bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3488: Surveying colorectal cancer genome for clinically actionable genomic amplifications with droplet digital PCR.
Authors: Rumma Rowza T. , Miotke Laura , Nadauld Lincoln , Natsoulis Georges , DiMaio Michael , Jalali Moe , Ji Hanlee 
Published: August 2014

Abstract
New cancer therapies are increasingly geared towards exploiting critical genetic and genomic features specific to the tumor. These mutations and genomic aberrations are the basis for precision cancer medicine. Thus, rapid molecular characterization of clinical cancer samples has become increasingly important for cancer targeted therapy development. Our study addresses this need by identifying ‘druggable’ gene amplifications in colorectal cancer (CRC). Along these lines, we developed an accurate and rapid droplet-digital PCR (ddPCR) assay to analyze cancer-specific copy number variations (CNV) in 13 genes with oncogenic function that are the targets of specific cancer therapies. These genes were selected based on the availability of approved and early-phase targeted therapeutics that inhibit their oncogenic function. Using TCGA data, we vetted our targets by identifying frequent CRC amplifications and a correlation with gene expression.
The ddPCR method involves emulsifying matched-normal cancer sample DNA that provides specific advantages for highly sensitive and specific detection of cancer CNVs. Post-amplification, emulsion droplets are streamed single-file into a capillary that leads past a two-color detector, where the positive droplets for the target and reference genes are “counted” for quantitation. This technology requires nanogram amounts of genomic DNA, thus facilitating the study of clinical cancer samples from small biopsies. It works well with genomic DNA extracted from formalin fixed paraffin embedded tumor samples. Furthermore, we demonstrated high sensitivity for detecting copy number amplifications even in samples containing a prominent fraction of normal tissue.
We are extending our analysis to the full 13 “druggable” gene targets and evaluating patterns of mutual exclusivity and co-occurrence among a cohort of over 200 CRC tumors with information on clinical outcome. For example, we have demonstrated FGFR1 amplifications in 5.2% of our CRC tumor population. For ERBB2 variations in the same cohort, we detected amplifications in 3.6% of our population. ERBB2 and FGFR1 amplification events displayed a mutually exclusive pattern of segregation (p value &lt;0.0001 per Chi-squared test with Yates correction). This efficient and inexpensive assay offers a significant potential to extend personalized therapeutic options available to CRC patients.
Citation Format: Rowza T. Rumma, Laura Miotke, Lincoln Nadauld, Georges Natsoulis, Michael DiMaio, Moe Jalali, Hanlee Ji. Surveying colorectal cancer genome for clinically actionable genomic amplifications with droplet digital PCR. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3488. doi:10.1158/1538-7445.AM2013-3488
Abstract 349: Molecular pathogenesis of mucinous adenocarcinoma of the lung.
Authors: Maeda Yutaka , Whitsett Jeffrey 
Published: August 2014

Abstract
Human mucinous adenocarcinoma of the lung is a subtype of highly invasive pulmonary tumors and is associated with decreased or absent expression of the respiratory epithelium transcription factor NKX2-1 (NK2 homeobox 1, also known as TTF-1). Here, we show that haploinsufficiency of Nkx2-1 in combination with oncogenic Kras.G12D (hereafter; Kras.G12D;Nkx2-1+/-), but not with oncogenic EGFR.L858R, causes pulmonary tumors in transgenic mice that are phenotypically similar to human mucinous adenocarcinomas. Expression of both CK7 and CK20, biomarkers for human mucinous adenocarcinoma of the lung, were confirmed in lungs of the Kras.G12D;Nkx2-1+/- mice. Expression of mucins, such as MUC5AC, and mucin/metastasis-related protein AGR2 was observed in tumorigenic mucous cells in the Kras.G12D;Nkx2-1+/- mice as well as non-tumorigenic airway mucous cells induced by allergen; however, mucous cell master regulators, such as SPDEF and FOXA3, were seen only in the non-tumorigenic airway mucous cells but not in the tumorigenic mucous cells, indicating a distinct mucous gene regulation in the tumorigenic mucous cells. NKX2-1 cell-autonomously inhibited mRNA expression of MUC5AC and AGR2 in A549 human lung carcinoma cells that harbor a KRAS mutation. Chromatin immunoprecipitation with massively parallel DNA sequencing (ChIP-seq) analysis identified a direct association of NKX2-1 with the promoter and intron of MUC5AC and AGR2 genes in A549 cells, indicating that NKX2-1 functions as a transcriptional repressor for the mucous gene expression. The ChIP-seq analysis further revealed that NKX2-1 associated with the AP-1 binding element (TGAnTCA) as well as the canonical NKX2-1 binding element (CTTG). NKX2-1 inhibited AP-1-mediated activity and tumor colony formation in vitro, suggesting that NKX2-1 suppresses mutant KRAS-driven lung tumorigenesis in part by inhibiting AP-1 activity. These results demonstrate that NKX2-1 suppresses mutant KRAS-driven mucinous pulmonary adenocarcinoma in part by directly inhibiting expression of genes induced in mucinous tumors.
Citation Format: Yutaka Maeda, Jeffrey Whitsett. Molecular pathogenesis of mucinous adenocarcinoma of the lung. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 349. doi:10.1158/1538-7445.AM2013-349
Abstract 3493: A single-tube, multiplexed, transcript-based assay to detect ALK, ROS1 and RET fusions in lung cancer.
Authors: Lira Maruja , Choi Yoon-La , Deng Shibing , Huang Donghui , Ozeck Mark , Han Joungho , Jeong Ji Yun , Park Keunchil , Kim Jhingook , Ahn Myung-Ju , Mao Mao 
Published: August 2014

Abstract
Oncogenic fusions involving ALK, ROS1 and RET define a small subpopulation (∼7%) of non-small cell lung carcinomas (NSCLC). Tumors harboring ALK and ROS1 rearrangements are highly sensitive to crizotinib whereas RET inhibitors may be of potential benefit for the treatment for RET-fusion positive tumors1. Current methods for detection of ALK, ROS1, and RET rearrangements involve fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) or RT-PCR, each test offering its own advantages and disadvantages, and making it difficult for screening large numbers of patient samples for all three targetable fusions.
To explore screening modalities for the simultaneous detection of ALK, ROS1 and RET fusions from a single analyte, we designed a multiplexed, transcript-based assay to detect for presence or absence of fusions. Utilizing a combined 3’ over-expression and fusion-specific detection strategy, we developed a single-tube multiplex assay with a quantitative scoring modality that is highly sensitive, reproducible and capable of detecting low abundant ALK, ROS1 and RET fusion transcripts. We successfully validated the assay in 273 NSCLC specimens. For ALK, our results were highly concordant (97.4%) to prior results obtained by IHC (n=189). We confirmed ROS1 (n=7) and RET (n=11) fusion-positive tumors by RT-PCR plus sequencing. There is a significant enrichment for ROS1 and RET fusions in triple negative NSCLC (i.e. KRAS/EGFR/ALK wildtype) (Table 1). ALK, ROS1, RET, KRAS and EGFR mutations are mutually exclusive in this study. Our assay offers an easy to perform, high-throughput, and FFPE-compatible screening method for detection of ALK, ROS1 and RET fusions.
Table 1. Incidence of ALK, ROS1 and RET fusions cohorts clinical/molecular feature # cases ALK+ ROS1+ RET+ Set 1 ALK IHC+, Kras/EGFR wt 95 91 0 0 Set 2 ALK IHC−, Kras/EGFR wt 94 1 5 11 Set 3 never smokers 84 10 2 1
Citation Format: Maruja Lira, Yoon-La Choi, Shibing Deng, Donghui Huang, Mark Ozeck, Joungho Han, Ji Yun Jeong, Keunchil Park, Jhingook Kim, Myung-Ju Ahn, Mao Mao. A single-tube, multiplexed, transcript-based assay to detect ALK, ROS1 and RET fusions in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3493. doi:10.1158/1538-7445.AM2013-3493
Abstract 3497: Pathway profiling for personalized medicine: Comparison of two immunoassays.
Authors: Stresemann Antje , von Ahsen Oliver , Politz Oliver , Kim Phillip , Singh Sharat , Asadullah Khusru , Ziegelbauer Karl , Krahn Thomas 
Published: August 2014

Abstract
Cancer therapy is evolving to a detailed molecular analysis of the patient's tumor followed by treatment with selective drug(s) targeting the individual properties of the tumor based upon identification of prognostic and predictive biomarkers. This requires comprehensive, highly sensitive test systems. We therefore sought to develop a sensitive diagnostic test for functionally profiling a spectrum of signaling pathway proteins in tumor samples. Here, we evaluated and compared two assay platforms: CEER (Collaborative Enzyme Enhanced Reactive-Immunoassay; Prometheus Labaratories) and MSD (Meso Scale Discovery).
Breast, lung, and prostate cancers as well as glioblastoma and melanoma model cell lines (in all 10 cell lines) with various oncogenic pathway signatures were treated with different concentrations of PI3K inhibitor (BAY 806946) or an inhibitor targeting HER1 and HER2 (Lapatinib). Cells were lysed and the activation status as well as abundance of ten pathway proteins (HER1, HER2, cMET, PI3K, AKT, ERK, MEK, PRAS40, RPS6, and P70S6K) was measured by MSD at Bayer in Berlin and by CEER in a blinded fashion at Prometheus Laboratories. Target-specific inhibition (IC50) and downstream signal modulations were determined and compared. Overall we found a high concordance between the two assays. While target specific inhibitions were observed in relevant cell lines, varying mechanisms of treatment resistance due to redundant pathway activation, feedback loop or pathway cross talks were observed between the PI3K/AKT and RAS/ERK pathways.
This study shows that sensitive immunoassays are a suitable tool for the detection and monitoring of biomarkers and provides new insights into the mode of action of targeted agents. Comprehensive profiling of signaling pathways holds promise as an approach to personalize selection of anticancer therapy.
Citation Format: Antje Stresemann, Oliver von Ahsen, Oliver Politz, Phillip Kim, Sharat Singh, Khusru Asadullah, Karl Ziegelbauer, Thomas Krahn. Pathway profiling for personalized medicine: Comparison of two immunoassays. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3497. doi:10.1158/1538-7445.AM2013-3497
Abstract 35: Phase I study of dasatinib in combination with bevacizumab in advanced solid tumors (NCT01445509).
Authors: Lee Jung-Min , Annunziata Christina , Noonan Anne M. , Hays John L. , Minasian Lori , Zujewski Jo Anne , Chen Helen , Wright John , Houston Nicole , Kohn Elise C. 
Published: August 2014

Abstract
Background: Inhibition of the MAPK pathway with sorafenib and neutralization of VEGF with bevacizumab (B) resulted in clinical benefit with interactive toxicity. Dasatinib (D) is a broad spectrum tyrosine kinase inhibitor with high affinity for SRC family kinases. We hypothesized that using this upstream inhibitor of the MAPK pathway with B would maintain activity with less interactive toxicity.
Methods: A 3+3 dose escalation design incorporated with B 5mg/kg q2wk plus daily D 50, 70 and 100 mg in dose levels [DL] 1/2/3, then B 10mg/kg q 2wk plus D 100mg in DL4. DLT was defined during the first 6 weeks of treatment. Safety was assessed each 28d cycle and disease was reassessed every 2 cycles.
Results: 19 pts were treated in the dose escalation portion on 4 DLs. Pts (17F/2M) had a median age of 64 yrs (25-79), ECOG PS 0-1, and normal end-organ function. Most (14/19) pts had metastatic gynecologic cancers (6 endometrial/5 ovarian-peritoneal/2 cervix/1 rectovaginal GIST). Other cancers included breast (2), pancreatic neuroendocrine (1), medullary thyroid (1) and melanoma (1). Median number of prior treatments was 4 (1-11). The highest planned dose combination was examined without exceeding the MTD. No DLT was observed. Grade (g) 3 events included hypertension (2), pleural effusion (2), dyspnea (1) and pulmonary hypertension (1). D-mediated marrow suppression was observed in 12 pts: anemia (g1/2 [12 pts]), lymphopenia (g1/2 [9pts]; g3 [1pt]), thrombocytopenia (g1/2 [5pts]), and neutropenia (g1/2 [4pts]). Confirmed PR was seen in 1/17 evaluable pts, a pt with HER2+ breast cancer (5 mo). Stabilization &gt;/= 4 mo occurred in 9 pts (median 9 mo [4-18+mo]), yielding clinical benefit in 59%.
Conclusions: D 100 mg daily with B 10mg/kg q2wk appears to be active and is well-tolerated in pts with advanced solid tumors. G 3 adverse events were uncommon and g 4 events or severe marrow toxicities were not observed at the doses planned and examined. An expansion cohort is now accruing with functional imaging, tumor biopsies, and blood sampling for measurement of biochemical changes in SRC and VEGF signaling pathways.
Citation Format: Jung-Min Lee, Christina Annunziata, Anne M. Noonan, John L. Hays, Lori Minasian, Jo Anne Zujewski, Helen Chen, John Wright, Nicole Houston, Elise C. Kohn. Phase I study of dasatinib in combination with bevacizumab in advanced solid tumors (NCT01445509). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 35. doi:10.1158/1538-7445.AM2013-35
Abstract 3503: A method for quantifying soluble folate receptor 1 in IMGN853 0401 clinical trial patients.
Authors: Testa Nathan , Bartle Laura , Ab Olga , Cheng Judy , Payne Gillian , Lutz Robert J. , Wolf Ben , Carrigan Christina 
Published: August 2014

Abstract
IMGN853, an antibody-“drug” conjugate (ADC), consists of a human folate receptor 1 (FOLR1)-binding monoclonal antibody, M9346A, conjugated to the maytansinoid, DM4, via the cleavable sulfo-SPDB linker. A phase I clinical study has been initiated to identify the maximum tolerated dose, safety, pharmacokinetics (PK), and preliminary efficacy of IMGN853 in patients with FOLR1-positive tumors, including ovarian cancer, non-small cell lung cancer, and other epithelial malignancies. The levels of soluble FOLR1 antigen (sFOLR1) in plasma may vary depending on factors such as tumor antigen expression level, tumor type, and disease stage, and may affect the PK of IMGN853and response to treatment. Previously reported studies describing the detection of sFOLR1 in patient samples are limited and not quantitative.
The aim of this study was to develop a sandwich ELISA to quantify levels of sFOLR1 present in plasma samples from cancer patients for use as a potential biomarker of IMGN853 PK and/or clinical response.
A panel of murine anti-FOLR1 antibodies was generated at ImmunoGen by standard hybridoma technology. Two clones were chosen for use as capture (FR1-9) and detector (FR1-13) antibodies in the ELISA due to their high affinity and ability to bind to FOLR1 even in the presence of IMGN853 or the FOLR1 ligand, folate. The extracellular domain of FOLR1 fused to murine IgG2a Fc region (FOLR1-Fc) was used as a reference standard. A sandwich ELISA was developed using FR1-9 antibody to capture sFOLR1 from patient plasma, and bound sFOLR1 was detected using biotinylated FR1-13 antibody and streptavidin-HRP with TMB as the substrate. The ELISA was used to quantify sFOLR1 in ovarian carcinoma patient plasma using a reference standard curve generated with FOLR1-Fc antigen.
A robust sandwich ELISA was developed to quantify sFOLR1 in patient plasma. The quantitation range of the assay was determined to be 0.2 to 90 nanomolar. Coated plates stored frozen from 0-14 days and protein reagents freeze-thawed over two cycles gave repeatable results. The ELISA was able to detect sFOLR1 in 5 of 10 ovarian cancer patient plasma samples, where the levels of detectable sFOLR1 ranged from 0.7-31 nM. This ELISA is considered suitable to quantify levels of sFOLR1 in patients enrolled in the phase 1 trial over the course of IMGN853 treatment, and resulting data will be assessed for correlations with IMGN853 PK and with clinical response.
Citation Format: Nathan Testa, Laura Bartle, Olga Ab, Judy Cheng, Gillian Payne, Robert J. Lutz, Ben Wolf, Christina Carrigan. A method for quantifying soluble folate receptor 1 in IMGN853 0401 clinical trial patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3503. doi:10.1158/1538-7445.AM2013-3503
Abstract 353: Gliomagenesis arising from Pten- and Ink4a/Arf-deficient neural progenitor cells is mediated by the p53-Fbxw7/Cdc4 pathway, which controls c-Myc.
Authors: Kim Hongsug 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor and may arise from a cell with neural stem-like properties. Deregulation of the RB, PI3K and p53 pathways are molecular hallmarks of this disease. Recent work has demonstrated that p53-/-Pten-/- mice form gliomas in a c-Myc dependent manner. To explore the role of the INK4A/ARF locus and Pten deletions in gliomagenesis, we generated Pten-/-Ink4a/Arf-/- mNSCs and such cells were highly proliferative, self- renewing, relatively refractory to differentiation and induced both low and high grade glioma formation in vivo. In contrast to p53-/- Pten-/- mNSCs, however, Pten-/-Ink4a/Arf-/- mNSCs do not express appreciable levels of c-Myc in vitro although glioma stem cells (GSCs) derived from these same cells did. Sequencing of Pten-/-Ink4a/Arf-/-mNSCs- derived tumors revealed spontaneous mutations in Tp53 in vivo with subsequent downregulation of Fbxw7. Expression of p53 mutants in Pten-/-Ink4a/Arf-/- mNSCs, or knockdown of Fbxw7, resulted in re-expression of c-Myc with enhanced Pten-/-Ink4a/Arf- /- mNSCs tumorigenecity. We propose that p53 mutations contribute to gliomagenesis by both allowing the overexpression of c-Myc through downregulation of Fbxw7 and by protecting against c-Myc-induced apoptosis.
Citation Format: Hongsug Kim. Gliomagenesis arising from Pten- and Ink4a/Arf-deficient neural progenitor cells is mediated by the p53-Fbxw7/Cdc4 pathway, which controls c-Myc. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 353. doi:10.1158/1538-7445.AM2013-353
Abstract 3533: Clinical impact of NF-KB activation in diffuse large B cell lymphoma.
Authors: Odqvist Lina , Montes-Moreno Santiago , Sánchez-Beato Margarita , Sánchez-Verde Lydia , Mollejo Manuela , Young Ken H. , Fresno Manuel F. , Mazorra Francisco , Ruíz-Marcellán Carmen , Piris Miguel A. 
Published: August 2014

Abstract
Deregulated nuclear factor KB (NF-KB) activity has been associated with a number of lymphoproliferative diseases, including diffuse large B cell lymphoma (DLBCL), but the importance and consequence of this activation are still not fully understood. In this study, we describe the extent of NF-KB activation in a range of human lymphoma types and observe a frequent concurrent activation of both classical and alternative pathways in DLBCL. The activation of the classical and alternative NF-KB pathways, was present in 34.8% and 29.3% of DLBCL cases respectively, as assessed by nuclear expression of p50 (classical pathway) and p52 (alternative pathway) by immunohistochemistry in a series of 167 samples. Activation of NF-KB was observed in both germinal centre B-cell like (GC) and activated B-cell like (ABC) subtypes, although with a predominance of classical NF-KB in the ABC subtype (41,8% positive cases versus 21,2% in the GC subtype). In our cohort of samples from 167 R-CHOP treated DLBCL patients, excluding cases positive for Epstein-Barr virus, nuclear expression of NF-KB was significantly associated with a superior overall survival (Log Rank p&lt;0.05), as compared to those without nuclear NF-KB. The 3-year overall survival rate in the NF-KB positive group was 83.6% compared to 68.0% in the NF-KB negative group. While p50 expression alone did not give rise to any significant differences in the survival curves, p52 expression did associate significantly with better clinical outcome (p=0.032). Thus, alternative NF-KB activation is frequently present in DLBCL tumors, is not associated with the ABC subtype, and is characterized by an enhanced overall survival.
Citation Format: Lina Odqvist, Santiago Montes-Moreno, Margarita Sánchez-Beato, Lydia Sánchez-Verde, Manuela Mollejo, Ken H. Young, Manuel F. Fresno, Francisco Mazorra, Carmen Ruíz-Marcellán, Miguel A. Piris. Clinical impact of NF-KB activation in diffuse large B cell lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3533. doi:10.1158/1538-7445.AM2013-3533