tbuckley/cabot-search huggingface dataset:
Abstract 4984: Chemotherapy induces a coordinate autoantibody and T-cell response against tumor-associated antigens in pancreatic cancer patients
Authors: Francesco Novelli, Giorgia Mandili, Emanuela Mazza, Sonia Bulfamante Bulfamante, Daniele Giordano, Laura Follia, Paola Cappello
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult cancer to treat, both for lack of effective screening method and for resistance phenomenon. At present surgical resection is the only potentially curative option, but the absence of early symptoms or clinical-pathological markers results in diagnosis at a late, inoperable stage in mostly of cases. Once diagnosed, a number of chemotherapy (CTX), radiation and combination therapy regimens are usually used to treat patients, but responses remain poor. However, chemotherapy is able to enhance tumor immunogenicity. Thus more immunogenic tumor associated antigens (TAA) can be induced by CTX and targeted by passive or active immunotherapy. We have previously identified a number of TAAs that are recognized by autoantibodies in PDAC patients. One of these, alpha-enolase (ENO1), was found to have good antigenic capability and immunization with DNA coding for ENO1 effectively enhanced the survival of genetically engineered mice that develop spontaneously PDAC. To discover TAAs that might be selected for immunotherapy, we have analyzed autoantibody response in 19 PDAC patients’ sera before and after CTX. The reactivity of PDAC patients’ sera obtained was analyzed on 2-dimensional gel electrophoresis proteome map of CF-PAC1 pancreatic cancer cell line and TAAs recognized by IgG autoantibodies were identified by mass spectrometry. The antibody response against 25 proteins was induced or up-regulated after CTX. Among CTX-induced TAA identified, only four, namely ENO1, FUBP1, CK8 and G6PDH were found able to ex novo induce or up-regulate IgG response in more than seven patients were selected and their ability to activate proliferation of autologous PBMC was evaluated following in vitro stimulation with the corresponding recombinant proteins. Notably, mostly of autologous T cells obtained after CXT displayed an increased proliferation in response to at least one or more of the four selected TAA after in vitro stimulation compared to autologous T cells obtained before CTX. Experiments are in progress to validate these CTX- induced TAA in a mouse model of PDAC and to evaluate the therapeutic value of the combination of CTX with the immunotherapy against these TAAs. Citation Format: Francesco Novelli, Giorgia Mandili, Emanuela Mazza, Sonia Bulfamante Bulfamante, Daniele Giordano, Laura Follia, Paola Cappello. Chemotherapy induces a coordinate autoantibody and T-cell response against tumor-associated antigens in pancreatic cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4984.
The Potent PI3K-δ,γ Inhibitor, IPI-145, Exhibits Preclinical Activity In Murine and Human T-Cell Acute Lymphoblastic Leukemia
Authors: Xiaoyan Huang, Jennifer Proctor, Yaling Yang, Xiuhua Gao, Weihong Zhang, Shenjiao Huang, Paul Changelian, Jeffery L. Kutok, Karen McGovern, M. James You
Journal: Blood (2013)
Abstract 5281: Fast and scalable software for comparative variant analysis and visualization of massive next-generation sequencing data
Authors: Riku Katainen, Veli Mäkinen, Lauri A. Aaltonen, Esa Pitkänen
Journal: Cancer Research (2016)

Abstract Next-generation sequencing (NGS) techniques produce high quantities of DNA and RNA sequencing data, enabling variation analysis at a whole genome level. Due to the massive availability of NGS data, the processing and analysis now constitute a serious challenge for research in life sciences. This necessitates the development of novel, user-friendly and scalable software tools, which are able to jointly handle large NGS data sets in order to break the bottleneck that has already moved from data generation to data analysis in high-throughput biology. Here we introduce a highly efficient NGS analysis and visualization software tool (Rikurator), which is designed for researchers who are struggling with NGS data analysis and may not have access to a dedicated bioinformatics team. Rikurator can be applied to a multitude of genomic analysis tasks, including discovery of pathogenic mutations in familial or sporadic sample sets, analysis of structural variants and somatic characterization of cancer genomes. To these ends the software implements interactive variant filtering and annotation methods based on sample comparison, control data (e.g. ExAC), amino acid changes and quality scores, which provide an intuitive view at the studied samples. Shared candidate genes in a set of dozens of individuals can be discovered in a matter of minutes with an ordinary laptop computer. Importantly, the software is able to analyze hundreds of whole-genome sequenced samples using only a modest amount of RAM. The tool also visualizes and integrates genes, variants (VCF file format), sequence reads (BAM) and user defined features (BED/GFF). In addition, Rikurator is not limited to human studies, supporting reference genomes and genome annotations in standard formats. The software supports targeted (e.g. exome), whole-genome, RNA, Oxford Nanopore and PacBio sequencing data. Rikurator can be run on Windows, Linux and Mac, and it will be freely available after publication. Citation Format: Riku Katainen, Veli Mäkinen, Lauri A. Aaltonen, Esa Pitkänen. Fast and scalable software for comparative variant analysis and visualization of massive next-generation sequencing data. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5281.
Gain of 1q As a Prognostic Biomarker in Wilms Tumors (WTs) Treated With Preoperative Chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 Trial: A SIOP Renal Tumours Biology Consortium Study
Authors: Tasnim Chagtai, Christina Zill, Linda Dainese, Jenny Wegert, Suvi Savola, Sergey Popov, William Mifsud, Gordan Vujanić, Neil Sebire, Yves Le Bouc, Peter F. Ambros, Leo Kager, Maureen J. O'Sullivan, Annick Blaise, Christophe Bergeron, Linda Holmquist Mengelbier, David Gisselsson, Marcel Kool, Godelieve A.M. Tytgat, Marry M. van den Heuvel-Eibrink, Norbert Graf, Harm van Tinteren, Aurore Coulomb, Manfred Gessler, Richard Dafydd Williams, Kathy Pritchard-Jones
Journal: Journal of Clinical Oncology (2016)

Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series.
Long-Term Outcomes From Acute Rheumatic Fever and Rheumatic Heart Disease
Authors: Vincent Y.F. He, John R. Condon, Anna P. Ralph, Yuejen Zhao, Kathryn Roberts, Jessica L. de Dassel, Bart J. Currie, Marea Fittock, Keith N. Edwards, Jonathan R. Carapetis
Journal: Circulation (2016)

We investigated adverse outcomes for people with acute rheumatic fever (ARF) and rheumatic heart disease (RHD) and the effect of comorbidities and demographic factors on these outcomes.
Phase III trial of etirinotecan pegol (EP) versus Treatment of Physician’s Choice (TPC) in patients (pts) with advanced breast cancer (aBC) whose disease has progressed following anthracycline (A), taxane (T) and capecitabine (C): The BEACON study.
Authors: Edith A. Perez, Ahmad Awada, Joyce O'Shaughnessy, Hope S. Rugo, Chris Twelves, Seock-Ah Im, Carol Zhao, Ute Hoch, Alison L. Hannah, Javier Cortes
Journal: Journal of Clinical Oncology (2015)

1001 Background: EP is the first long-acting topoisomerase 1 inhibitor providing sustained levels of SN38. In Phase II, EP demonstrated a 29% ORR following a median of 2 prior regimens for aBC. BEACON study (NCT01492101) randomized (1:1) pts with aBC and progressive disease following A,T and C to EP (145 mg/m2q3w over 90 minutes) or TPC (any of 7 cytotoxics). Methods: Eligible pts had any ER/HER2 and ECOG 0-1; stable brain metastases were allowed. 852 pts enrolled over 20 months and reached target for events in Dec2014. The choice of TPC: eribulin 40%, vinorelbine 23%, gemcitabine 18%, taxane 15%, ixabepilone 4%. Primary efficacy endpoint was overall survival (OS) by 2-sided log-rank test stratified by region, prior eribulin and receptor status; the study had 90% power to detect a target Hazard Ratio (HR) of 0.77. Circulating tumor cells (CTCs) were isolated in ~80% of pts and analyzed for target-specific pharmacodynamic biomarkers. This is the first presentation of these data. Results: EP provided a 2.1 month improvement in median OS over TPC (12.4 vs 10.3 months; HR 0.87, p = 0.08). In a pre-specified subgroup of 67 pts with brain metastases, EP showed an improvement of 5.2 months in median OS (10.0 vs 4.8 months; HR 0.51, p < 0.01); the proportion of pts with brain metastases alive at 12-mo survival was higher with EP (44.4% vs 19.4%). Similarly, in pts with liver metastases (n = 456) median OS improved with EP (10.9 vs 8.3 months; HR 0.73, p = 0.002). Grade (G) ≥ 3 AEs were lower with EP (48%) than TPC (63%). Common G ≥ 3 AE with EP: diarrhea (9.6%), neutropenia (9.6%), anemia (4.7%) and fatigue (4.5%); TPC: neutropenia (30.5%), anemia (4.7%) and dyspnea (4.4%). Severe neuropathy: 3.7% of pts (TPC) vs 0.5% (EP). Alopecia was less with EP (10% vs 23%). Data on efficacy in CTC biomarker defined sub-groups (TOP1, TOP2) will be presented. Conclusions: EP provided a clinically meaningful benefit to pts with late-stage aBC, although this did not reach statistical significance. In pts with brain metastases, median OS doubled; improved survival was also seen in other pt subsets. Toxicity with EP was less than with TPC. Clinical trial information: NCT01492101.
Abstract 415: A new, highly sensitive ALK antibody improves the screening of rearranged-ALK by IHC
Authors: Hsiangmin Lu, Rachel Gonzalez, Yi Shen, Mu-lan Jin, Yipan Wu, Yungang Zhang, Kehu Yuan, Boyang Chu, Lili Qi, Huibo Liu, Chenlin Wang, Guangli Wang, Youmin Shu, Julie McDowell, Donghui Ma, Wei-wu He, Jian Chen, Ray Lin
Journal: Cancer Research (2016)

Abstract All non-small cell lung cancer (NSCLC) patients are recommended to be screened for anaplastic lymphoma kinase (ALK)-rearrangement despite its low occurrence (&amp;lt; 7%). This is due to recent advances in treatment for patients with ALK-positive NSCLC with receptor tyrosine kinase inhibitors Crizotinib and Ceritini. Current rearranged-ALK testing includes fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), and immunohistochemistry (IHC). Despite the high sensitivities and specificities, the limitations of the first two assays include time-consuming, infeasible, and specialized techniques that make them unsuitable for the routine screening for which IHC has been proposed. However, the biggest obstacle to detecting rearranged-ALK in lung cancer patients by IHC is the lack of highly sensitive ALK antibodies that detect the extremely low abundance of ALK in patients. To overcome this limitation, we have developed an ALK mouse monoclonal antibody (clone OTI1A4) with higher sensitivity in comparison to a rabbit ALK antibody (clone D5F3). Moreover, OTI1A4 identified ALK-positive NSCLC samples (16/16 cases) and showed negative staining for ALK-negative samples (11/11 cases) previously validated by FISH (10/16 ALK-positive cases) or qPCR (10/16 ALK-positive cases). This indicated the potential advantage of using clone OTI1A4 over FISH or qPCR to detect ALK rearrangements. Lastly, there was 100% concordance between OTI1A4 and D5F3 in detecting ALK-rearranged NSCLC samples previously confirmed by FISH (76 ALK-positive and 438 ALK-negative samples). These results support the possibility that ALK clone OTI1A4 could be used for routine screening of patients with ALK-positive NSCLC by IHC. Citation Format: Hsiangmin Lu, Rachel Gonzalez, Yi Shen, Mu-lan Jin, Yipan Wu, Yungang Zhang, Kehu Yuan, Boyang Chu, Lili Qi, Huibo Liu, Chenlin Wang, Guangli Wang, Youmin Shu, Julie McDowell, Donghui Ma, Wei-wu He, Jian Chen, Ray Lin. A new, highly sensitive ALK antibody improves the screening of rearranged-ALK by IHC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 415.
A first-in-human, phase I pharmacodynamic (PD) and pharmacokinetic (PK) study of BNC105P, a novel vascular disrupting agent (VDA) and inhibitor of cancer cell proliferation.
Authors: G. Chong, J. Desai, D. C. Bibby, G. Kremmidiotis, S. S. Wong, A. F. Leske, C. A. Matthews, M. A. Rosen, D. Rischin
Journal: Journal of Clinical Oncology (2010)

3054 Background: BNC105P is a novel agent which inhibits tubulin polymerization and acts as a VDA. BNC105P is a phosphorylated parent compound which rapidly converts to the active agent BNC105. BNC105 exhibits 100-fold specificity for activated endothelial cells (cf. quiescent). Methods: BNC105P was administered IV over 10 min on day 1 and 8 every 21 days to patients (pts) with advanced solid tumors. PD effects were evaluated using DCE-MRI (detection of blood flow and vascular permeability) with two baseline and two post dose assessments (3-6, 24h). In addition, a novel assay for detection of tubulin polymerization in PBMCs was developed as a biomarker of BNC105 on-target action. Furthermore, the effects of BNC105 on the levels of VEGF, PAI-1, and cytokeratin 18 were measured. Response by RECIST was determined at the end of cycle 2. Results: 21 pts (13M; 8F; median 60 yr) were enrolled on six dose levels (2.1, 4.2, 8.4, 12.6, 16, 18.9 mg/m2). Stable disease (SD) was observed in 4 pts, including one pt with mesothelioma (progression at entry) with SD up to week 22 (8.4 mg/m2), one pt at 12.6 mg/m2 and 2 at 16 mg/m2. One pt in the 16 mg/m2 cohort demonstrated significant Ktrans decline at 24h (-42%). At the highest (18.9 mg/m2) dose cohort, DCE-MRI demonstrated significant declines in tumor Ktrans (mean change -39%, range -14 to -60%) at 24h post dosing. Levels of polymerized tubulin detected in PBMCs decreased by >80% from 1h to 7h post dosing (cycle 1), reflecting the on-target activity of BNC105. Changes in blood borne biomarkers were seen at doses >8.4 mg/m2. PK data of BNC105 indicated a generally linear increase in plasma AUC levels and plasma half life of <0.5h. DLTs at 18.9 mg/m2 included one episode of Gr 3 elevated LFT (ALT) and one episode of Gr 4 N-STEMI (observed in an 83 yr old pt exhibiting an AUC >4 times higher than other pts in this cohort). BNC105P was well tolerated without any DLTs at doses below 18.9 mg/m2. Conclusions: Stable disease was observed in 4 pts dosed at 8.4 mg/m2 or higher. Both DCE-MRI and PBMC-polymerized tubulin content confirm that pharmacodynamically active doses have been achieved and correlate well with plasma exposure. The MTD was identified as 16 mg/m2. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bionomics Ltd. Bionomics Ltd. Bionomics Ltd. Bionomics Ltd.
Updated analysis of circulating tumor cells (CTCs) in patients with urothelial cancer (UC) undergoing systemic treatment: Implications across the clinical stages.
Authors: Andrea Necchi, Emanuela Fina, Patrizia Giannatempo, Maurizio Colecchia, Chiara Iacona, Elena Farè, Daniele Raggi, Massimo Maffezzini, Nicola Nicolai, Roberto Salvioni, Alessandro M. Gianni, Luigi Mariani, Maria Grazia Daidone, Vera Cappelletti
Journal: Journal of Clinical Oncology (2014)

4544 Background: CTCs from patients (pts) at different clinical stages were analyzed by a never explored experimental approach based on a combination of two techniques. Provision of this information may contribute to optimize tailored therapies. Methods: 3 cohorts of have been analyzed: pts with muscle-invasive bladder cancer receiving neoadjuvant (NA) sorafenib + chemotherapy (CT) (NCT01222676), and metastatic pts receiving first-line MVAC (M1), and second-line (M2) anti-TGFβ receptor ALK1 PF-03446962 in a phase 2 trial (NCT01620970). 5 ml of whole blood were filtered by ScreenCell Cyto devices and CTC status was assessed with centralized scoring by referral pathologists. Additional 5 ml of whole blood were processed by immunomagnetic beads (AdnaTestSelect® kit) and the expression level of a panel of markers (including EPCAM and MUC1) was studied using RT-multiplex PCR. The objective was the association with clinical endpoints (pathologic/clinical response, and relapse). Results: From 07/2012 to 1/2014, 65 pts (20 NA, 31 M1, and 14 M2) were enrolled. Rates of baseline CTC+ were: 92, 75, 91%, and 31, 50, 64% with the 2 techniques, respectively. NA setting: all pts had a stepwise reduction of CTC count/5 ml blood by ScreenCell (median baseline of 14 [0-40] to 0 [0-9] – end of treatment). Increase in circulating EPCAM±MUC1 levels by CTC was seen in accordance with the 3 disease progressions (PD). M1 setting: While there was a discrepancy between CTC signals and partial/complete response (PR/CR), a trend towards an increase in CTC levels was observed in 7/9 evaluable relapsers. Pts who relapsed had a median of 43 CTC/5 ml (IQR: 17-51.5) at the end of CT, while all the others had levels <13. EPCAM profile was not concordant in all cases (median 1.01 vs 1 ng/ul). Interestingly, an increase in both CTC signals anticipated relapse in 5/9 evaluable responders (CR+PR). M2 setting: an increase in CTC was documented by both methods in each case, in accordance with PD. Conclusions: This combined technique was endowed with promising utility to anticipate the detection of clinical relapse. Refining molecular characterization might help designing informed clinical trials.
Abstract 5065: Role of EpCAM in EGFR signaling and tumorigenesis
Authors: Lincoln Muhoro, Timothy Fleming, Narendra Sankpal, William Gillanders
Journal: Cancer Research (2016)

Abstract EpCAM is a transmembrane glycoprotein that functions as a homophilic cell adhesion molecule. EpCAM is expressed in normal epithelium and at even higher levels in epithelial cancers, including breast, pancreatic and lung cancers. Since its discovery in the 1980s, EpCAM has been targeted in several different epithelial cancers. Even though numerous novel therapeutic strategies targeting EpCAM have been investigated, the biological role and functional significance of EpCAM expression in cancer remains unclear. EpCAM expression appears to be associated with prognosis in several epithelial cancers -in some cancers it is associated with a favorable prognosis (renal cell, rectal) and in others it is associated with a poor prognosis (lung, pancreatic, breast). Thus, the function of EpCAM appears to be context-dependent in epithelial cancers. To understand the impact of EpCAM in human cancer, we specifically ablated EpCAM expression in over 40 cancer cell lines, and assessed the impact on invasion. We identified the A431 epidermoid cancer cell line as a cell line that overexpresses EpCAM, but is exquisitely sensitive to manipulation of EpCAM expression. A431 is known to overexpress EGFR and serves as a model cell line for EGFR signaling. Specific ablation of EpCAM significantly enhanced the migration and invasion of the A431 cell line. Specific ablation of EpCAM was also associated with increased EGFR activity, as demonstrated by phospho-immunoblot. Immunoprecipitation studies demonstrate that EpCAM binds directly to EGFR. Using specific EpCAM mutant constructs, we showed that the N-terminal domain of EpCAM is required for binding and suppression of EGFR activity. Using a soft agar colony growth assay, we were able to confirm that N-terminal EpCAM domain mutants (NTD288) inhibited colony growth in 3T3-transfected cells relative to the wildtype. In addition, a transformation assay showed that the same N-terminal mutant was able to inhibit transformation of 3T3 cells. To assess the effects of EpCAM ablation on in vivo tumor growth, we specifically ablated EpCAM and then performed tumor challenge experiments using immunocompromised mice. Specific ablation of EpCAM increased tumor growth relative to control. These data suggest that EpCAM may modulate EGFR signaling. Further studies are ongoing to define the mechanisms by which EpCAM inhibits EGFR activity. Citation Format: Lincoln Muhoro, Timothy Fleming, Narendra Sankpal, William Gillanders. Role of EpCAM in EGFR signaling and tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5065.