bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3971: MEK inhibitors limit inflammatory cytokine production and modulate the immune response in the setting of Cholangiocarcinoma.
Authors: Ruggieri Amanda N. , Farren Matthew R. , Yarchoan Mark , Azad Nilofer S. , Dennison Lauren , El-Reyes Bassel , Lesinski Gregory B. 
Published: August 2019

Abstract
Cholangiocarcinoma (CC) is a rare but aggressive cancer of the bile ducts with a five-year survival rate of only 2% in patients with metastatic disease. MAP kinase signaling is important in the pathogenesis of CC and serves as a key regulator of cell proliferation and survival. Our data indicate this pathway is constitutively active in several CC cell lines and accompanied by production of immunomodulatory cytokines including IL-6, MCP-1 and GM-CSF. Cobimetinib is a potent and selective inhibitor of MEK that has been utilized clinically in patients with advanced CC. Although MEK inhibitors (MEKi) have been studied in a variety of solid tumors, the mechanisms by which they act upon CC cells are not completely defined. These agents have modest single agent activity in CC, and their impact in combination with immunotherapy is under active investigation. We hypothesized that MEKi can modulate cytokine and chemokine expression from CC tumors, thereby complementing immunotherapy in this aggressive disease. Using a novel panel of human CC cell lines, we demonstrated a variable impact of cobimetinib on in vitro cell proliferation, with a reduction in viability no greater than 35%. However, MEKi reproducibly limited cytokine (GM-CSF and IL-1β) and chemokine (MIP-1α) production from human CC cell lines in vitro. The ability of cobimetinib to limit MAPK signal transduction in these cells was confirmed via immunoblot. These data complement prior published observations by Ebert et al.in 2016 indicating that single agent MEKi is sufficient to elicit T cell infiltration into tumors. We have completed enrollment of a Phase II clinical trial (NCT03201458) evaluating the efficacy of cobimetinib in combination with the PD-L1 inhibitor, atezolizumab. An extensive series of correlative studies are underway in peripheral blood and tumor biopsies to examine the impact of cobimetinib on modulating cytokine and chemokine signatures in the context of PD-L1 targeted therapy. These data will provide new insight into the impact of MEK inhibitors as a complement to immunotherapy in a disease that is refractory to most conventional therapies.
Citation Format: Amanda N. Ruggieri, Matthew R. Farren, Mark Yarchoan, Nilofer S. Azad, Lauren Dennison, Bassel El-Reyes, Gregory B. Lesinski. MEK inhibitors limit inflammatory cytokine production and modulate the immune response in the setting of Cholangiocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3971.
Abstract 3980: Molecular profiling of cell-free DNA and RNA in the blood of patients with non-small cell lung cancer
Authors: Reese Jordan , Jackson Leisa , Mellert Hestia S. , Pestano Gary 
Published: August 2019

Abstract
Lung cancer is the leading cause of cancer-related deaths in the United States with Non-Small Cell Lung Cancer (NSCLC) being the most commonly diagnosed subtype. However, up to 30% of advanced NSCLC patients are not eligible for tissue biopsy. As a result, liquid biopsies are becoming increasingly utilized in clinical testing as they are non-invasive and have an overall decreased risk to patients. This approach also addresses other challenges associated with tissue-based profiling, including tumor heterogeneity and low yield of quality nucleic acid for the identification of actionable targets of treatment. In this study, cell-free total nucleic acid (cfTNA) was isolated from donor patient plasma samples collected and shipped at ambient temperatures in blood collection tubes to the Biodesix CAP/CLIA laboratory in Boulder, CO. cfTNA was profiled with a targeted cancer NGS (next generation sequencing) panel, using the Ion Torrent GeneStudio S5 Plus System. Variant analyses were conducted using a threshold of ≥0.3% percent variant allele frequency to assess concordance in the patient donor specimens. A high level of concordance (R2=0.99) was observed between inter-laboratory/inter-instrument NGS runs using 6 clinical samples. In the 0.1% single nucleotide variant (SNV) positive control sample which encompasses 23 hotspots, there was slightly lower concordance (R2=0.90) due to low variant allele frequency (0.06-0.3%). Validation studies are in progress and include RNA fusions and additional variants present in blood from patients diagnosed with NSCLC.
Citation Format: Jordan Reese, Leisa Jackson, Hestia S. Mellert, Gary Pestano. Molecular profiling of cell-free DNA and RNA in the blood of patients with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3980.
Abstract 4000: Development of a patient navigation training program for the Caribbean context
Authors: Ashing Kimlin T. , Badal KImberly 
Published: August 2019

Abstract
Introduction
For the Caribbean context, a patient navigator (PN) is one who is responsible for coordinating and streamlining care in a complex cancer care continuum by providing support in physical, mental and emotional challenges; educating and empowering patients in their journey; tracking patient medical records electronically and addressing barriers to care. As a first step to introducing this role to the Caribbean, a comprehensive training program for new navigators was developed and conducted.
Methods
A multi-disciplinary steering committee consisting of a behavioral scientist, two oncology registered nurses and educators, a clinical psychologist, two cancer survivors, a cancer researcher, a physician and an experienced oncology nurse navigator was formed in Trinidad and Tobago. The steering committee had these objectives: (i) develop a comprehensive list of PN core competencies; (ii) determine PN skill requirements; (iii) develop and execute a training curriculum that met the PN core competencies.
Results
Two categories of navigators and requisite skill requirements were developed for each (Table 1). Three skill domains were defined as patient navigator skills, research skills and professional skills. Each domain was then divided into specific competencies which translated into 11 curriculum topics. Candidates who met the skill requirements filled a form-based application, provide a curriculum vitae and completed 0.5hr scenario-based interview. A 5-day, 30 contact hour patient navigation training program was successfully conducted with candidates from 4 Caribbean territories. Results of the pre- and post- test assessment as well as the training evaluation will be reported in the presentation.
Conclusion
A productive international collaboration between City of Hope an NCI designated Comprehensive Cancer Center and CCRI a civil society cancer organization successfully developed and conducted a comprehensive program to train patient navigators for the Caribbean context.
Table 1:Skill requirements for oncology nurse navigators and lay navigatorsOncology Nurse NavigatorLay NavigatorPrimary Skill RequirementsOncology-trained Registered Nurse. Registered Nurse with 2 years clinical experience in OncologyCancer survivor. Care giverAlternative Skill Requirements SkillsRetired medical personnel. Any Registered NurseAny person with interest, holding a minimum Bachelor degree in a related area of expertise such as counselling pharmacy, psychology, social work etc.
Citation Format: Kimlin T. Ashing, KImberly Badal. Development of a patient navigation training program for the Caribbean context [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4000.
Abstract 4007: Decipher the myth between progression-free survival and overall survival in HER-2 positive metastatic nreast cancer: Anti-HER2 antibody as the constant winner—A hypothesis-driven meta-regression analysis
Authors: Chen I-Chun , Hu Fu-Chiang , Lin Ching-Hung , Lu Yen-Shen 
Published: August 2019

Abstract
Purpose: Traditionally, the predictive value of progression free survival (PFS) hazard ratio (HR) on overall survival (OS) HR in metastatic breast cancer (MBC) was low. We observed that when trials were designed as adding on an anti-HER2 antibody, either trastuzumab or pertuzumab, to the control treatment, the OS increment is usually greater than the PFS increment. We aim to investigate the interaction of increment of median PFS and median OS in HER-2 positive MBC stratified by drug difference patterns between treatment arms using trial-level information.
Methods: All randomized phase II or III trials of systematic therapy specifically for HER-2 positive MBC with available OS information were included after a systematic literature review. Treatment arms with shorter PFS were defined as control arm in the analysis. The correlation and interaction of HR for PFS and OS as well as the absolute increment for median PFS and OS were evaluated by fixed-effect or random-effect meta-regression meta-analysis. Drug difference between two treatment arms were specified as a categorical variable in the analysis.
Results: A total of 28 trials with 10928 patients published between January 1999 and December 2017 were included in the final analysis. The correlation of median PFS HR (0.73, 95% C.I.= 0.68-078) and median OS HR (0.82, 95% C.I.= 0.77-0.87) was modest as reported by other investigators. However, when the drug difference between treatment arms was anti-HER2 antibody, the absolute increment in median OS is 2 fold of the absolute increment in median PFS (p = 0.0005), showing a linear correlation. This linear correlation was not observed when the drug difference between treatments was non-anti-HER2 antibody. Anti-HER2 antibody as drug difference would translate the absolute increment of median PFS into absolute increment of median OS, suggesting a good predictive value of median PFS on median OS.
Conclusion: Anti-HER2 antibody as the drug difference between treatment arms provides consistently longer OS improvement than PFS improvement in HER-2 positive MBCs.
Citation Format: I-Chun Chen, Fu-Chiang Hu, Ching-Hung Lin, Yen-Shen Lu. Decipher the myth between progression-free survival and overall survival in HER-2 positive metastatic nreast cancer: Anti-HER2 antibody as the constant winner—A hypothesis-driven meta-regression analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4007.
Abstract 4018: Pan-cancer predictions of drug sensitivity based on protein-coding and non-coding RNA biomarkers
Authors: Lloyd John P. , Merrill Nathan , Lachacz Eric , Li Jun Z. , Merajver Sofia , Soellner Matthew 
Published: August 2019

Abstract
Molecular characteristics that accurately forecast tumor response to drug therapies represent an important target for precision cancer treatment. However, it is not known whether tumor drug response can be predicted in a tissue-agnostic manner or if predictions must be established within historically-defined cancer types and subtypes. To address this question, we utilized public datasets to test whether multi-omics biomarkers in 346 tumor cell lines representing 17 cancer types can predict response to five small molecule therapies (2 MEK, 2 PI3K, and 1 FGFR inhibitors). The pool of potential biomarkers tested included 51,268 total RNA expression levels and DNA variants. We identify a panel of 45 gene expression levels capable of accurately predicting response to MEK inhibitors (AUC-ROC &gt;0.90), indicating that tumor response to small molecule drugs can be predicted regardless of cancer type. We found that RNA expression levels, notably among non-coding sequences, were most important for predictions. Experimental validation of the 45-gene panel is demonstrated based on predicted and observed MEK inhibitor sensitivity in 12 cell lines from 5 cancer types without previously known drug sensitivities. Successful pan-cancer predictions of drug response in cancer cell lines represents a critical step toward truly personalized treatment in real time, based on the characteristics of individual tumors.
Citation Format: John P. Lloyd, Nathan Merrill, Eric Lachacz, Jun Z. Li, Sofia Merajver, Matthew Soellner. Pan-cancer predictions of drug sensitivity based on protein-coding and non-coding RNA biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4018.
Abstract 4060: Discovery and screening of protein biomarkers with the FirePlex Technology Platform
Authors: Perea Amy , Neuner Russell , Heinrich Bianca , Doran Graeme , Austin Wayne , Rafferty Conor , Camilleri Matt , Tackett Michael , To Long , Atabakhsh Elnaz , Murray James , Pregibon Daniel 
Published: August 2019

Abstract
In patients and animal models, molecular biomarkers are used as indicators of normal and pathogenic processes. In drug discovery and screening pipelines, molecular biomarkers are used to assess the mechanism of action, efficacy, and toxicity of lead compounds. To address the need for rapid and sensitive biomarker quantitation, we have developed the FirePlex® Technology Platform. Utilizing patented hydrogel particles and a three-region encoding design, FirePlex assays allow for true, in-well multiplexing, providing flexible and customizable quantification of miRNA and protein analytes. To facilitate biomarker discovery studies, we offer our standard-throughput, flow cytometry-based assays which enable quantitation of up to 75 miRNA or protein analytes per sample, from only 20 µl of input. These assays demonstrate 5 logs of dynamic range and offer highly sensitive quantitation of analytes in serum, plasma, cell culture supernatant, urine, and CSF without the need for sample processing or RNA isolation. For drug discovery and screening studies, we offer our high-throughput FirePlex (FirePlex®-HT) Immunoassays for quantitation of up to 10 protein analytes per sample from only 6.25 µl biofluid input, in 384-well plate format. FirePlex-HT assays provide 3-4 logs dynamic range, demonstrate 1-100 pg/ml sensitivity, and have been validated in serum, plasma, and cell culture supernatant. The two-step workflow, no-wash assay format, and readout on high-content imagers limit hands-on time and are amenable to automation, thus making FirePlex-HT ideally suited for high-throughput screening studies. In addition, here we introduce our high-throughput miRNA assays for screening miRNA biomarkers in 96-well or 38-4well plate format, with readout on high-content imagers. Here we present data from miRNA and protein profiling studies using the FirePlex platform, and introduce the simplified workflow of the FirePlex-HT® immunoassays with data demonstrating the performance for quantifying key cytokines in multiplex, in biological samples. Together, this novel combination of multiplexed, high-sensitivity assays and bioinformatics tools enables rapid quantitation of protein biomarker signatures in biofluid specimens.
Citation Format: Amy Perea, Russell Neuner, Bianca Heinrich, Graeme Doran, Wayne Austin, Conor Rafferty, Matt Camilleri, Michael Tackett, Long To, Elnaz Atabakhsh, James Murray, Daniel Pregibon. Discovery and screening of protein biomarkers with the FirePlex Technology Platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4060.
Abstract 4067: PD-L1 expression, CD8 cells and MHC-class-1 Beta-2-microglobulin expression in advanced non-small lung cancer
Authors: Hijmering-Kappelle Lucie , Hiltermann Jeroen , Hiddinga Birgitta , Wekken Anthonie van der , Hart Nils 't , Groen Harry , Timens Wim 
Published: August 2019

Abstract
Introduction: PD-L1 expression has been approved as predictive biomarker for immune checkpoint inhibitors (ICI) in non-small cell lung carcinoma (NSCLC). In case of lack of PD-L1 expression in tumor biopsies, 8-10% of patients will respond to ICI. However, in case of &gt; 50% PD-L1 tumor expression half of patients show no response. Tumor immune escape phenotypes are characterized by loss of MHC-class-I and a lower grade of CD8 T-cell infiltration, despite upregulation of PD-L1 expression. At least one of the four phenotypes of MHC-class-I and PD-L1 co-expression is considered responsible for non-responsiveness. We investigated the frequency of PD-L1, MHC-class-I β2-microglobulin (β-2M) co-expression and presence of CD8 cells in advanced NSCLC.
Methods: Analysis was performed on formalin fixed, paraffin embedded (FFPE) transbronchial or transthoracic tumor biopsies of 27 patients with advanced NSCLC. Immunohistochemistry was performed using Ventana Benchmark Ultra immunostainer. PD-L1 was detected using Ventana PD-L1 (SP263) Assay (CE IVD), CD8 by Ventana CONFIRM anti-CD8 (SP57) antibody and MHC-class I β2-M by Agilent-Dako polyclonal rabbit anti-human beta-2-Microglobulin. PDL1 expression was scored as percentage positive tumor cells according to the manufacturers guideline, β2-M was scored as positive or negative in tumor cells and CD8 cells as low (+), intermediate (++) or high (+++) numbers in tumor or peritumoral stroma.
Results: In 27 patients IHC staining was performed. PDL1 expression was scored as &lt;1%, 1-49% and ≥50% in 17, 3, and 7 patients, respectively. PD-L1 positive (&gt;1%) patients had positive β-2M in 10 of 10 cases. PD-L1 negative tumors showed presence of β-2M in 10 of 17 cases. Seven out of 27 cases (26%) were β-2M negative; all of them were PD-L negative cases. Low CD8 score was seen in 7 patients and 2 of these patients have a PD-L1 expression &gt;1% and positive β-2M.
Conclusion: In this ongoing study one quarter of advanced NSCLC patients had no tumor MHC-class-1 β-2M expression. In our cohort β-2M negative phenotype was associated with lack of PD-L1 tumor expression.
Citation Format: Lucie Hijmering-Kappelle, Jeroen Hiltermann, Birgitta Hiddinga, Anthonie van der Wekken, Nils 't Hart, Harry Groen, Wim Timens. PD-L1 expression, CD8 cells and MHC-class-1 Beta-2-microglobulin expression in advanced non-small lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4067.
Abstract 4069: Development of PSB205, a bifunctional MabPair product that targets PD-1 and CTLA-4
Authors: Fanslow William C. , Liu Zhi , Hu Zhonghua , Liu Hua , Shen Min , Peng Yufeng , Domeier Cristina , Treiber David , Schoner Ron , Yan Wei 
Published: August 2019

Abstract
Here we describe a novel platform that enables the production of two full length IgG molecules from a single production cell line. This technology was achieved using a molecular engineering approach to precisely control the cognate pairing of antibody heavy chains and light chains during the assembly of two antibodies in the same cell line. This technology platform, which has been designated as MabPair, can be applied for the development of therapeutic antibody products that contain a mixture of two different antibodies. The antibody cocktail is produced by the same cell line in a predefined ratio and can be manufactured using a conventional antibody production process. When addressing multiple targets, MabPair products can offer significant advantages and flexibility over a bispecific antibody. MabPair technology represents a novel approach for developing antibody combination products. This approach is exemplified by the development of PSB205, our lead MabPair product candidate. PSB205 targets two immune checkpoint pathways, PD-1 and CTLA-4. The development of PSB205, as a potential anti-cancer immunotherapeutic, is discussed.
Citation Format: William C. Fanslow, Zhi Liu, Zhonghua Hu, Hua Liu, Min Shen, Yufeng Peng, Cristina Domeier, David Treiber, Ron Schoner, Wei Yan. Development of PSB205, a bifunctional MabPair product that targets PD-1 and CTLA-4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4069.
Abstract 4079: EVT801: a selective VEGFR3 inhibitor with the potential for combination with immune-checkpoint therapies, preclinical evidences and plans for first-in-human evaluation
Authors: Fons Pierre , Esquerre Michael , Paillasse Michael , Visentin Virgile , Dol Frederique , Meneyrol Jerome , Badet Gaelle , Cogo Eric , Vidaud Lionel , Alam Antoine , Blanc Isabelle , Bono Francoise , Lisztwan Joanna , Poublanc Muriel , Filleron Thomas , Hunneyball Ian , Delord Jean-Pierre , Whittaker Mark 
Published: August 2019

Abstract
We have identified a highly selective VEGFR3 inhibitor drug candidate, which strongly inhibits angiogenesis without inducing hypoxia, reputed as one of the main causes of cancer-associated immunosuppression. Combination of EVT801 and Immune Checkpoint Therapy (ICT) could be synergistic as hypoxia-induced-immunosuppression should be avoided. We have demonstrated that EVT801 is a narrow spectrum inhibitor of the VEGFR3 tyrosine kinase with residual activity against VEGFR2 and TAK1 and with an activity on VEGFRs different from Fruquitinib and Lenvatinib. We then showed that EVT801 inhibited human endothelial cell proliferation in vitro and tumor angiogenesis on ex-vivo mouse ring aortic assay. EVT801 was active in vivo in the RIP1-Tag2 mouse model during the angiogenic switch. In comparison to sorafenib, EVT801 in 2 different tumors mouse model decreased tumor development without inducing increase of hypoxia which is in favor to a sustained blood vessel tumor normalization. In orthotopic 4T1 mammary carcinoma, we demonstrated that EVT801 in combination with PD1 mAb was significantly superior than single agent treatment and a decrease of lung metastasis spreading was observed. We observed that decrease of MDSCs in blood in response to EVT801 was correlated with decrease in tumor weight. By IHC analysis, we showed that treatment with EVT801 increases CD8+ T-cells infiltration inside the tumor. Taken together, these results indicated that EVT801 represents an innovative anti-angiogenic drug for cancer immunotherapy which may improve the frequency of response to ICT. Clinical trial design including patient stratification and biomarkers of activity has been proposed in order to be ready for first-in-human evaluation by mid-2019.
Citation Format: Pierre Fons, Michael Esquerre, Michael Paillasse, Virgile Visentin, Frederique Dol, Jerome Meneyrol, Gaelle Badet, Eric Cogo, Lionel Vidaud, Antoine Alam, Isabelle Blanc, Francoise Bono, Joanna Lisztwan, Muriel Poublanc, Thomas Filleron, Ian Hunneyball, Jean-Pierre Delord, Mark Whittaker. EVT801: a selective VEGFR3 inhibitor with the potential for combination with immune-checkpoint therapies, preclinical evidences and plans for first-in-human evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4079.