bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B28: Novel combination treatment designed to target both metastatic cells and proliferation in pancreatic ductal adenocarcinoma
Authors: Karl Michelle , Russo Gabriella , Starich Bartholomew , Tan Haotian , Wirtz Denis 
Published: March 2020

Abstract
Pancreatic cancer is the 4th most common cause of cancer-related deaths in the United States, with only a 7-9% 5-year survival rate. While there are a few combination treatments that have been shown to increase overall survival by several months, gemcitabine monotherapy, which has been used to treat PDAC since 2006, is still the most commonly administered first-line treatment. Our objective is to improve patient survival by providing a novel combination therapy designed to inhibit the growth of solid tumors and prevent metastatic cancer cells from reaching secondary organs. Our lab has recently shown that secreted interleukin 6 (IL-6) and interleukin 8 (IL-8) can induce a migratory phenotype in tumorigenic, metastatic cancer cells in triple-negative breast cancer models. Cells exposed to these cytokines display enhanced invasion through stromal environments, and this phenotype can be reversed by blocking the IL-6 and IL-8 receptors with the combined treatment of tocilizumab and reparixin. We hypothesized that this simultaneous blocking of IL-6 and IL-8 receptors would improve PDAC patient outcomes when used in combination with gemcitabine by targeting both proliferation and metastasis. Preliminary results show that this combination treatment has a positive effect in in vivo PDAC models. Our novel treatment combination was able to significantly reduce the tumor size, exceeding that seen from gemcitabine monotherapy. In addition, the triple combination reduced the metastatic burden and normalized the effect of the treatment among the mice in the group.
Citation Format: Michelle Karl, Gabriella Russo, Bartholomew Starich, Haotian Tan, Denis Wirtz. Novel combination treatment designed to target both metastatic cells and proliferation in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B28.
Abstract B31: Type 1 conventional dendritic cells are progressively and systemically dysregulated early in pancreatic carcinogenesis
Authors: Lin Jeffrey H. , Huffman Austin P. , Furth Emma E. , Vonderheide Robert H. 
Published: March 2020

Abstract
Dendritic cell (DC) dysregulation in cancer has long been hypothesized to be a tumor-associated phenomenon. Using the KPC autochthonous mouse model of pancreatic ductal adenocarcinoma, we reveal that dysfunction of type 1 conventional DCs (cDC1s)—critical mediators of antitumor T-cell immunity—instead develops in the preinvasive stage of carcinogenesis and impacts the host systemically prior to malignancy. Both cDC1 survival and function are impacted, with cDC1s suspended in a state of semi-maturation in which genes involved in response to inflammation and proteasomal degradation are successfully upregulated while genes encoding T cell-polarizing cytokines necessary for T-cell activation fail to be induced. cDC1 dysfunction subsequently impairs CD8+ T-cell activation in vivo. However, this defect remains reversible even following progression to invasive cancer. CD40 activation induces an IFNg response signature that drives cDC1 maturation and migration to draining lymph nodes, restoring CD8+ T-cell activation to normal levels. This study therefore reveals the unexpected depths of cDC1 dysregulation in carcinogenesis but nevertheless elaborates therapeutically tractable strategies towards cDC1 repair.
Citation Format: Jeffrey H. Lin, Austin P. Huffman, Emma E. Furth, Robert H. Vonderheide. Type 1 conventional dendritic cells are progressively and systemically dysregulated early in pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B31.
Abstract B46: Targeting pancreatic cancer organoids with dual BET and CBP/P300 inhibitor NEO2734
Authors: Radulovich Nikolina , Tamblyn Laura , Seo Heewon , Haibe-Kains Benjamin , Lupien Mathieu , Gilles Francis , Tsao Ming S. 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis due to largely ineffective therapeutics available for this disease. Recently, inhibitors of bromodomain and extraterminal domain (BET) inhibitors have been shown to have therapeutic efficacy against various malignancies, including PDA. Here we present data on sensitivity of PDA patient-derived organoids (PDO) to a novel dual BET and CBP/P300 inhibitor, NEO2734 (Epigene Therapeutics Inc.). Our cell viability screen on a panel of 30 PDOs derived from PDA patient and xenograft tumor tissue revealed differential drug sensitivities to NEO2734 inhibitor. Antitumor effect of NEO2734 on the most sensitive PPTO.2 model was further confirmed in vivo using patient-derived xenograft PPTO.2 model. To identify potential biomarkers associated with differential sensitivities of PDA PDOs to NEO2734 inhibitor, we generated gene expression profiles from 13 PDOs derived from primary patient tumors. Using the probabilistic concordance index (C-index), 13 genes (Bonferroni corrected P&lt;1.0E-10) were identified as potential therapeutic targets. Among the biomarkers identified, we found three associations with known BET inhibitor target genes, including CA9 (C-index= 0.38, PBonferroni= 2.7E-19), which is known to be downregulated by BET inhibitor and coexpressed with the target gene BRDT. Furthermore, the biomarker SLC7A2 (0.28, 3.4E-37) has a known genetic interaction with BRD4, and ABCB6 (0.31, 1.5E-27) is predicted to be coexpressed with CREBBP. Overall, this work reveals that dual BET and CBP/P300 inhibitor, NEO2734, could be a novel therapeutic option for a subset of PDA patients.
Citation Format: Nikolina Radulovich, Laura Tamblyn, Heewon Seo, Benjamin Haibe-Kains, Mathieu Lupien, Francis Gilles, Ming S. Tsao. Targeting pancreatic cancer organoids with dual BET and CBP/P300 inhibitor NEO2734 [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B46.
Abstract B52: The T-cell architecture of pancreatic ductal adenocarcinoma
Authors: Sivakumar Shivan , Shah Enas Abu , Ahern David , Mangal Nagina , Reddy Srikanth , Rendek Aniko , Soonawalla Zahir , Silva Michael , Middleton Mark , Dustin Michael 
Published: March 2020

Abstract
Pancreatic cancer has the worst prognosis of any human malignancy. Our recent work has shown that immune infiltrate by transcriptomics and histopathology can predict prognosis after a Whipple’s operation, with lymphocyte infiltration being the most important prognostic marker. We have profiled T cells within primary pancreatic cancer to understand the T-cell architecture within the tumor. We have used a 37-marker T cell-focused panel to study the immune infiltrate. We see a diverse immunosuppressive immune microenvironment within the primary tumor. There is a complex architecture of macrophages, neutrophils, and T cells. The commonest CD4 T cells in the microenvironment are Tregs. There are potential novel therapeutic strategies for Tregs using unique checkpoint inhibitors. The CD8 T cells have PD-1 activity but are not activated or proliferating. The poor prognosis of pancreatic cancer could be explained by the immunosuppressive microenvironment, but there are opportunities to drug Tregs in this disease.
Citation Format: Shivan Sivakumar, Enas Abu Shah, David Ahern, Nagina Mangal, Srikanth Reddy, Aniko Rendek, Zahir Soonawalla, Michael Silva, Mark Middleton, Michael Dustin. The T-cell architecture of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B52.
Abstract B58: A phase I/II study of durvalumab and stereotactic radiotherapy in locally advanced pancreatic cancer
Authors: Tuli Richard , Nissen Nicholas , Lo Simon , Tighiouart Mourad , Placencio Veronica , Hendifar Andrew 
Published: March 2020

Abstract
Purpose/Objective: Blockade of the PD-1/PD-L1 pathway with radiotherapy (RT) can enhance both local and systemic control in varying tumor types. Yet, no significant responses have been seen in pancreatic cancer (PC). We have previously shown that RT induces PD-1 and PD-L1 in PC following upregulation of interferon-gamma. This mechanism of adaptive immune resistance by PC may serve as an ideal therapeutic target for combined RT and PD-L1 blockade. We report interim results of an ongoing phase 1/2 clinical trial in locally advanced (LA) and borderline resectable (BR) PC (NCT03245541).
Materials/Methods: Patients with LA or BR PC treated with standard-of-care gemcitabine and nab-paclitaxel for 3 to 6 cycles were enrolled. Treatment consisted of durvalumab (750 mg Q14 days) on D1. Stereotactic ablative radiotherapy (SABR; 6.6 Gy/fraction) was delivered every other day x 5 fractions beginning D8. Durvalumab continued as maintenance Q14 days until resection or progression. The run-in phase I utilized a standard 3+3 design prior to phase 2 expansion. Dose-limiting toxicities (DLTs), adverse events (AEs), and serious adverse events (SAEs) were assessed during the first 10 weeks of study treatment. CT scans were obtained every 2 months for response assessment. Endoscopic research biopsies were obtained pre- and 6-8 weeks post-SABR, and weekly blood samples were obtained on D1, weekly for 10 weeks, and then every 2 months until resection or progression to assess for immune correlates of response.
Results: From 8/2017-5/2019, 18 of 30 planned patients were enrolled of whom 13 (72%) were LA and 5 (28%) were BR. Median age was 70 and 44% were female. No DLTs were identified in the phase 1 run in, and enrollment in the phase 2 study continues. Median follow-up from diagnosis is 14 months (range 6-26 months). Median cycles of chemotherapy received prior to enrollment were 4. Grade 3 toxicities have been identified in 2 patients (nausea, anorexia). No patients experienced dose-limiting toxicities. Median PFS was 14 months with median OS not reached. 9 of 18 patients have undergone resection and all were margin negative. BOR: PR (54%); CR (6%), SD (34%), PD (6%).
Conclusion: To our knowledge, this is the first report of a PD-L1 inhibitor-RT combination in LA PC. The regimen was safe, well tolerated and appears to be clinically active with high rates of margin-negative resection.
Citation Format: Richard Tuli, Nicholas Nissen, Simon Lo, Mourad Tighiouart, Veronica Placencio, Andrew Hendifar. A phase I/II study of durvalumab and stereotactic radiotherapy in locally advanced pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B58.
Abstract C01: Porcupine inhibition redirects mitochondrial metabolism in Wnt-dependent pancreatic cancer
Authors: Aguilera Kristina Y. , Riahi Rana , Saadat Edris A. , Lay Anna R. , Le Thuc , Donahue Timothy R. , Radu Caius , Dawson David W. 
Published: March 2020

Abstract
Wnt/β-catenin signaling plays important roles in pancreatic ductal adenocarcinoma (PDA) tumor initiation and progression via broad-ranging effects on proliferation, differentiation, survival, and stemness. Although Wnt has been shown to promote glycolysis in colon cancer, its role in regulating metabolism in PDA has not been well explored. For this study, RNF43-mutant cell lines were selected as exemplars of ligand-dependent autocrine Wnt signaling in PDA. These cell lines harbor an inactivating mutation in RNF43 that confers Wnt growth-dependency and response to LGK974, a PORCN inhibitor that blocks Wnt ligand secretion and signaling. Global transcriptomic, proteomic, and metabolomic analysis revealed several metabolites and putative mediators of metabolism that are directly or indirectly linked to autocrine Wnt signaling. Pharmacologic inhibition of Wnt by LGK974 led to the accumulation of pyruvate and lactate, as well as reduced tricarboxylic acid cycle metabolites and decreased mitochondrial membrane potential as measured by tetramethylrhodamine and JC-1 assays. These metabolic changes were accompanied by cell cycle arrest and downregulation of transcriptional programs involved in cell cycle progression, DNA replication, and nucleotide metabolism. Importantly, LGK974 results were phenocopied by siRNA-mediated knockdown of WNT7B and rescued with WNT3A conditioned media. Thus, inhibition of mitochondrial oxidative phosphorylation by LGK974 in RNF43-mutant PDA appears linked to its inhibition of canonical Wnt signaling, an adaptation and potential metabolic vulnerability that could be leveraged to therapeutic advantage via combinatorial strategies. Altogether, these results suggest tissue context and mechanisms of Wnt pathway activation may profoundly influence its role in regulating cancer metabolism.
Citation Format: Kristina Y. Aguilera, Rana Riahi, Edris A. Saadat, Anna R. Lay, Thuc Le, Timothy R. Donahue, Caius Radu, David W. Dawson. Porcupine inhibition redirects mitochondrial metabolism in Wnt-dependent pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C01.
Abstract C06: Cholesterol deprivation induces TGFβ signaling to promote basal differentiation in pancreatic cancer
Authors: Gabitova Linara , Peri Suraj , Francescone Ralph , Franco-Barraza Janusz , Shah Neelima , Nicolas Emmanuelle , Handorf Elizabeth A. , Cai Kathy Q. , Sloma Ido , Chiaverelli Rachel , Moffitt Richard , Golemis Erica A. , Fang Carolyn , Lynch Shannon , Cukierman Edna , Astsaturov Igor 
Published: March 2020

Abstract
Oncogenic transformation alters the metabolism of cellular nutrients to sustain tumor growth. We here define a mechanism by which modifications in cholesterol metabolism control the formation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by means of conditional inactivation of Nsdhl in mice bearing a tumor-inducing Kras mutation (KrasG12D) prevented PDAC formation in the context of a heterozygous Trp53f/+ genotype without impairing normal pancreatic development. In mice with pancreatic Nsdhl ablation and homozygous loss of Trp53, the emerging tumors presented with the aggressive basal (mesenchymal) phenotype as opposed to the classic (glandular) PDAC. This paralleled significantly reduced expression of cholesterol metabolic pathway genes in human basal PDAC subtype. Mechanistically, we demonstrate that genetic or metabolic reduction in cellular cholesterol induces the expression of transforming growth factor beta (TGF) and activates pro-mesenchymal effectors in human and murine PDAC, providing a direct transcriptional mechanism by which cholesterol metabolism can condition tumor differentiation. Activity of TGF beta pathway estimated via pSMAD2 expression in surgical PDAC samples inversely correlated with patients’ blood cholesterol levels, especially in patients taking cholesterol-lowering statins. Conclusions: Low levels of cellular cholesterol induce autocrine TGF beta signaling in PDAC. Malnutrition or cholesterol-lowering statins may be mechanistically linked to basal PDAC differentiation.
Citation Format: Linara Gabitova, Suraj Peri, Ralph Francescone, Janusz Franco-Barraza, Neelima Shah, Emmanuelle Nicolas, Elizabeth A. Handorf, Kathy Q. Cai, Ido Sloma, Rachel Chiaverelli, Richard Moffitt, Erica A. Golemis, Carolyn Fang, Shannon Lynch, Edna Cukierman, Igor Astsaturov. Cholesterol deprivation induces TGFβ signaling to promote basal differentiation in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C06.
Abstract C10: Glutamine deprivation triggers hexosamine salvage in pancreatic cancer cells
Authors: Campbell Sydney L. , Mesaros Clementina A. , Tsang Tiffany , Noji Michael , Kruijning Salisa , Trefely Sophie , Izzo Luke , Blair Ian A. , Wellen Kathryn E. 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDA) remains one of the most difficult cancers to effectively treat. Over 90% of PDA are driven by oncogenic KRAS, which leads to metabolic rewiring in the cell, including increased glucose uptake and increased flux through the hexosamine biosynthesis pathway (HBP). The HBP, which branches off from glycolysis at fructose-6-phosphate and also requires glutamine, acetyl-CoA, and uridine triphosphate, is responsible for synthesizing uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a major substrate for glycosylation in the cell. UDP-GlcNAc can also be generated through recycling of GlcNAc via N-acetylglucosamine kinase (NAGK). Glycans are important for maintaining protein homeostasis and cell signaling. However, while there is increased HBP flux in PDA and glycosylation is elevated in a range of cancers, how this is regulated and the functional significance of increased glycosylation in cancer are not well understood. Because of the multiple metabolic inputs required for UDP-GlcNAc synthesis, the HBP has been proposed as a nutrient sensing pathway. Surprisingly, however, we found that PDA cells robustly maintain both O-GlcNAc and N-glycosylation when exposed to nutrient deprivation. The enzyme N-acetylglucosamine kinase (NAGK) is upregulated under low glutamine conditions, and through stable isotope tracing studies, we demonstrate that PDA cells are able to switch to use of the salvage pathway over the HBP for generation and maintenance of the UDP-GlcNAc pool via NAGK. Together, this work points to a mechanism of metabolic flexibility in generating UDP-GlcNAC that allows PDA cells to grow in a nutrient-poor environment.
Citation Format: Sydney L. Campbell, Clementina A. Mesaros, Tiffany Tsang, Michael Noji, Salisa Kruijning, Sophie Trefely, Luke Izzo, Ian A. Blair, Kathryn E. Wellen. Glutamine deprivation triggers hexosamine salvage in pancreatic cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C10.
Abstract C13: A “mouse hospital” for preclinical testing of diagnostic and treatment modalities in pancreatic ductal adenocarcinoma (PDA)
Authors: Clendenin Cynthia , Sor Rina , McMenamin Deirdre , Stanger Ben Z. , Beatty Gregory , Vonderheide Robert H. 
Published: March 2020

Abstract
A major challenge for cancer drug development is deciding which compounds to bring forward to clinical trials. Mouse models provide a helpful prescreening tool, but xenograft and subcutaneous models can be poorly predictive of a treatment’s efficacy against a naturally occurring tumor. Preclinical models that more accurately reproduce all the features of a tumor, including its microenvironment, may provide a more accurate readout for response to therapy. Genetically engineered mouse (GEM) models of pancreatic ductal adenocarcinoma (PDA) have been developed that exploit the fact that virtually all PDAs exhibit activating mutations in Kras (exon 12) and that over 75% have mutations in p53. These models use a pancreas-specific Cre recombinase to create mutations in Kras and p53 in the pancreatic epithelium. Tumors in these “KPC” mice recapitulate the salient clinical, histopathologic, and molecular features of the human disease. Importantly, the tumor arises in an immune-competent host. A variant of the KPC model, known as KPCY, also has a fluorescent lineage label on pancreatic epithelial cells, permitting the evaluation of a treatment’s effects on metastatic incidence or growth. Our KPC and KPCY mice are on the C57 BL/6 strain background. Alternatively, syngeneic models provide a less labor-intensive tool for evaluating the efficacy of cancer therapies in the presence of a functional immune system. The mouse hospital employs both laparotomy and a relatively new technique of ultrasound-guided injection for orthotopic implantation of a murine PDA cell line in C57 BL/6 mice. This technique is faster, less invasive, and requires less recovery time than a traditional laparotomy. The mission of the Pancreatic Cancer Mouse Hospital of the Abramson Cancer Center is to evaluate novel PDA therapies on behalf of investigators who are at the University of Pennsylvania or are collaborating with Penn investigators. Our mouse studies are designed to mimic human clinical trials, including the use of eligibility criteria and randomized treatment assignment. Ultrasound is used for screening and to measure changes in tumor in response to therapy; serial studies permit measurement of time to diagnosis and rate of tumor progression. Additional endpoints include overall survival, serum chemistries, histology, tissue collection for pharmacodynamics studies, and immune subtyping as would be performed in a human clinical trial.
Citation Format: Cynthia Clendenin, Rina Sor, Deirdre McMenamin, Ben Z. Stanger, Gregory Beatty, Robert H. Vonderheide. A “mouse hospital” for preclinical testing of diagnostic and treatment modalities in pancreatic ductal adenocarcinoma (PDA) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C13.