bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA27: MYC drives molecular and therapeutically distinct subtype of SCLC
Authors: Mollaoglu Gurkan , Guthrie Matthew R. , Bohm Stefanie , Bragelmann Johannes , Chalishazar Milind D. , Ireland Abbie S. , Huang Fang , Hu Zeping , Cardnell Robert J. , Sen Triparna , Gertz Jason , Johnson Jane E. , Gazdar Adi F. , Byers Lauren A. , DeBerardinis Ralph J. , Wechsler-Reya Robert J. , Sos Martin , Oliver Trudy G. 
Published: February 2019

Abstract
Small cell lung cancer (SCLC) has largely been treated in the clinic as a homogeneous disease for the last 40 years. However, it is become increasingly appreciated that SCLC exhibits both intra- and intertumoral heterogeneity. Genetic loss of the tumor suppressors RB1 and TP53 is nearly universal in SCLC, while amplifications in MYC family members including C-, L-, and N-MYC are mutually exclusive. Using genetically engineered mouse models (GEMMs), we show that MycT58A expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low ‘‘variant’’ subset of SCLC with low ASCL1 and high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. The MYC-driven subset of SCLC is also low for other clinically relevant biomarkers such as TTF1/NKX2.1 and DLL3. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival. These findings are consistent with the results of recent clinical trials in patients with relapsed SCLC who received paclitaxel with or without the AURKA inhibitor alisertib. Furthermore, recent preclinical studies demonstrate that the MYC-driven subset of SCLC is preferentially sensitive to CHK1 inhibition and other metabolic targets compared to MYCL-driven SCLC. These data identify molecular features for patient stratification and uncover potential targeted treatment approaches for MYC-driven SCLC.
Citation Format: Gurkan Mollaoglu, Matthew R. Guthrie, Stefanie Bohm, Johannes Bragelmann, Milind D. Chalishazar, Abbie S. Ireland, Fang Huang, Zeping Hu, Robert J. Cardnell, Triparna Sen, Jason Gertz, Jane E. Johnson, Adi F. Gazdar, Lauren A. Byers, Ralph J. DeBerardinis, Robert J. Wechsler-Reya, Martin Sos, Trudy G. Oliver. MYC drives molecular and therapeutically distinct subtype of SCLC [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA27.
Abstract IA38: Progress and unanswered questions in EGFR mutation-positive lung cancer
Authors: Sequist Lecia V. 
Published: February 2019

Abstract
A summary of the major advances in management of EGFR mutation-positive lung cancer will be provided, along with a discussion of missing pieces of information that could improve the care of patients.
Citation Format: Lecia V. Sequist. Progress and unanswered questions in EGFR mutation-positive lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA38.
Abstract PR09: Alterations in cell junctions and neuroendocrine differentiation are key early steps in Crebbp/Ep300 mutation-driven SCLC development
Authors: Kim Dong-Wook , Kim Keebeom , Dunn Colin T. , Park Kwon-Sik 
Published: February 2019

Abstract
The abundance and heterogeneity of somatic alterations in small cell lung cancer (SCLC) present immense challenges in identifying key mechanisms of tumor development. Functional characterization of recurrent mutations is an essential step towards understanding the early stages of SCLC development, but this remains extremely difficult due to the scarcity of relevant and tractable models for defining oncogenic drivers and molecular pathways. In a previous study, we derived precancerous cells (preSCs) from the Rb/p53/Rbl2-mutant mouse model of SCLC and developed an engineered preSC-based model of early tumor development. In this model, activation of oncogenic drivers transforms preSCs into tumorigenic cells that form spheroid clusters characteristic of SCLC in culture and subcutaneous tumors in athymic nude mice. Using this streamlined approach, we found that both retroviral amplification of the Myc family members and CRISPR/Cas9-mediated mutation of Crebbp/Ep300 were sufficient to cause transformation of preSCs into SCLC cells. Notably, both sets of mutant preSC underwent a similar phenotypic change from adherent monolayers to spheroid aggregates, suggesting that the two different types of alterations interact with or converge on common molecular pathways. Comparative profiling of control preSCs and mutant preSCs carrying either a Myc family amplification or Crebbp/Ep300 mutation revealed that alterations in cell junctions and neuroendocrine differentiation are the most significant molecular changes during cellular transformation. The transformed preSCs exhibited decreased expression of adhesion-related genes, including Cdh1 and Dsp, but increased expression of mesenchymal genes Vim and Twist1. The transformed cells also showed reduced expression of neuroendocrine (NE) differentiation genes, including Ascl1, Chga, and Syp. Furthermore, these changes coincided with increased expression of Notch receptors and decreased expression of their ligands Dlls and Jags. Taken together, these novel findings suggest that a phenotypic switch from Dll/Jag-expressing NE cells to Notch-expressing non-NE cells is a key event in early SCLC development. This study also demonstrated that the preSC-based model can facilitate functional validation of recurrent mutations in SCLC and molecular pathways that will be further explored for mechanistic elucidation and development of targeted therapies.
This abstract is also being presented as Poster A09.
Citation Format: Dong-Wook Kim, Keebeom Kim, Colin T. Dunn, Kwon-Sik Park. Alterations in cell junctions and neuroendocrine differentiation are key early steps in Crebbp/Ep300 mutation-driven SCLC development [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr PR09.
Abstract PR13: MET copy number gain is associated with gefitinib resistance in leptomeningeal carcinomatosis of EGFR-mutant lung cancer
Authors: Nanjo Shigeki , Arai Sachiko , Wang Wei , Hata Akito , Katakami Nobuyuki , Yano Seiji 
Published: February 2019

Abstract
Leptomeningeal carcinomatosis occurs frequently in EGFR-mutant lung cancer, and develops acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study aimed to clarify the mechanism of EGFR-TKI resistance in leptomeningeal carcinomatosis and seek a novel therapeutic strategy. We examined EGFR mutations, including the T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 leptomeningeal carcinomatosis and 20 extracranial lesions of EGFR-mutant lung cancer patients who became refractory to EGFR-TKI treatment. All 32 specimens had the same baseline EGFR mutations, but the T790M mutation was less frequent in leptomeningeal carcinomatosis specimens than in extracranial specimens (8% vs. 55%, P &lt; 0.01). To study molecular mechanisms of acquired EGFR-TKI resistance in leptomeningeal carcinomatosis, we utilized our previously developed mouse model of leptomeningeal carcinomatosis with the EGFR-mutant lung cancer cell line PC-9/ffluc cells, in which acquired resistance to gefitinib was induced by continuous oral treatment. Compared with subcutaneously inoculated gefitinib-resistant tumors, the T790M mutation was less frequent in leptomeningeal carcinomatosis that acquired resistance to gefitinib. PC-9/LMC-GR cells were established from the gefitinib-resistant leptomeningeal carcinomatosis model, and they were found to be intermediately resistant to gefitinib and osimertinib (third-generation EGFR-TKI). Although EGFR-T790M was negative, gefitinib resistance of PC-9/LMC-GR cells was related to MET copy number gain with MET activation. Moreover, combined use of EGFR-TKI and crizotinib, a MET inhibitor, dramatically regressed leptomeningeal carcinomatosis with acquired resistance to gefitinib or osimertinib. These findings suggest that combination therapy with MET inhibitors may be promising for controlling leptomeningeal carcinomatosis that acquires resistance to EGFR-TKIs.
This abstract is also being presented as Poster B29.
Citation Format: Shigeki Nanjo, Sachiko Arai, Wei Wang, Akito Hata, Nobuyuki Katakami, Seiji Yano. MET copy number gain is associated with gefitinib resistance in leptomeningeal carcinomatosis of EGFR-mutant lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr PR13.
Abstract A014: Phase I clinical trial with PD-1/MUC1 CAR-pNK92 immunotherapy
Authors: Li Qiao , Wang Yi , Lin Ming , Xia Leiming , Bao Yangyi , Sun Xiang , Yang Lin 
Published: February 2019

Abstract
Mucin1 (MUC1) proteins represent a family of high molecular weight trans-membrane glycoproteins that protect epithelial cells and mediate signal transduction by communication with extracellular stimuli. On the other hand, MUC1 has been observed to be overexpressed and glycosylated in adenocarcinoma, making it an ideal molecular target for cancer treatment. MUC1 based antibody and specific chimeric antigen receptors (CARs) modified T/NK cells exhibit strong antibody-dependent or direct-cell cytotoxicity to MUC1 positive tumor cells. However, treatment failure with MUC1-targeted therapy was usually caused by tumor microenvironment (TME)-driven immune suppression. PD-L1 has been identified as a negative checkpoint molecule that promotes immune evasion of tumor cells. The interaction of PD-1 and PD-L1 inhibits the function of tumor-infiltrating lymphocytes (TILs) or infused T/NK cells while activating the negative immune-regulatory cells in TME, such as regulatory T-cells and MDSCs. To overcome these barriers, we engineered clinically applicable NK-92 cells by lentiviral gene transfer to express chimeric antigen receptors comprising an anti-MUC1 scFv antibody fusion protein with CD28-CD137 as a signaling moiety and truncated PD-1 peptide. NK92 cells expressing anti-MUC1 CAR specifically and efficiently lysed MUC1 positive tumor cells in vitro and in vivo. The safety of NK-92 cell administration has been demonstrated by numerous phase I clinical trials. In our study, 13 patients with different kinds of tumors (lung cancer, pancreatic cancer, colon cancer and ovarian cancer) with positive PD-L1 and MUC-1 expression were enrolled. CAR-NK cells were infused (1×109 cells/time) into these patients. Of 13 patients, 3 patients were withdrawn, 9 patients (69.2%) showed stable disease and 1 patient showed progressive disease. The cytokine level and hematologic changes were monitored to evaluate the safety. Severe cytokine storm and/or bone marrow suppression were not observed. From this phase I clinical trial we found that CAR-NK therapy has a broad prospect of application as a new cellular immunotherapy due to its stable clinical efficacy, mild side effects and ease of preparation.
Citation Format: Qiao Li, Yi Wang, Ming Lin, Leiming Xia, Yangyi Bao, Xiang Sun, Lin Yang. Phase I clinical trial with PD-1/MUC1 CAR-pNK92 immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A014.
Abstract A038: Effective rerouting of NK cell cytotoxicity against B-cell malignancies upon TCR gene transfer
Authors: Morton Laura T. , Wouters Anne K. , Remst Dennis F. , Hagedoorn Renate S. , Loenen Marleen M. Van , Boer Renate de , Falkenberg J. H.F. , Heemskerk Mirjam H.M. 
Published: February 2019

Abstract
T-cell receptor (TCR) gene transfer involves ex-vivo introduction of a tumour-reactive TCR into patient-derived CD8 T-cells enabling specific-targeting of tumour cells. Competition for expression with CD3 from the endogenous TCR and the potential for TCR mixed- dimer formation necessitate optimisation of cellular therapeutics with sustained potency and increased safety. NK-cells (CD3-CD56+) are potent short-lived effector cells that lyse abnormal or stressed cells independent of antigen. Efficacy and safety of adoptive NK therapy has been demonstrated in the treatment of hematologic malignancies in both the autologous and allogeneic setting. Here,we aimed to exploit NK-cell cytotoxicity and redirect it toward antigen-specific recognition of tumors without the limitation of TCR mixed- dimer formation and competition for CD3.Firstly, peripheral blood derived NK-cells were expanded and retrovirally transduced to express BOB1-specific TCR, restricted to HLA- B*07:02, in combination with CD3 alongside CD8 co-receptor.BOB1 is a B-cell restricted transcription factor, important for B-cell survival. Purified BOB1-TCR expressing NK-cells demonstrated antigen-specific binding of BOB1-specific pMHC-tetramer and proliferated upon co-culture with HLA-B*07:02 positive B-lymphoblastic cell lines (B-LCL) but not with HLA-B*07:02 negative B-LCL. Furthermore, BOB1-TCR expressing NK-cells demonstrated in vitro cytotoxicity against HLA-B*07:02 positive B-LCL, multiple myeloma and B-ALL cell lines. Conversely, these tumor cell lines remained resistant to NK-cell mediated lysis when co-cultured with mock transduced NK-cells. Finally, NK sensitive cell line K562 was comparably lysed by both BOB1-TCR or mock transduced NK-cells demonstrating retained NK-cell mediated activity.These data demonstrated that NK-cell cytotoxicity can be redirected toward antigen-specific recognition of tumors and is TCR-dependent. Retention of NK-cell function in genetically modified cells allows for a double-hit therapeutic approach that can offer advantages over current cellular approaches.
Citation Format: Laura T. Morton, Anne K. Wouters, Dennis F. Remst, Renate S. Hagedoorn, Marleen M. Van Loenen, Renate de Boer, J. H.F. Falkenberg, Mirjam H.M. Heemskerk. Effective rerouting of NK cell cytotoxicity against B-cell malignancies upon TCR gene transfer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A038.
Abstract A098: SLC12A2 as a novel “brake” on immunogenic apoptotic cell clearance
Authors: Perry Justin Shaun Arnold , Morioka Sho , Medina Christopher , Raymond Michael , Ravichandran Kodi 
Published: February 2019

Abstract
Phagocytes face a key challenge during efferocytosis – they must engulf an apoptotic cell, often similar in size, while maintaining their own cell integrity, shape, and volume. Yet little is known about phagocyte volume homeostasis during apoptotic cell clearance. To this end, we performed an unbiased transcriptomics screen designed to reveal alterations of phagocyte gene expression after engulfment of apoptotic Jurkat lymphoma cells and identified several transcriptional programs distinctly modified in engulfing phagocytes. We identified a program involving cell volume regulation and potassium/chloride flux, the latter of which is thought to underlie immunogenic responses. Disruption of one member of this cell volume program, SLC12A2, resulted in “overeating” of apoptotic JurkaT-cells by individual phagocytes and a significant increase in cell size. Importantly, we demonstrate that SLC12A2-deficient phagocytes actively engulfing apoptotic JurkaT-cells led to a downregulation of the hallmark antiinflammatory efferocytosis program and robust upregulation of a proinflammatory program. In particular, we observed robust upregulation of immunogenic programs, including a type I interferon signature, in SLC12A2-deficient engulfing phagocytes that were not observed in phagocytes over-expressing the phosphatidylserine receptor TIM4, Mechanistically, we found that the chloride-sensing kinase WNK1 and downstream kinases OSR1 and SPAK function to regulate chloride flux into engulfing phagocytes via SLC12A2, and that this pathway regulates the apoptotic JurkaT-cell “overeating” observed in SLC12A2-deficient phagocytes. Collectively, these data elucidate a novel mechanism by which phagocytes protect themselves from potentially dangerous apoptotic cell-derived inflammatory ligands and suggest that SLC12A2 serves to actively suppress immunogenic responses by phagocytes and limits the rate of corpse uptake during efferocytosis.
Citation Format: Justin Shaun Arnold Perry, Sho Morioka, Christopher Medina, Michael Raymond, Kodi Ravichandran. SLC12A2 as a novel “brake” on immunogenic apoptotic cell clearance [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A098.
Abstract A101: IDO2 host genetic status influences progression and radiotherapy response in pancreatic ductal adenocarcinoma
Authors: Prendergast George C. , Nevler Avinoam , Muller Alexander J. , Sutanto-Ward Erika , DuHadaway James B. , Nagatomo Kei , Londin Eric , O'Hayer Kevin , Cozzitorto Joseph A. , Lavu Harish , Yeo Theresa P. , Curtis Mark , Villatoro Tatiana , Leiby Benjamin E. , Winter Jordan M. , Yeo Charles J. , Brody Jonathan R. 
Published: February 2019

Abstract
Sporadic pancreatic ductal adenocarcinoma (PDAC) develops into a lethal disease that has remained refractory to different treatment approaches including recent advances in cancer immunotherapy. Variations in host genetic status affecting the inflammatory microenvironment can impact cancer susceptibility, malignant progression and clinical outcomes. In this study, we present genetic evidence from mouse and human genetic studies supporting a role for IDO2, an immunometabolic modifier of B cell-mediated autoimmune responses, in promoting pancreatic ductal adenocarcinoma (PDAC). In an established transgenic mouse model of KRAS-induced pancreatic cancer, IDO2 genetic inactivation markedly reduced malignant progression. In retrospective clinical analyses of PDAC patients (N=200), the biallelic occurrence of either of two inactivating polymorphisms in the IDO2 coding region trended with favorable disease-free survival. In PDAC tissues, an inactive IDO2 host genotype corresponded with changes in expression of genes involved in tryptophan catabolism and immune modulation, along with a reduced neutrophil to lymphocyte ratio. Notably, subset analysis revealed a striking association of inactive IDO2 status with improved disease-free survival in patients who had received adjuvant radiotherapy, a treatment modality that has been highly debated due to its variable efficacy in patients. Accordingly, our findings suggest that host IDO2 genetic status may offer a simple incisive marker to stratify PDAC patients who stand to gain the most from adjuvant radiotherapy, addressing the long-standing debate of its benefits.
Citation Format: George C. Prendergast, Avinoam Nevler, Alexander J. Muller, Erika Sutanto-Ward, James B. DuHadaway, Kei Nagatomo, Eric Londin, Kevin O'Hayer, Joseph A. Cozzitorto, Harish Lavu, Theresa P. Yeo, Mark Curtis, Tatiana Villatoro, Benjamin E. Leiby, Jordan M. Winter, Charles J. Yeo, Jonathan R. Brody. IDO2 host genetic status influences progression and radiotherapy response in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A101.
Abstract A112: OncoPeptTUME: A novel computational approach analyzes the tumor microenvironment to predict response to checkpoint inhibitors
Authors: Shi Xiaoshan , Manoharan Malini , Mandloi Nitin , Priyadharshini Sushri , Iyer Laxman , Gupta Rohit , Chakraborty Papia , Chaudhuri Amitabha , Gupta Ravi 
Published: February 2019

Abstract
Cancer immunotherapy is now an established treatment option for many cancers. Cancer immunotherapy boosts host antitumor immunity to provide long-term benefit; however, only a small fraction of the treated patients show a durable clinical response. The tumor microenvironment ecosystem, with its complex mixture of non-malignant and malignant cells, is a major contributor in regulating the response to checkpoint blockade and development of resistance. Ongoing efforts to characterize the tumor microenvironment to stratify patients for immunotherapy and find biomarkers of response often use methods that are limited by the availability of adequate tumor tissue from needle biopsy material and loss of tissue viability during sample processing that precludes the use of single-cell sequencing platforms. Therefore, genomic methods that use deconvolution to assess the relative proportion of different cell types and their phenotypes in the tumor microenvironment are desirable for clinical use. To this end, we have developed OncoPeptTUME, a novel computational approach that utilizes a proprietary minimal gene expression signature to assign immune scores for eight broad categories of immune cells present in the tumor microenvironment. To validate the approach, we used 9,640 TCGA gene expression datasets from 33 different tumors, defined their immune cell content, organized samples into clusters based on their immune cell content, and identified the molecular differences that predict survival in samples belonging to different clusters. We further performed a deeper analysis of samples enriched in infiltrating CD8+ T-cells to identify T-cell phenotype that correlated with a long-term survival benefit. A small set of genes associated with functional T-cell phenotype was used on a dataset of melanoma samples to show that higher expression of the genes discriminated responders from the nonresponders to nivolumab treatment. In conclusion, our analysis demonstrates that OncoPeptTUME is a powerful immunogenomic tool to predict patient prognosis, stratify patients who will benefit from cancer immunotherapy and identify pathways and novel biomarkers of long-term benefit from the use of cancer immunotherapy drugs.
Citation Format: Xiaoshan Shi, Malini Manoharan, Nitin Mandloi, Sushri Priyadharshini, Laxman Iyer, Rohit Gupta, Papia Chakraborty, Amitabha Chaudhuri, Ravi Gupta. OncoPeptTUME: A novel computational approach analyzes the tumor microenvironment to predict response to checkpoint inhibitors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A112.