane localization of the multidrug resistance-associated protein, MRP1, a regulator of taxane efflux, and increases intracellular accumulation of fluorescent paclitaxel. Baseline acetylation of tubulin, which is proportional to the number of stable MT, is lower in DIAPH3-silenced cells. In contrast, the fold-increase of tubulin acetylation after treatment with MT stabilizing drugs is greater in DIAPH3 knockdown compared to control cells. Further, cytotoxicity induced by paclitaxel, docetaxel or epothilone B is enhanced by DIAPH3 silencing. Analysis of gene expression profiles of breast cancer patients treated with chemotherapeutic regimens containing taxanes in a neoadjuvant phase-2 clinical trial revealed that low DIAPH3 expression is associated with increased relapse free survival. Collectively, the data demonstrate that DIAPH3 deficiency increases responsiveness to widely used MT stabilizing drugs. These findings have implications for the inclusion of DIAPH3 in biomarker panels that stratify patients for treatment with taxanes, in particular in the neoadjuvant setting.
Citation Format: Samantha Morley, Sara G. Pollan, Sungyong You, Beatrice S. Knudsen, Michael Freeman. The formin, DIAPH3, regulates response to MT stabilizing drugs in prostate and breast 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 5474. doi:10.1158/1538-7445.AM2014-5474
Abstract 5495: BET bromodomain inhibitors abrogate cell cycle progression and induces apoptosis in Myc-induced mouse lymphoma cells without affecting MYC transcription
Authors: Bhadury Joydeep , Nilsson Lisa M. , Green Lydia , Li Zhoulei , Gesner Emily M. , Muralidharan Somsundar Veppil , Hansen Henrik C. , Keller Ulrich B. , Mclure Kevin G. , Nilsson Jonas A. 
Published: May 2015

Abstract
Overexpression of one of the three MYC genes is a hallmark of many human cancers. They encode transcription factors that regulate expression of a number of genes critical for tumor development. Conditional transgenic mouse models have shown that Myc inhibition causes tumor regression; Myc is therefore an attractive target for therapy, and effective pharmacological Myc inhibition has been a long-standing goal in cancer research. Recent publication have shown that selective inhibition of BET bromodomain and extra-terminal (BET) domain family of proteins, that bind to acetylated lysines on histones, show promise as potent anti-cancer drugs via down-regulation of the MYC oncogene. Here we confirm that two structurally different BET protein inhibitors (BETi), JQ1 (proto-type) and RVX2135, inhibit the proliferation and induce apoptosis of lymphoma cells arising in Myc-transgenic mice. BETi have been reported to directly inhibit MYC transcription. Surprisingly, in our system BET inhibition had no effect on MYC transcription, despite exhibiting broad transcriptional effects evident from expression profiling. Our data challenge the prevailing view that BETi operate primarily via suppression of MYC transcription in hematological malignancies. Instead we suggest that BET proteins have Myc-independent pleiotropic effects that should be exploited to treat a wide range of cancers. Myc still remains a challenging target for therapy to date.
Citation Format: Joydeep Bhadury, Lisa M. Nilsson, Lydia Green, Zhoulei Li, Emily M. Gesner, Somsundar Veppil Muralidharan, Henrik C. Hansen, Ulrich B. Keller, Kevin G. Mclure, Jonas A. Nilsson. BET bromodomain inhibitors abrogate cell cycle progression and induces apoptosis in Myc-induced mouse lymphoma cells without affecting MYC transcription. [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 5495. doi:10.1158/1538-7445.AM2014-5495
Abstract CT102: Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia
Authors: Sadelain Michel , Brentjens Renier , Davila Marco , Riviere Isabelle , Wang Xiuyan , Bartido Shirley , Park Jae , Bouhassira Diana , Curran Kevin , Chung Stephen , Stefanski Jolanta , Borquez-Ojeda Oriana , Giralt Sergio 
Published: May 2015

Abstract
Chimeric antigen receptors (CARs) are artificial receptors for antigen that redirect antigen specificity, activate T cells and further enhance T cell function through their costimulatory component. Three groups, including our own, have reported objective tumor responses when infusing autologous T cells genetically modified with CD19-targeted CARs into patients with chronic lymphocytic leukemia (CLL), other indolent non-Hodgkin lymphomas (NHL) and, most dramatically in patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL). Here we report on 16 patients with relapsed or refractory B-ALL that we treated with autologous T cells expressing the 19-28z CAR specific to the CD19 antigen. The overall complete response rate was 88%, as assessed by morphological criteria and IgH deep sequencing. This allowed us to transition a majority of these patients to a standard of care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Ph+ disease as in those with relapsed disease following prior allo-SCT. Through systematic analysis of clinical data and serum cytokine levels over the first 21 days following T cell infusion, we have defined diagnostic criteria for a severe cytokine release syndrome (sCRS), with the goal of better identifying the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the CRS. Additionally, we found that serum C-reactive protein (CRP), a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS and a road map for patient management at centers now contemplating the use of CAR T cell therapy. Based on these remarkably robust clinical results and the toxicity management algorithm we present here, we will soon open a multi-center Phase II clinical trial to further evaluate the efficacy of 19-28z CAR T cells and prospectively validate our proposed CRS monitoring and intervention guidelines in patients who are treated with CAR therapy.
Citation Format: Michel Sadelain, Renier Brentjens, Marco Davila, Isabelle Riviere, Xiuyan Wang, Shirley Bartido, Jae Park, Diana Bouhassira, Kevin Curran, Stephen Chung, Jolanta Stefanski, Oriana Borquez-Ojeda, Sergio Giralt. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. [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 CT102. doi:10.1158/1538-7445.AM2014-CT102
Abstract CT228: A phase II study of afatinib (A) in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab (T) refractory esophagogastric (EG) cancer
Authors: Janjigian Yelena Y. , Imtiaz Tooba , Ilson David H. , Solit David B. , Berger Michael F. , Vakiani Efsevia 
Published: May 2015

Abstract
Background: Trastuzumab (T) combined with chemotherapy has been the standard of care for pts with HER2+ EG cancer. Resistance to T is now emerging in this population. Afatinib (A), a potent ErbB Family Blocker, induced nearly complete tumor regression in MSKCC HER2+ patient derived xenografts (PDX). We report the initial results of a phase II study of afatinib in patients with T refractory EG cancer.
Methods: Pts with HER2+ (IHC 3+ or FISH&gt;2.0) EG cancer -progressive on trastuzumab -received A 40 mg. Archival pre-T tissue, tumor biopsy after progression on T and after 1 week on A mandated on protocol. The primary endpoint-overall disease control: stable disease (SD) or partial response (PR).
Results: 14 pts treated with A; median duration 5.1 mos (1.7 to 12.1 mos), median 2 (1 to 4) prior T regimens, 64% of tumors IHC3+; 36% IHC2+/FISH&gt;2.2. Adverse events included: diarrhea (Grade 1/2:69%), fatigue (Grade1/2: 54%), rash (Grade 1/2:54%), mucositis (Grade1: 23%), paronychia (Grade 1/2:15%). 4 of 14 pts (28%) with disease control (PR or SD); including 1 pt with confirmed PR - a durable 75% regression of biopsy proven metastases. Median OS 6.6 mos (1.9 to NR). PDXs established from biopsies of T refractory tumors of 5 pts. EGFR amplification was detected in the tumor of the patient with PR on afatinib, suggesting EGFR amplification as a predictor of response to afatinib. High level of HER2 amplification was retained in post-trastuzumab resistance sample suggesting ongoing dependence on HER2. PIK3CA mutations were observed in tumors of 33% (2 of 6) patients, ERBB3 mutations in 33% cases (2 of 6), and MTOR or FBXW7 mutations in 50% (3 of 6) patients.
Conclusions:
Afatinib shows clinical efficacy in patients with T refractory EG cancer. The study met the criteria for expansion of the accrual based on original Simon's minimax two-stage design. Efforts to elucidate the mechanisms of T resistance including validation of potential drivers of T resistance using HER2+ PDXs are ongoing. Updated molecular and clinical data will be presented.
Citation Format: Yelena Y. Janjigian, Tooba Imtiaz, David H. Ilson, David B, Solit, Michael F. Berger, Efsevia Vakiani. A phase II study of afatinib (A) in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab (T) refractory esophagogastric (EG) 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 CT228. doi:10.1158/1538-7445.AM2014-CT228
Abstract CT411: Immune profiling of patients vaccinated with the survivin targeted therapeutic vaccine DPX-Survivac demonstrates durable polyfunctional CD4+ and CD8+ T cells in ovarian cancer patients
Authors: Peretz Yoav , Sauvé Dominike , Gagnon Dominic , Khan Salim Ahmed , Lévesque Geneviève , Saha Nathalie , Croteau Gilbert , Hébert Valérie , Savard Karyne , Diab Bader Yassine , Poulin Jean-Francois , Landry Claire , Karkada Mohan , Mansour Marc 
Published: May 2015

Abstract
Survivin is a member of the inhibitor of apoptosis protein family and its over-expression has been reported in many cancer types such as melanoma, colon, brain, breast, and ovarian cancers making it a promising target for immunotherapy. DPX-Survivac is a Survivin multi-epitope vaccine that covers a broad range of HLA haplotypes (HLA-A1, A2, A3, A24, B7). The adjuvanted water free depot vaccine is designed to specifically induce CD8+ T cells. In a Phase I study in ovarian cancer patients (n=18), we aimed to evaluate one dose level of the vaccine (0.5 mL) without cyclophosphamide (Cohort A) and two dose levels (0.1 mL and 0.5 mL) combined with oral low dose cyclophosphamide as an immune modulator (Cohorts B and C). Using multiparametric flow cytometry, we measured the ex-vivo frequency, phenotype and function of Regulatory T cells (CD25+FoxP3+Ki67+) and Survivin-specific CD4 and CD8 T cells. Our data shows that cohort C preferentially mounted survivin-specific CD8 T cells which significantly peaked at one month following the third vaccination (study day 70) and persisted until at least day 126 post-vaccination. This polyfunctional T cell response was endowed with cytotoxic and proliferative functions as measured by the expression of IL-2, IFNγ, TNFα, Granzyme B and CD107a. The immune responses identified in this cohort functionally diversified over time and were distributed within the Effector memory (CD45RA-CD27-), Central Memory (CD45RA-CD27+) and Late Differentiated CD8 T cell pool (CD45RA+CD27-). Of note, polyfunctional CD4 helper responses directed against tetanus toxoid and Survivin were induced by DPX-Survivac and possibly contributed to the maintenance of the CD8 T cell response. Taken together, the data presented herein shows that DPX-Survivac induced durable polyfunctional CD4 helper and CD8 T cells providing a strong rationale for combining the targeted immune therapy with immune modulation using metronomic cyclophosphamide.
Citation Format: Yoav Peretz, Dominike Sauvé, Dominic Gagnon, Salim Ahmed Khan, Geneviève Lévesque, Nathalie Saha, Gilbert Croteau, Valérie Hébert, Karyne Savard, Bader Yassine Diab, Jean-Francois Poulin, Claire Landry, Mohan Karkada, Marc Mansour. Immune profiling of patients vaccinated with the survivin targeted therapeutic vaccine DPX-Survivac demonstrates durable polyfunctional CD4+ and CD8+ T cells in ovarian cancer patients. [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 CT411. doi:10.1158/1538-7445.AM2014-CT411
Abstract DDT02-01: In vitro and in vivo characterization of a novel anti-fibroblast growth factor receptor (FGFR) 2 antibody (BAY 1179470) for the treatment of gastric cancer
Authors: Kopitz Charlotte , Sommer Anette , Hammer Stefanie , Harrenga Axel , Stelte-Ludwig Beatrix , Dittmer Frank , Reetz Frank , May Ekkehard , Zierz Ruprecht , Wittemer-Rump Sabine , Schatz Christoph , Huynh H. T. , Ziegelbauer Karl , Kreft Bertolt 
Published: May 2015

Abstract
Gastric cancer is the second most common cause of cancer-related mortality worldwide, thus new treatment options are urgently needed. In a subset of gastric cancers, over-expression of fibroblast growth factor receptor 2 (FGFR2), a receptor tyrosine kinase, has been described and may represent a potential therapeutic target for the treatment of FGFR2-positive gastric cancer patients. To this end, we have generated a fully human anti-FGFR2 antibody (BAY 1179470) using the BioInvent Phage Display library. BAY 1179470 binds to a unique FGFR2-specific epitope that is present in all FGFR2 isoforms. Upon binding to FGFR2, BAY 1179470 induces receptor dimerization, internalization and degradation, resulting in significant tumor growth inhibition in vivo in cell line-based and patient-derived gastric cancer models overexpressing FGFR2. Additive anti-tumor efficacy in vivo was achieved by combining BAY 1179470 with either cisplatin or paclitaxel. BAY 1179470 is fully cross-reactive with FGFR2 orthologues of mouse, rat, pig, cynomolgus monkey and rhesus macaque. No significant safety findings have been seen in animal studies. Thus, BAY 1179470 represents a novel anti-FGFR2 antibody with high anti-tumor activity in gastric cancer models and an excellent preclinical safety profile. BAY 1179470 is currently being tested in a first-in-man study in all-comers (NCT01881217) in Japan.
Citation Format: Charlotte Kopitz, Anette Sommer, Stefanie Hammer, Axel Harrenga, Beatrix Stelte-Ludwig, Frank Dittmer, Frank Reetz, Ekkehard May, Ruprecht Zierz, Sabine Wittemer-Rump, Christoph Schatz, H. T. Huynh, Karl Ziegelbauer, Bertolt Kreft. In vitro and in vivo characterization of a novel anti-fibroblast growth factor receptor (FGFR) 2 antibody (BAY 1179470) for the treatment of gastric 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 DDT02-01. doi:10.1158/1538-7445.AM2014-DDT02-01
Abstract LB-139: IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism
Authors: Grassian Alexandra R. , Parker Seth , Davidson Shawn , Divakaruni Ajit , Green Courtney , Zhang Xiamei , Slocum Kelly , Pu Minying , Lin Fallon , Vickers Chad , Joud-Caldwell Carol , Chung Franklin , Yin Hong , Handly Erika , Straub Christopher , Growney Joseph D. , Heiden Matt Vander , Murphy Anne , Pagliarini Raymond , Metallo Christian 
Published: May 2015

Abstract
Mutations in the genes encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a variety of tumor types, resulting in production of the proposed oncometabolite, 2-hydroxyglutarate (2-HG). How mutant IDH alters central carbon metabolism, though, remains unclear. To address this question, we performed 13C metabolic flux analysis (MFA) on an isogenic cell panel containing heterozygous IDH1/2 mutations. We observe a dramatic and consistent decrease in the ability of IDH1, but not IDH2, mutant cell lines to utilize reductive glutamine metabolism via the carboxylation of α-ketoglutarate to isocitrate. Additionally we find that cells with IDH1 mutations exhibit increased oxidative tricarboxylic acid (TCA) metabolism. Similar metabolic trends were observed in vivo as well, and also in endogenous, non-engineered IDH1/2 mutant cell lines. Interestingly, IDH1-mutant specific inhibitors were unable to reverse the decrease in reductive metabolism, suggesting that this metabolic phenotype is independent of 2-HG. Furthermore, this metabolic reprogramming increases the sensitivity of IDH1 mutant cells to hypoxia or electron transport chain (ETC) inhibition in vitro. IDH1 mutant cells also grow poorly as subcutaneous xenografts within hypoxic in vivo microenvironments. These results suggest that exploiting metabolic defects specific to IDH1 mutant cells could be an interesting avenue to explore therapeutically.
Citation Format: Alexandra R. Grassian, Seth Parker, Shawn Davidson, Ajit Divakaruni, Courtney Green, Xiamei Zhang, Kelly Slocum, Minying Pu, Fallon Lin, Chad Vickers, Carol Joud-Caldwell, Franklin Chung, Hong Yin, Erika Handly, Christopher Straub, Joseph D. Growney, Matt Vander Heiden, Anne Murphy, Raymond Pagliarini, Christian Metallo. IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. [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 LB-139. doi:10.1158/1538-7445.AM2014-LB-139