bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 598: Circulating peptides for predicting subsequent cardiotoxicity in cancer patients with chemotherapies
Authors: Fan Jia , Meng Qing H. , Bone Christopher , Igo Stephen , Hu Ye 
Published: August 2015

Abstract
In recent years with the development of new anticancer therapies, cardiotoxicity has been a known adverse event resulting from direct myocyte damage, and leads to increased treatment-associated mortality. However, the effective approach of early diagnosis and monitoring treatment-induced cardiac dysfunction is not available because its underlying mechanism is still unclear. Traditional screening that relied on left ventricular ejection fraction (LVEF) is lack of sensitivity to early detect subclinical changes or predict the subsequent declines in cardiac functions with treatment. A more noninvasive approach to early diagnose and monitor treatment-induced cardiotoxicity is in an urgent need. Our group has developed nanoporous silica thin films (Nanotraps) for peptide enrichment prior to mass spectrometry (MS) analysis as a robust technology platform for accurate and reproducible peptide biomarkers detection. Cancer patients with chemotherapies were split into three groups, non-toxicity (NT, n = 36), slight cardiotoxicity (SCT, n = 26) and cardiotoxicity (CT, n = 23). After statistical analysis and sequencing by LC-MS/MS, two peptides candidates (a fragment from serum amyloid A-1525 (SAA-1525)) and Hepcidin-25) were identified with significant up-regulation in cardiotoxic groups (with the cut off ratio of 1.5-fold and p-value ≤ 0.01 among cohorts). The area under curve (AUC) values of SAA-1525 and hepcidin-25 are 0.929 and 0.844 for distinguishing CT from NT, respectively (95% CI = 0.839-1.000 and 0.696-0.993); if combining two peptides as a biomarker pattern, the AUC value can be increased to 0.942 (95% CI = 0.864-1.00). SCT patients could also be classified by this two-marker pattern (AUC = 0.771, 95%CI = 0.606-0.936). In addition, we investigated the proteolytic process analysis of cathepsin B, which was identified as the key protease to generate SAA-1525. SAA-1525 was detected in the mixture of recombinant SAA1 full protein and purified cathepsin B, and its expression level increased with reaction time and enzyme amount. Both cathepsin B inhibitors, E64 and ALLM, could stop the generation of SAA-1525. Our study provides strong evidence to support the application of circulating peptides as minimally invasive way for predicting/monitoring chemotherapy-induced cardiotoxicity.
Citation Format: Jia Fan, Qing H. Meng, Christopher Bone, Stephen Igo, Ye Hu. Circulating peptides for predicting subsequent cardiotoxicity in cancer patients with chemotherapies. [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 598. doi:10.1158/1538-7445.AM2015-598
Abstract 599: A panel of mass spectrometry based serum protein tests for predicting graft-versus-host disease (GvHD) and its severity
Authors: Roder Heinrich , Hoffmann Andreas-Claudius , Roder Joanna , Koldehoff Michael 
Published: August 2015

Abstract
Allogeneic hematopoietic stem cell transplantation (AHSCT) has been shown to provide longterm disease-free survival for otherwise fatal malignant or nonmalignant hematological disorders. Acute and chronic graft-versus-host disease (aGvHD and cGvHD) are a major complication following AHSCT and are associated with a substantial morbidity and mortality. Identification of patients (pts) likely to develop severe forms of GvHD could allow the selection of more aggressive therapeutic regimens for patients assessed to be at high risk.
Serum samples and clinical data were available from 124 pts (age 18-70) who had received AHSCT. Five pts suffered no GvHD, 15 de novo cGvHD, 21 aGvHD but no cGvHD and 83 both aGvHD and cGvHD (overlap). Of pts with aGvHD 51% had grade I disease and of pts with cGvHD 53% had limited disease. Matrix assisted laser desorption/ionization (MALDI) mass spectra were acquired from the samples using the deep MALDI method, allowing a deep probing of the proteome. Spectra were preprocessed and spectral features defined. The integrated intensities of these features were combined with the clinical data using deep learning based machine learning to create classifiers able to stratify patients into groups depending on occurrence and severity of GvHD.
Classifiers could be developed with significant power to predict occurrence and severity of GvHD. The area under the curves (AUCs) obtained for the clinical questions investigated and examples of the sensitivity and specificity achievable are summarized in the table.
AUCSensitivity/SensitivityaGvHD ?0.7463%/80% or 80%/65%Grade II or severe aGvHD?0.6560%/67%cGvHD post aGvHD?0.7563%/75%severe vs mild cGvHD?0.6867%/69%
It is possible to provide information on occurrence and severity of GvHD from mass spectral analysis of post-transplant serum samples. If validated, this panel of tests could provide additional information useful for clinicians choosing treatment regimens for pts following AHSCT.
Citation Format: Heinrich Roder, Andreas-Claudius Hoffmann, Joanna Roder, Michael Koldehoff. A panel of mass spectrometry based serum protein tests for predicting graft-versus-host disease (GvHD) and its severity. [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 599. doi:10.1158/1538-7445.AM2015-599
Abstract 625: The frequency of gene amplifications in cancer revealed by a droplet digital PCR (ddPCR) based pan-cancer gene panel test
Authors: So Austin P. , Wong Amy , Pecson Jennifer , Putcha Girish , Jensen Gregory , Lucero Michael , Stone Gary , Gillman Jason , Mishra Pravin , Loughmiller David , Haslem Derrick S. , Nadauld Lincoln 
Published: August 2015

Abstract
The development of molecular assays designed to detect gene amplifications has largely been hampered by technical challenges such as limited DNA quantity and tumor heterogeneity, which demand methods of very high precision and sensitivity. The recent introduction of affordable digital PCR platforms, such as droplet digital PCR (ddPCR), that are capable of providing single molecule resolution of target abundances thus provides a unique opportunity to address this gap in molecular diagnostics. A ddPCR-based test was therefore developed under CLIA-CAP guidelines to determine the amplification status of 12 commonly amplified genes targeted by FDA approved drugs. Termed the Amplinome Test, this test was applied to 49 clinical samples received over a period of 6 months and compared to the results obtained from a commercially available clinical sequencing test applied that also reports copy number alterations (CNAs). An overall concordance rate of 90% (532/588 calls) was observed between the two tests across the entire gene set, 5 of which were identified as amplified. There were 56 discordant copy number amplifications between the two testing modalities. The vast majority (55/56) of discordant calls arose from gene amplifications identified by the Amplinome test, but not detected by sequencing, indicating an 11-fold increase in sensitivity in detecting amplifications. One discordant call (HER3) was identified as amplified via sequencing, but confirmed to be unamplified via FISH. At the patient level, the Amplinome test identified 5-fold more patients as having actionable amplifications in at least one of the 12 assayed genes versus clinical sequencing (29 vs. 6). Clinical management was altered in 14 of the 29 patients with an actionable CNA identified on the Amplinome test; those patients received targeted therapy directed against the amplified gene. The ddPCR-based Amplinome test thus provides a highly sensitive method for measuring gene amplifications in cancer that alters patient management, and suggests that the prevalence of actionable amplifications may be significantly underestimated by standard clinical next-generation sequencing tests.
Citation Format: Austin P. So, Amy Wong, Jennifer Pecson, Girish Putcha, Gregory Jensen, Michael Lucero, Gary Stone, Jason Gillman, Pravin Mishra, David Loughmiller, Derrick S. Haslem, Lincoln Nadauld. The frequency of gene amplifications in cancer revealed by a droplet digital PCR (ddPCR) based pan-cancer gene panel test. [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 625. doi:10.1158/1538-7445.AM2015-625
Abstract 659: Sustained inhibition of HER3 and EGFR is necessary to induce regression of HER2-amplified gastrointestinal carcinomas
Authors: Leto Simonetta Maria , Sassi Francesco , Catalano Irene , Migliardi Giorgia , Zanella Eugenia Rosalinda , Bertotti Andrea , Trusolino Livio 
Published: August 2015

Abstract
Purpose: Preclinical studies in HER2-amplified gastrointestinal cancer models have shown that co-targeting HER2 with a monoclonal antibody and a small molecule is superior to monotherapy with either inhibitor, but the underlying cooperative mechanisms remain unexplored. We investigated the molecular underpinnings of this synergy to identify key vulnerabilities susceptible to alternative therapeutic opportunities.
Experimental Design: The signaling consequences of HER2, HER3 and EGFR (HERs) blockade were evaluated in HER2-overexpressing colorectal and gastric cancer cell lines by Western blotting. HERs’ canonical downstream transducers were quantitatively gauged by multiplex phospho-proteomics. The in vivo outcome of antibody-mediated HER2 blockade by trastuzumab, reversible HER2 inhibition by lapatinib, and irreversible HER2 inhibition by afatinib was assessed in patient-derived tumorgrafts and cell-line xenografts by monitoring tumor growth curves and by using antibody-based proximity assays for phosphoprotein analysis.
Results: Trastuzumab monotherapy reduced HER3 phosphorylation, with minor consequences on downstream transducers. Lapatinib alone acutely inhibited all HER receptors and effectors but led to delayed rephosphorylation of HER3 and EGFR and partial restoration of ERK and AKT activity. When combined with lapatinib, trastuzumab prevented HER3/EGFR reactivation and caused prolonged inhibition of ERK/AKT. Afatinib alone was as effective as trastuzumab plus lapatinib in counteracting the reinstatement of HER3, EGFR, and downstream signaling activation. In vivo, the combination of trastuzumab and lapatinib - or monotherapy with afatinib - resulted in overt tumor shrinkage.
Conclusions: Only prolonged inhibition of HER3 and EGFR, achievable by dual blockade with trastuzumab and lapatinib or irreversible HER2 inhibition by single-agent afatinib, led to regression of HER2-amplified gastrointestinal carcinomas.
Citation Format: Simonetta Maria Leto, Francesco Sassi, Irene Catalano, Giorgia Migliardi, Eugenia Rosalinda Zanella, Andrea Bertotti, Livio Trusolino. Sustained inhibition of HER3 and EGFR is necessary to induce regression of HER2-amplified gastrointestinal carcinomas. [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 659. doi:10.1158/1538-7445.AM2015-659
Abstract 661: Increasing sensitivity of SAIT301, a specific monoclonal antibody of c-Met, with paclitaxel combination in c-Met positive gastric cancer
Authors: Kang Sun Kyoung , Kim Jeong Min , Lee Won Suk , Kwon Woo Sun , Kim Tae Soo , Shim Seon-hui , Kim Kyung-Ah , Lim Ho-Yeong , Chung Hyun Cheol , Rha Sun Young 
Published: August 2015

Abstract
The c-Met is frequently overexpressed and related to a worse prognosis in gastric carcinoma (GC). This study aimed to determine a c-Met targeting monoclonal antibody (SAIT301) with effects on the proliferation and to increase efficacy of SAIT301 administered in combination with paclitaxel in gastric cancer cell lines. Anticancer effect of SAIT301 was assessed using CCK-8 assay in 52 GC cell lines. c-Met status was identified using RTK array and qPCR. Cell cycle distribution was determined with flow cytometry. Expression levels of c-Met and cleaved PARP, apoptosis induction marker, were determined by western blot analysis. Combination index (CI) evaluated by CalcuSyn software. We screened 52 cell lines for growth inhibition by SAIT301.Among 11 c-Met positive GC cells, 5 cell lines were sensitive to SAIT301 (5/11, 45%) with 40∼60% inhibition rate at 5 μg/ml.SAIT301 sensitivity of 5 cell lines has a tendency of correlation between MET amplification, c-Met/p-Met co-expression, low Cbl level or exon14 deletion of MET. Next, we performed combination treatment with SAIT301 and paclitaxel in 5 cell lines. The results exhibited increasing anti-proliferative effects with synergism. In cell cycle analysis, SAIT301 increased the percentage of cells in the G1 phase, while paclitaxel increased the G2/M phase(3-19%). Combination of SAIT301 and paclitaxel significantly increased in sub G1(2-17%) and G2/M arrest(4-19%). Western blot analysis showed paclitaxel induced c-Met expression. In addition, SAIT301 and paclitaxel combination down-regulated c-Met expression and enhanced PARP cleavage more than monotherapy. Our results indicate that the SAIT301 combined with paclitaxel therapy had synergistic effects in the treatment of c-Met positive gastric cancer.
Citation Format: Sun Kyoung Kang, Jeong Min Kim, Won Suk Lee, Woo Sun Kwon, Tae Soo Kim, Seon-hui Shim, Kyung-Ah Kim, Ho-Yeong Lim, Hyun Cheol Chung, Sun Young Rha. Increasing sensitivity of SAIT301, a specific monoclonal antibody of c-Met, with paclitaxel combination in c-Met 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 661. doi:10.1158/1538-7445.AM2015-661
Abstract 684: Nelfinavir inhibits the growth of small cell lung cancer cells and patient-derived xenograft tumors
Authors: Kawabata Shigeru , Connis Nick , Zhang Chunyu , Gills Joell J. , Hann Christine L. , Dennis Phillip A. 
Published: August 2015

Abstract
Small cell lung cancer (SCLC) is an aggressive lung cancer with a poor prognosis that is characterized by frequent metastasis at the time of diagnosis. Although SCLC is more responsive to chemotherapy and radiation therapy compared to other types of lung cancer, cure is difficult because of frequent recurrence. Molecular alterations in SCLC include inactivation of TP53 and RB1, high copy number of Myc family, and amplifications of FGFR1 and SOX2. Additionally, achaete-scute homolog 1 (ASCL1), a transcription factor for development of pulmonary neuroendocrine cells, is a lineage-dependent oncogene for SCLC. New drugs and molecular targets need to be identified. Previously, we reported nelfinavir (NFV), a HIV protease inhibitor, inhibited proliferation of non-small cell lung cancer (NSCLC) cells in vitro and human NSCLC xenograft tumors through induction of the unfolded protein response (UPR). Here we demonstrate that the effect of NFV in SCLC cells and preclinical treatment studies using SCLC patient-derived xenograft (PDX) mouse models. NFV inhibited SCLC cell proliferation and induced cell death in vitro. Activating transcription factor 4 (ATF4), a marker of the UPR, was rapidly increased, whereas Myc was decreased after 4 hr treatment with NFV. AMP-activated protein kinase (AMPK), which plays a role in cellular energy homeostasis, was activated in the early phase of NFV treatment, whereas the mammalian target of rapamycin (mTOR) that is a serine/threonine kinase that regulates cell growth, was inactivated. NFV inhibited the expression of SOX2, ASCL1 and Aurora B in a cell line- and time-dependent manner. Taken together, NFV had pleiotropic effects against multiple targets during the inhibition of SCLC cell proliferation. In vivo, NFV inhibited growth of SCLC PDX tumors, which correlated with induction of the UPR and decreased expression of ASCL1 and Aurora B. Collectively, these findings show that NFV is highly effective in SCLC in vitro and in vivo, suggesting possible value of incorporating NFV into clinical trials for patients with SCLC.
Citation Format: Shigeru Kawabata, Nick Connis, Chunyu Zhang, Joell J. Gills, Christine L. Hann, Phillip A. Dennis. Nelfinavir inhibits the growth of small cell lung cancer cells and patient-derived xenograft tumors. [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 684. doi:10.1158/1538-7445.AM2015-684
Abstract 689: Characterization of two novel oncogenic FGFR2 fusions sensitive to the FGFR-selective inhibitor Debio 1347 in cholangiocarcinoma
Authors: Vaslin Anne , Rigotti Stefania , Lembrez Nathalie , Vuagniaux Grégoire , Moulon Corinne , Tanaka Hiroaki 
Published: August 2015

Abstract
Dysregulation of the fibroblast growth factor receptor (FGFR) signaling pathway due to receptor overexpression, gene amplification, point mutations or fusions/chromosomal translocations is associated with cancer development and progression. FGFR gene fusions have recently been discovered in several indications including bladder cancer, glioblastoma, lung squamous cell cancer and cholangiocarcinoma. Predominant gene fusions have been identified in some indications such as FGFR3-TACC3 (with different genomic variations in the two genes) for bladder cancer whereas for other indications the genomic-altered landscape is a lot more heterogeneous, as seen in cholangiocarcinoma where at least ten FGFR2 fusions each with a different fusion partner have been identified.
We herein report for the first time the discovery of two novel FGFR fusions in intra hepatic cholangiocarcinoma patient samples. These new fusions contain an intact FGFR2 tyrosine kinase domain and fused partner harbor oligomerization domains that suggest similar mechanism of constitutive kinase activation.
Both fusions display oncogenic activities when introduced into Rat 2 cells in in vitro colony formation assays as compared to parental cells. The two fusions are also tumorigenic in vivo when implanted subcutaneously in NMRI nude mice, whereas parental cell do not grow in vivo. FGFR inhibition by the FGFR selective inhibitor Debio 1347 (CH5183284) reduced cell proliferation in vitro. In vivo sensitivity to FGFR inhibition could also be demonstrated for the two fusions.
Altogether, these results suggest that these two novel oncogenic fusions are actionable targets in cholangiocarcinoma and that patients harboring these fusions could benefit from targeted FGFR inhibition, such as Debio 1347, currently investigated in a Phase I trial in selected patients harboring FGFR genetic alterations (NCT01948297).
Citation Format: Anne Vaslin, Stefania Rigotti, Nathalie Lembrez, Grégoire Vuagniaux, Corinne Moulon, Hiroaki Tanaka. Characterization of two novel oncogenic FGFR2 fusions sensitive to the FGFR-selective inhibitor Debio 1347 in cholangiocarcinoma. [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 689. doi:10.1158/1538-7445.AM2015-689
Abstract 716: Targeting Mek-Erk pathway abrogates hypoxia-mediated lapatinib resistance in ErbB2-positive breast cancer cells
Authors: Karakashev Sergey , Reginato Mauricio 
Published: August 2015

Abstract
Overexpression/amplification of the tyrosine kinase ErbB2 is often observed in breast cancers. ErbB2 expression activates EGFR signaling pathway promoting tumorigenesis. Breast cancer ErbB2-positive patients are treated with lapatinib, a dual EGFR/ERBB2 inhibitor. Despite lapatinib clinical efficacy, acquired resistance has been reported and its mechanism is poorly understood. Another factor that is associated with mammary tumors is hypoxia. Hypoxia stabilizes hypoxia inducible factor 1 (HIF-1), a transcription factor that regulates cell growth, proliferation and survival. As a result, hypoxic tumors are often chemoresistant.
Here, we show that hypoxia decreases lapatinib-mediated growth inhibition and apoptosis in three-dimensional cultures. In agreement with this data, hypoxia also promotes activation of signaling pathways downstream from ErbB2/EGFR including AKT and ERK in the presence of lapatinib. This protective effect depends on HIF-1 and can be abrogated by HIF-1 RNAi. Moreover stable overexpression HIF-1 in ErbB2-expressing cells under normoxic conditions is sufficient to rescue cell proliferation and survival and maintain ERK and AKT signaling in the presence of lapatinib. We also show that activation of ERK signaling is required for hypoxia-mediated lapatinib resistance and inhibition of MEK (a kinase upstream of Erk) reverses hypoxia protective effect on ErbB2-expressing cells. One potential mechanism of how hypoxia/HIF-1 may lead to activation of ERK pathway is via regulation of dual-specificity phosphatase 2 (DUSP2). DUSP2 is a negative regulator of ERK pathway. Here we demonstrate that cells exposed to hypoxia have decreased levels of DUSP2 and it correlate with increased activation of Erk signaling. Moreover, reducing DUSP2 expression alone in ErbB2-positive breast cancer cells is sufficient to reduce lapatinib-mediated effects. And DUSP2 overexpression abrogates hypoxia-mediated protective effect on ErbB2-expressing cells treated with lapatinib.
All these data suggests that targeting MEK-Erk signaling pathway may reverse hypoxia mediated lapatinib resistance and might be a viable option for lapatinib resistant ErbB2-posive tumors. Indeed, a combination of lapatinib and an FDA approved MEK inhibitor trametinib abrogates hypoxia protective effect on cell growth inhibition and apoptosis in three dimensional (3D) cultures. Thus targeting MEK/ERK pathway in hypoxic breast cancer may improve an anti-ErbB2 therapy in breast cancer.
Citation Format: Sergey Karakashev, Mauricio Reginato. Targeting Mek-Erk pathway abrogates hypoxia-mediated lapatinib resistance in ErbB2-positive breast cancer cells. [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 716. doi:10.1158/1538-7445.AM2015-716