bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT159: Olaparib combinations (OLAPCO)for homology-directed DNA repairdefects (HDR)
Authors: Eder Joseph P. , Shapiro Geoffrey I. , Cleary James M. , Keedy Vickie L. , Keedy Vickie L. , Bindra Ranjit , Shuch Brian , Sklar Jeffrey , Do Khanh , Juergensmeier Juliane 
Published: August 2018

Abstract
INTRODUCTION: Genetic profiling of tumors used to identify treatment choices for cancer patients focus on kinase mutations and well-defined translocations; multiple clinical trials have been initiated for specific kinase-targeted agents. About 15-20% of patients have actionable mutations. HDR have been found in ~ 20 % of patient tumors molecularly profiled at the Yale Cancer Center. Mutations in HDR related genes often occur in addition to other mutations in signaling pathways. Specific targeted treatment options for these patients are limited, as breast and ovarian cancer mutations are the only indication for the HDR pathway targeted PARP inhibitors. Additional drugs are in development, but few clinical studies based on HDR other than BRCA1/2 mutations are open.
METHODS: The OLAPCO study targets HDR in patients irrespective of tumor origin. The protocol includes four arms to which patients can be enrolled based on tumor profiling results: olaparib monotherapy (PARP inhibitor) for HDR; olaparib & AZD5363 ( AKT inhibitor) for PIK3CA/AKT/PTEN pathway dysregulation and ARID1A mutations; olaparib & AZD1775 ( wee1 inhibitor) for TP53 mutations and olaparib & AZD6738 (ATR inhibitor) for HDR and olaparib pre-treated patients. The clinical endpoints are to determine tumor overall response rate (ORR) and clinical benefit rate (CBR) by RECIST after 16 weeks of treatment.
RESULTS: Arms a and b are open to patient accrual. Together, 34 pts have been treated, 12 remain on treatment, with no new or &gt; Gr 2 (CTCAE4) treatment-related toxicities.
TABLE 1Olaparib total = 23; median # cycles= 2, range 1-10+ ; 7 ongoingMutationATMBRCA1IDH1/2FHPALB2CHK2BAP1ARID 1A#52821212ORR1 PRCBR10201000TABLE 2Olaparib & AZD 5363 total = 12; median # cycles = 2, range 1-8+; 5 ongoingMutationAKT1AKT3AKT2 & PALB2ARID 1AARID 1A & PIK3CAPTEN#321411ORR1CBR10101
DISCUSSION: HDR defects are actionable mutations, increasing the number of patients for whom tumor profiling can identify a therapeutic option. This exploratory trial is expanding the therapeutic spectrum of olaparib alone and in combination, to include heretofore non-canonical alterations in HDR, beyond BRCA1/2. This trial design allows additional molecular targets, agents & combinations to be rapidly evaluated.
AstraZeneca support is gratefully acknowledged.
Citation Format: Joseph P. Eder, Geoffrey I. Shapiro, James M. Cleary, Vickie L. Keedy, Vickie L. Keedy, Ranjit Bindra, Brian Shuch, Jeffrey Sklar, Khanh Do, Juliane Juergensmeier. Olaparib combinations (OLAPCO)for homology-directed DNA repairdefects (HDR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT159.
Abstract LB-005: Anti-tumoral effects of novel lymphatic delivery of anti-CTLA-4 in a metastatic murine breast cancer model
Authors: Kwon Sunkuk , Velasquez Fred Christian , Ross Russel F. , Hwu Wen-Jen , Sevick-Muraca Eva M. 
Published: August 2018

Abstract
The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is an immune checkpoint receptor expressed by the activated T-cells and plays a key role in modulating T-cell function. Blockade of CTLA-4 after systemic administration can induce an antitumor immune response by promoting the activation and proliferation of tumor-specific T cells. Despite important clinical benefits, systemic intravenous administration of anti-CTLA-4 antibody often results in off-target toxicities (i.e., severe immune-related adverse events) by inappropriately activating naïve-T cells in distant lymph nodes (LNs) and other lymphoid tissues where non-tumor, self-antigens rather than tumor antigens are presented. Thus, efficient direct delivery of checkpoint inhibitors into the regional lymphatics could provide maximal drug exposure to targets within tumor-draining LN basins and their efferent lymphatic vessels before emptying into the blood vasculature for systemic delivery to the tumor. In this study, we used a novel, infusion device, SOFUSATM, consisting of a 66 mm2 microneedle array with a 6 micron polyether ketone nanotopographical film heat-formed over each microneedle to infuse therapeutic doses into the lymphatics in mice. 4T1 mouse mammary tumor cells transfected with luciferase (4T1-luc) were injected into the mammary fat pad of BALB/C mice. Anti-(cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody (10mg/kg) was administered on days 11, 15, 19, and 23 via SOFUSATM. SOFUSATM infusion occurred on the right dorsal back. While further studies are underway, our preliminary data demonstrated that when the repeated dose of anti-mCTLA-4 was successfully delivered via SOFUSATM, significant tumor shrinkage occurred when compared to the untreated group and the group of mice treated with conventional intraperitoneal (i.p.) administrations. Our bioluminescence imaging data showed no lymph node and distant organ metastases in mice dosed with SOFUSATM as compared to the untreated mice and mice with i.p. treatment, both of which showed LNs, lung, or liver metastases. Our study may revolutionize immunotherapies by moving from advanced, systemic to “first-line” loco-regional, cancer treatment.
Citation Format: Sunkuk Kwon, Fred Christian Velasquez, Russel F. Ross, Wen-Jen Hwu, Eva M. Sevick-Muraca. Anti-tumoral effects of novel lymphatic delivery of anti-CTLA-4 in a metastatic murine breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-005.
Abstract LB-015: Differential therapeutic responses of MET oncogenic activations to Met kinase inhibitor and neutralizing antibody
Authors: Kou Jianqun , Staal Ben , Musich Phillip R. , Kang Liang , Qin Yuan , Yao Zhi Q. , Zhang Boheng , Angela Tam , Huang Alan , Hao Huaixiang , Woude George F. Vande , Xie Qian 
Published: August 2018

Abstract
Purpose: MET inhibitors are in clinical trials against several cancer types, but the mechanisms toward vulnerability remain elusive. Here we characterized the molecular basis of MET amplification (METamp) and HGF-autocrine driven tumors in response to MET tyrosine kinase inhibitors (TKI) and neutralizing antibodies.
Experimental Design: METamp (MKN45 and MHCC97H) and HGF-autocrine activation (JHH5 and U87) cells were treated by the MET kinase inhibitor (INC280) and the anti-MET monoclonal antibody (MetMab) to determine the sensitivity and biological responses in vitro. Tumor inhibition was evaluated in vivo using SCID and SCIDhgf mouse models, respectively. HGF-mediated angiogenesis was measured by using the human endothelial cells (HUVEC) tube formation assay.
Results: MKN45 and MHCC97H cells are more sensitive than JHH5 and U87 cells to INC280 treatment but are unresponsive to MetMab. In METamp cells, INC280 induced a DNA damage response with activation of repair through the p53BP1/ATM signaling pathway. Although INC280 and MetMab showed a moderate inhibitory effect on - JHH5 and U87 cells in vitro, both treatments potently suppressed tumor growth in mouse models. We found that HGF stimulation promotes human HUVEC cell tube formation via the Src pathway. INC280 or MetMab inhibited tube formation; thus in HGF-autocrine tumors, the endothelial cells are the secondary targets of tumor-derived HGF and MET inhibition.
Conclusion: METamp and HGF-autocrine activation favor different molecular mechanisms, such as a DNA damage response or angiogenesis. Because individual types of MET oncogenic activation may respond to MET inhibitors differently, combination strategies should be developed based upon the molecular subtypes of the tumors.
Citation Format: Jianqun Kou, Ben Staal, Phillip R. Musich, Liang Kang, Yuan Qin, Zhi Q. Yao, Boheng Zhang, Tam Angela, Alan Huang, Huaixiang Hao, George F. Vande Woude, Qian Xie. Differential therapeutic responses of MET oncogenic activations to Met kinase inhibitor and neutralizing antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-015.
Abstract LB-026: iDEP: integrated differential expression and pathway analysis of RNA-Seq data
Authors: Ge Steven X. 
Published: August 2018

Abstract
Analysis and interpretation of RNA-Seq data remain a challenge for bench scientists. We aim to develop a user-friendly web application for exploratory data analysis (EDA), differential expression, and pathway analysis using summarized gene-level data from RNA-Seq, DNA microarray or other platforms. The key idea of iDEP (integrated Differential Expression and Pathway analysis) is to make many powerful R/Bioconductor packages easily accessible by wrapping them under a graphical interface, alongside annotation databases. For EDA, it performs hierarchical clustering, k-means clustering, and principal component analysis. iDEP detects differentially expressed genes using the limma and DESeq2 packages. For a group of co-expressed genes, it identifies enriched gene ontology (GO) terms as well as transcription factor binding motifs in promoters. Pathway analysis can be performed using packages like GAGE, GSEA, PGSEA, or ReactomePA. iDEP can also detect chromosomal gain or loss using the PREDA package. iDEP uses annotation of 163 metazoa and 45 plant genomes in Ensembl for ID mapping and GO functional categorization. Common gene IDs including microarray probe names can be automatically recognized. Pathway information was also compiled from databases like KEGG, Reactome, MSigDB, GSKB, GeneSetDB, and araPath. As an example, we analyzed an RNA-Seq dataset involving siRNA-mediated Hoxa1 knockdown in lung fibroblasts, and identified the downregulation of cell-cycle genes, in agreement with previous studies. Our analyses also reveal the possible roles of E2F1 and its target genes, including microRNAs, in blocking G1/S transition, and the upregulation of genes related to cytokines, lysosome, and neuronal parts. iDEP enables users to conduct in-depth bioinformatics analysis of transcriptomic data through a graphical interface. Freely available at http://gelab.org/idep/
Citation Format: Steven X. Ge. iDEP: integrated differential expression and pathway analysis of RNA-Seq data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-026.
Abstract LB-028: Deep genomic, immune-infiltrate and neoantigen-based stratification of cancer predicts response to immune checkpoint inhibition
Authors: Ronen Roy , Kluge Boguslaw , Dutkowski Janusz 
Published: August 2018

Abstract
Background: Immunotherapies are revolutionizing cancer care but identifying patients which are most likely to achieve clinical benefit remains a key challenge. Available predictors such as PD-1/PD-L1 expression, tumor mutation burden or MSI-H/d-MMR status have shown promise in predicting response in specific cancer types, they fail to explain or predict response for many patients. A more comprehensive understating of biology underlying response to therapy is needed.
Approach: We developed an integrated machine-learning system that uses a mathematical model of cancer subtypes and a neoantigen fitness model to stratify multimodal omics data along with associated profiles of immune infiltration and immune pathway activity. The system holistically determines the underlying pathway-level architecture of genomic and other molecular alterations in each cancer. It further uses a new immune pathway deconvolution approach to determine subtype-specific immune-infiltrates and activation of key immune and immune-modulating pathways that may be associated with response to therapy.
Results: The system is applied to stratify and interrogate subtypes in over 40 cancer types. Here we discuss results for two of the histologies for which immunotherapies are being pursued clinically. Comprehensive systems-level interrogation of tumor genomic architecture and tumor microenvironment leads to new molecular sub-typings for colorectal adenocarcinoma and skin cutaneous melanoma, here referred to as COADREAD_MUT_CNV_MODEL_6 and SKCM_MUT_CNV_MODEL_3, respectively. The model-based subtypes uncover critical patterns of co-occurring and mutually-exclusive somatic alterations not apparent using previous approaches, and show strong correlation with immune infiltration. Further integration of the subtyping model with a new neoantigen fitness model significantly improves performance in predicting response to checkpoint inhibition compared to existing methods.
Citation Format: Roy Ronen, Boguslaw Kluge, Janusz Dutkowski. Deep genomic, immune-infiltrate and neoantigen-based stratification of cancer predicts response to immune checkpoint inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-028.
Abstract LB-032: Magnetic 3D bioprinting for the identification of tumor-specific therapies from PDX-derived 3D cultures
Authors: Souza Glauco , Bartholomeusz Geoffrey 
Published: August 2018

Abstract
Great efforts have been undertaken in the field of cancer to develop clinically relevant pre-clinical models to permit the translation of research advances into agents that can improve patient outcomes. The use of 2D monolayer and 3D multicellular tumor spheroid cell culture systems has made this process remarkably costly and inefficient. This outcome is a result of discrepancies between simplified in-vitro 2D cell culture models used in drug screening platforms and the complex 3D tumor microenvironment targeted by these same drugs. Patient-derived xenograft (PDX), in which patient tumor tissue implanted into immune-deficient mice, provide improved models of human tumor biology relative to immortalized cancer cell lines. Such models offer possibilities for better preclinical testing of new therapies for the treatment of cancer. A drawback associated with the use of PDX systems is its requirement for immense resources and animals. Also, animal models have limited relevance as a platform for high throughput drug screening. To overcome such limitations, we applied magnetic 3D bioprinting to develop a PDX-derived ex-vivo tumor tissue platform for high-throughput drug screening. The PDX-derived tissue generated using magnetic 3D bioprinting mirrors the original PDX tumor in both tissue architecture and genetic signature. We confirm the predictive value of our screening template by demonstrating a similar response outcome between our model and a PDX mouse system generated from the same original tumor tissue and treated with the same panel of drugs. Utilizing an Inflammatory Breast Cancer (IBC) PDX system as our model system, we screened our ex-vivo tumor tissue template with the anti-cancer drug library and identified 7 lead candidates that had a stronger anti-tumor activity compared to the standard of care agents used to treat IBC patients in the clinics. Incorporating our ex-vivo tumor tissue high throughput screening platform as an early step in a PDX system will permit the identification of new and effective tumor-specific therapies at a time, cost, and resource efficient manner.
Citation Format: Glauco Souza, Geoffrey Bartholomeusz. Magnetic 3D bioprinting for the identification of tumor-specific therapies from PDX-derived 3D cultures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-032.
Abstract LB-048: c-Kit enhances ovarian cancer stemness via upregulating phospho-PHB in the lipid raft domain of the plasma membrane
Authors: Liang Shu-Mei Y. , Fang Chia-Hsun , Chang Pu-Yuan , Liang Chi-Ming 
Published: August 2018

Abstract
Phosphorylation of prohibitin (PHB) at threonine 258 (phospho-PHBT258) and tyrosine 259 (phospho-PHBY259) in human cancer-cell membranes is associated with an increase in the invasiveness and metastasis of cancer cells. Phospho-PHBY259 can regulate phospho-PHBT258 but not vice versa. Here, we found that stably overexpressing c-Kit in SKOV3 ovarian cancer cells (SKOV3_c-Kit) increased phospho-PHBY259, phospho-PHBT258 and PHB levels in the lipid raft domain of the plasma membrane. On the other hand, inhibition of c-Kit expression decreased PHB expression in SKOV3_c-Kit and Kuramochi ovarian cancer cells. Immunoprecipitation analysis showed that c-Kit interacts with PHB. SKOV3_c-Kit cells or SKOV3 cells overexpressing PHB in the lipid raft had higher levels of Notch3, NICD3 (Notch3 intracellular domain) and ABCG2 protein expression as compared to wild-type SKOV3 cells. Moreover, generation of SKOV3-G4 cells through serial passage of SKOV3 cells into nude mice ovary 4 times, revealed that the levels of c-Kit, Notch3, NICD3, phospho-PHBY259, phospho-PHBT258 and PHB in the lipid raft domain of SKOV3-G4 were significantly higher than wild-type SKOV3 cells. The SKOV3-G4 cells formed spheroids with stem cell-like properties such as higher expression of stem cell markers (Oct4, Nanog, SOX2). In addition, SKOV3-G4 cells exhibited more clonogenic potential and migration/invasion ability than wild-type SKOV3. These results suggest that c-Kit interacts with PHB in the lipid raft domain to phosphorylate PHB to increase invasiveness and stemness in ovarian cancer.
Citation Format: Shu-Mei Y. Liang, Chia-Hsun Fang, Pu-Yuan Chang, Chi-Ming Liang. c-Kit enhances ovarian cancer stemness via upregulating phospho-PHB in the lipid raft domain of the plasma membrane [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-048.
Abstract LB-065: An enzyme-directed pro-immunotherapeutic activated by muliti-drug resistance
Authors: Nielsen Amy E. , Mancini Rock J. 
Published: August 2018

Abstract
Synthetic agonists of innate immune cells are of interest to immunologists due to their synthesis from well-defined materials, optimized activity, and monodisperse chemical purity. Recently we have reported the approach of Bystander-Assisted ImmunoTherapy (BAIT) that exploits the phenomenon of drug efflux in multi-drug-resistant cancers to elicit a localized anti-cancer immune response. In this context we examine the imidazoquinoline class of immunostimulants for susceptibility to drug efflux and begin to determine structural characteristics that drive efflux susceptibility for the Toll-Like Receptor agonist family of immmunsotimulants.
Citation Format: Amy E. Nielsen, Rock J. Mancini. An enzyme-directed pro-immunotherapeutic activated by muliti-drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-065.
Abstract LB-117: Role of ectoenzymes CD39 and CD73 in the immune response to multiple myeloma
Authors: Yang Rui , Elsaadi Samah , Misund Kristine , Slupphaug Geir , Menu Eline , Hay Carl , Cooper Zac , Vanderkerken Karin , Børset Magne , Sponaas Anne Marit 
Published: August 2018

Abstract
Multiple Myeloma is a cancer of the plasma cells in the bone marrow. Despite from the fact that new drugs have increased survival in the past decade, it is still an incurable cancer. It is therefore important to develop new drugs. Tumor immunosurveillance contributes to the control of cancer growth, but there many different escape mechanisms utilized by tumour to evade anti-tumour immune responses. One of the largely unexplored mechanisms of immune suppression in multiple myeloma is the role of adenosine in the bone marrow microenvironment, which now represents an attractive new therapeutic target for cancer therapy. 2 ectoenzymes, CD39 and CD73 are important for converting extracellular ATP to adenosine. When investigating the role of adenosine in the immune response to multiple myeloma, we found increased concentration of adenosine in the bone marrow plasma from myeloma patients compared with healthy controls. CD39 (ENTPD1) was expressed by myeloma cell lines and on myeloma cells from patients. CD73 was found on leukocytes and stromal cells in the bone marrow. Although very few cells expressed CD73 in the bone marrow, these cells could clearly convert AMP to adenosine. ATP was converted to AMP by CD39+ myeloma cell lines, and CD73+ stromal cells converted AMP to adenosine. Importantly, co-culture of CD39+ myeloma cells and CD73+ stromal cells catalyzed extracellular ATP to immunosuppressive adenosine. Indeed, we found that CD3 T cells stimulated with anti CD3/CD28 beads in the presence of supernatants from co-cultured cells did not proliferate as well as T cell culture without this supernatant. The fact that this proliferation was inhibited by the ZM241385 inhibitor, suggested that the suppression was mediated by the A2AR receptor. The CD39 inhibitor POM1 inhibited adenosine generation in the co-culture system as well as T cell proliferation in vitro. We have recently obtained the CD73 antibody MEDI199447 from MedImmune and are testing the ability of this antibody to prevent adenosine production and T cell proliferation in vitro, as well as the ability to reduce tumor growth in a mouse model of multiple myeloma. The clinical importance of the adenosine pathway in multiple myeloma found when analyzing patient data. Using the publicly available coMMpass database, we found that patients with high expression of CD39 had significantly reduced progression free and overall survival.
Citation Format: Rui Yang, Samah Elsaadi, Kristine Misund, Geir Slupphaug, Eline Menu, Carl Hay, Zac Cooper, Karin Vanderkerken, Magne Børset, Anne Marit Sponaas. Role of ectoenzymes CD39 and CD73 in the immune response to multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-117.