bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C20: Smpd3 augments chemotherapy and thwarts PDA progression
Authors: Hendley Audrey M. , Urano Atsushi , Kerper Natanya R. , Duong Phat , Bailey Peter , Chang David K. , Biankin Andrew V. , Dawson David W. , Kim Grace , Raffai Robert L. , Hebrok Matthias 
Published: March 2020

Abstract
Deregulated sphingolipid metabolism alters pancreatic cancer progression; for that reason, bioactive lipid signaling molecules such as ceramide show promise as both biomarkers for disease progression and novel therapeutic targets. Intracellular ceramide levels are critical for regulating cellular senescence, apoptosis, and cell cycle arrest in response to stress stimuli such as chemotherapeutics. Our data show Sphingomyelin Phosphodiesterase 3 (Smpd3), a regulator of ceramide synthesis and exosome biogenesis, has a protumorigenic function in pancreatic ductal adenocarcinoma (PDA). Immunodeficient mice orthotopically implanted with Smpd3-deficient PDA cell lines demonstrate significantly reduced tumor burden and longer survival when compared with controls. This observation was mirrored by our KPC; Smpd3f/f mouse model, in which loss of Smpd3 expression significantly correlated with longer survival and decreased metastasis when compared to KPC; Smpd3wt/wt controls. Analysis of SMPD3 in PDA patients revealed that low SMPD3 RNA and protein expression is significantly associated with worse survival. Because chemotherapeutics have been shown to affect expression and function of SMPD3, we stratified patient cohorts into individuals who received adjuvant chemotherapy, more than 95% of which was gemcitabine, and those who did not receive adjuvant chemotherapy. We found that high SMPD3 expression in surgically resected PDA significantly correlated with longer patient survival only in patients receiving adjuvant chemotherapy, and not in the no-adjuvant-chemotherapy group. These data suggest an interaction between adjuvant chemotherapy with gemcitabine and SMPD3 expression. Furthermore, we found that gemcitabine stimulates both the enzymatic activity and expression of SMPD3 in vitro in a panel of human PDA cell lines. Our results suggest a crucial role for SMPD3 in facilitating a protumorigenic environment during PDA progression and implicate SMPD3 as a potential novel biomarker for guiding individualized chemotherapeutic regimens for PDA patients.
Citation Format: Audrey M. Hendley, Atsushi Urano, Natanya R. Kerper, Phat Duong, Peter Bailey, David K. Chang, Andrew V. Biankin, David W. Dawson, Grace Kim, Robert L. Raffai, Matthias Hebrok. Smpd3 augments chemotherapy and thwarts PDA progression [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 C20.
Abstract C29: Development of a circulating tumor DNA assay in pancreas cancer
Authors: King Dan , Olsen Mari , Fisher George , Diehn Max , Alizadeh Ash 
Published: March 2020

Abstract
Pancreas cancer is the third most common cause of cancer-related death, owing in part to high rates of unresectable disease at time of diagnosis and poor long-term response to chemotherapy. Biomarkers are needed to sensitively identify and monitor disease burden, and to measure response to therapy. The CA19-9 tumor marker lacks sufficient positive or negative predictive value to guide treatment decisions, and digital droplet PCR (ddPCR) assessment of circulating KRAS mutations suffers poor sensitivity on account of only assessing a single DNA locus. We hypothesize that a multitargeted circulating tumor DNA assay can outperform CA19-9 and ddPCR as biomarker for the detection and monitoring of pancreas cancer. Our lab has developed the cancer personalized profiling by deep sequencing (CAPP-Seq) method, which combines high-depth sequencing with several strategies of error-suppression to identify minute amounts of tumor DNA circulating in patients’ blood. The development of our CAPP-Seq targeted sequencing panel hinged primarily on capturing regions of the genome known to be recurrently mutated in pancreatic ductal adenocarcinoma (PDAC), based on The Cancer Genome Atlas project. These regions contain mutations in KRAS, TP53, SMAD4, and by a long-tail of mutations in many other genes for which we contributed approximately 200 kb of selector space. In addition to recurrent SNVs, we also contributed approximately 35 kb for recurrent copy number variant locations, 10 kb for recurrent noncoding variants, and 20 kb for regions with aberrant expression patterns in PDAC based on TCGA RNA-sequencing data. This purpose of this study is to employ CAPP-Seq in two pancreas cancer cohorts: patients who underwent resection at Stanford and had blood drawn before and after surgical resection (n=30), and a cohort of patients with metastatic disease who are undergoing chemotherapy with blood draws at multiple time-points (n=20). The former cohort will assess prediction of recurrence based on ctDNA level, and the latter will assess patients with early development of resistance to chemotherapy. Before assessing this ctDNA detection assay in patients with pancreas cancer, we first evaluated the CAPP-Seq approach on two healthy research subjects and achieved on average 4000x de-duplicated sequencing depth, for a theoretical limit of detection of 0.03% circulating tumor fraction. We next sequenced samples from 7 patients with resectable disease and 8 with metastatic disease, with results expected in early July.
Citation Format: Dan King, Mari Olsen, George Fisher, Max Diehn, Ash Alizadeh. Development of a circulating tumor DNA assay in pancreas 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 C29.
Abstract C33: Effects of curcumin on pancreatic ductal adenocarcinoma
Authors: Vaskas Adrianna M. , Fraietta Joseph A. , Long Kristen B. 
Published: March 2020

Abstract
Without an early method of diagnosis or effective treatment plan, the prognosis for pancreatic ductal adenocarcinoma (PDAC) is grim, which begs for the development of additional treatment options. The plant-derived chemical, curcumin, has recently shown some promise as a potential therapy when tested in xenograft models of PDAC, glioblastoma, lung, breast, cervical, and colon tumors and is currently being tested in early clinical trials of certain cancers. However, efficacy studies against PDAC have not included preclinical mouse models with an intact immune system. To address the potential complication of a fully functional immune system on curcumin effectiveness, we assessed the effects of curcumin on murine PDAC cell lines both in vitro and in vivo. Murine PDAC lines were previously derived from genetically engineered KrasG12D; Trp53R172H; Pdx-1 Cre (KPC) mice, which spontaneously produce metastatic PDAC that closely mimics human disease. The dose- and time-dependent toxicity of curcumin was assessed using various cell lines in vitro, and our findings support previously published results. To assess effectiveness in vivo, tumor cells were implanted subcutaneously into syngeneic, C57Bl/6J mice. Once tumors were established, curcumin (or vehicle alone) was administered via intraperitoneal (i.p.) or intratumoral injection. Treatment efficacy was assessed by measuring tumor growth and the overall survival of mice. We found that curcumin treatment had no impact on tumor growth or overall survival of immunocompetent mice. To circumvent potential solubility issues common to curcumin and illustrate the importance of the immune system in treatment resistance, we repeated our in vivo studies using curcumin encapsulated in liposomes. In addition, we used T cell-depleting antibodies for a subset of mice to mimic athymic mice used in previously published xenograft models. T-cell depletion was verified prior to tumor cell implantation by flow cytometry. Once tumors were established, liposomal curcumin or mock treatment was administered via i.p. injection. For T cell-depleted mice, we found that treatment with liposomal curcumin stalled tumor growth and increased overall survival compared to mock treated mice. For T cell-replete mice, we found that treatment with liposomal curcumin had no impact on tumor growth or overall survival compared to mock treated mice, which agrees with our findings. Taken together, our data suggest that the presence of T cells causes a difference in responsiveness to curcumin in vivo. This finding warrants additional studies in order to understand this mechanism and enhance its potential success in the clinic.
Citation Format: Adrianna M. Vaskas, Joseph A. Fraietta, Kristen B. Long. Effects of curcumin on 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 C33.
Abstract C36: A roadmap for targeting cysteine dependency in a subset of pancreatic cancer
Authors: Nwosu Zeribe C. , Ward Matthew H. , Sajjakulnukit Peter , Zhang Li , Magliano Marina Pasca di , Lyssiotis Costas A. 
Published: March 2020

Abstract
Cysteine is a crucial amino acid for glutathione biosynthesis, which is necessary for the maintenance of cellular antioxidant defense. Recent studies have shown that cysteine deprivation induces ferroptotic cell death in cancer cells, indicating an exploitable metabolic vulnerability for cancer therapy. However, the molecular variables that underpin cysteine dependency or can be selectively targeted to mimic cysteine deprivation are largely unknown. Here, we have studied cysteine dependency using over 20 pancreatic cancer cells (~35% of which are patient-derived), by measuring cell viability upon cystine withdrawal. In addition, we measured metabolite signatures by mass spectrometry, assessed genomic profile by bioinformatic analysis and qPCR, and also analyzed protein-level expression of cystine-glutamate antiporter SLC7A11 (xCT)—a known transporter for cystine uptake. We found that pancreatic cancer cells cluster at least into three groups, namely, cysteine-independent, moderately dependent, and highly dependent cells. The highly dependent group consistently showed low intracellular cysteine, methionine, and glutamine and a high level of intermediary metabolites of glycolytic pathway. This is accompanied by a downregulation of genes involved in apoptosis, lysosomal function, and the upregulation of cell cycle gene network as revealed by altered pathway enrichment. Further, while the cysteine-independent cells express high gene and protein levels of SLC7A11, which was further upregulated upon cysteine deprivation, the highly dependent cells expressed a very low level of SLC7A11 regardless of cysteine availability. Importantly, by analyzing the cysteine-dependent cell lines, we identified several metabolic genes that are upregulated in human pancreatic cancer and predict patient overall survival (e.g., HIF1A, LDHA, SLC16A1). In conclusion, we have uncovered differential cysteine dependency and the accompanying hallmarks in pancreatic cancer cells, thus providing impetus for targeting cysteine metabolism in a specific subset of pancreatic cancer.
Citation Format: Zeribe C. Nwosu, Matthew H. Ward, Peter Sajjakulnukit, Li Zhang, Marina Pasca di Magliano, Costas A. Lyssiotis. A roadmap for targeting cysteine dependency in a subset of 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 C36.
Abstract C40: Dissecting key biologic processes in pancreatic cancer metastasis using a genetically defined 3D organoid model
Authors: Pan Fong Cheng , Chong Angie Ai-Nok , Leach Steven D. , Chen Shuibing , Evans Todd 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with a dismal 5-year survival rate of 6-8% due to its late detection and limited response to treatment (1,2). Multiple combinations of genetic alterations are frequently found in human PDAC, with KRAS activating mutation representing the main driver, followed by loss of tumor-suppressor genes CDKN2A, TP53, and SMAD4 as the disease progresses (3). 90% of PDAC patients die of metastatic disease (1); however, the cellular and molecular mechanisms involved in establishing the metastatic disease are understudied compared to those involved in tumor initiation. Owing to this, improved biologic understanding of PDAC metastasis remains warranted in order to develop effective therapeutic regimens for this disease. 3D organoid cultures derived from human and mouse PDAC tumors have recently become a model of choice to study PDAC tumorigenesis, gradually replacing more commonly used 2D cancer cell lines. Organoids maintain similar gene expression profiles as the in vivo situation when cultured in a 3D matrix, and genetic manipulation is feasible. We generated a panel of isogenic murine pancreatic intraepithelial neoplasia (PanIN) and PDAC organoids containing genetic mutations commonly found in human PDAC (KRAS, TP53, SMAD4, CDKN2A), either alone or in combination, using CRISPR-Cas9 technology. Since large-scale in vitro production of these PDAC organoids is achievable, the platform can be used for a multitude of downstream analyses in vitro and in vivo, such as drug screening and metastasis-related studies. The parental of these organoids is isolated from C57/Bl6 mice, which can be orthotopically transplanted into immunocompetent mice, and the resulting tumor recapitulates human and GEMM PDAC development. In the process of systematic characterization of these organoid lines, we found that organoids with more mutations exhibit higher proliferation rates in vitro and tumor formation rates in vivo. These organoids also showed genotype-dependent organotropism during metastatic colonization. We further used this unique tool to systematically address if each combination of tumor suppressor loss utilizes distinct molecular mechanisms to drive metastasis initiation and invasion. This will allow us to identify druggable pathways that could inhibit metastasis initiation/invasion and progression. Thus, these organoids provide a powerful platform for disease modeling and drug discovery both in vitro and in vivo.
Citation Format: Fong Cheng Pan, Angie Ai-Nok Chong, Steven D. Leach, Shuibing Chen, Todd Evans. Dissecting key biologic processes in pancreatic cancer metastasis using a genetically defined 3D organoid model [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 C40.
Abstract C47: Plasma ANP and soluble cell adhesion molecule X are novel risk factors for pancreatic cancer-associated thrombosis
Authors: Sano Makoto , Ijichi Hideaki , Ishigaki Kazunaga , Takahashi Ryota , Miyabayashi Koji , Tateishi Keisuke , Isayama Hiroyuki , Koike Kazuhiko 
Published: March 2020

Abstract
Cancer-associated thrombosis/thromboembolism (CAT) is a serious clinical complication and leads to occasional cause of death in patients with cancers, including pancreatic ductal adenocarcinoma (PDAC). However, diagnostic and inhibitory approach for CAT is still unestablished. We found that CAT with cardiomegaly and increase of plasma atrial natriuretic peptide (ANP) were frequently observed in the PDAC mice containing conditional KrasG12D mutation and knockout of TGF-β receptor type II (Tgfbr2) (PKF mice). Similar to usual thrombotic patients without cancer, high plasma level of cytokines including soluble cell adhesion molecule X was detected in the mice. Molecule-X was immunohistochemically observed in activated endothelium and thrombi. Injection of neutralized anti-molecule-X antibody reduced onset of CAT and cardiac weight in the PKF mice. Meanwhile, high plasma levels of ANP and/or molecule-X were detected in PDAC patients before and after diagnosis of CAT. Taken together, increase of ANP and/or molecule-X is a new risk factor of CAT in PDAC patients. Blocking molecule-X, at least in part, would be an inhibitory approach for CAT in PDAC.
Citation Format: Makoto Sano, Hideaki Ijichi, Kazunaga Ishigaki, Ryota Takahashi, Koji Miyabayashi, Keisuke Tateishi, Hiroyuki Isayama, Kazuhiko Koike. Plasma ANP and soluble cell adhesion molecule X are novel risk factors for pancreatic cancer-associated thrombosis [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 C47.
Abstract C49: Knockdown of FOXN2 enhances adhesion and reduces migration in pancreatic cancer cells
Authors: Santibanez Blanca , Oliveira Sabrina , Duggan Kelsie , Lu Kate , Johnson Kristen 
Published: March 2020

Abstract
FOXN2, a member of the forkhead domain binding protein family, was identified as a master regulator whose expression and activity are increased in the progression from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDA). Forkhead transcription factor proteins have been identified as essential components of both oncogenic and tumor suppressive pathways. Deregulation of FOX proteins has a direct role in cancer initiation, maintenance, progression, and drug resistance. In particular, other studies have linked FOXN2 expression to better outcomes in T-cell leukemia and glioblastoma multiforme. Additionally, recent studies indicate that FOXN2 impairs lung cancer cell proliferation in vivo and in vitro. Finally, recent studies in breast cancer cells indicate potential conflicting roles for the FOXN2 transcription factor in maintenance of cancer stem cell phenotypes and in migration and invasion. In the present study, we sought to understand the role of FOXN2 specifically in human pancreatic malignancy. Data from the TCGA database indicates that high levels of FOXN2 are associated with poor overall survival. While knockdown of FOXN2 does not significantly affect proliferation or colony formation of pancreatic cancer cells, we report that knockdown of FOXN2 in PANC-1 and BxPC-3 cells significantly enhances cellular adhesion. Additionally, FOXN2 knockdown reduces cellular invasion through collagen in transwell migration assays. Preliminary data suggest that FOXN2 may mediate some of its effects on adhesion and migration through regulation of Akt2 expression. Overall, our studies suggest that high FOXN2 expression and activity contribute to pancreatic malignancy. A better understanding of the regulation and function of the FOXN2 transcription factor should help us to uncover its potential as a therapeutic target, as well as a predictive marker for cancer.
Citation Format: Blanca Santibanez, Sabrina Oliveira, Kelsie Duggan, Kate Lu, Kristen Johnson. Knockdown of FOXN2 enhances adhesion and reduces migration 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 C49.
Abstract C53: Liver X receptor ligand targets glutamine metabolism in pancreatic cancer
Authors: Srivastava Shivangi , Widmann Scott , Lin Chin-Yo 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form of pancreatic cancer. It is predicted to become the third leading cause of cancer-related deaths by 2030. PDAC has a poor survival rate of 5 years with a 7% success rate. Current treatments include nontargeted highly toxic chemotherapeutic agents. More than 95% of PDAC patients have activating mutations of Kristen RAt Sarcoma virus (KRAS) gene, and it is known to drive metabolic reprogramming that increases cancer cell survival and resistance against the chemotherapeutic drugs. KRAS promotes noncanonical consumption of glutamine by upregulating the expression of glutaminase 1 (GLS1) enzyme. This, in turn, supports PDAC growth and survival by maintaining redox homeostasis and also by replenishing citric acid cycle intermediates. Liver X receptor beta (LXRβ), a nuclear receptor, is a ligand-dependent transcription factor that is ubiquitously expressed in all tissues. It plays an important role in maintaining cholesterol, lipid, and glucose homeostasis under normal physiologic conditions. Agonist-bound LXRβ activates the transcription of genes involved in lipogenesis, reverse cholesterol transport, and glucose metabolism. Our group has previously shown that LXRβ is expressed in PDAC tissues, and treatment with GW3965, an LXRβ agonist, reduced PDAC proliferation. However, LXRβ agonists have adverse side effects of increasing liver and circulating triglycerides. This study identified a novel ligand of LXRβ 1E5, which significantly reduced PDAC cell proliferation. 1E5 decreased the basal expression of LXRβ target genes such as sterol regulatory element-binding protein 1 (SREBP1c) and ATP binding cassette subfamily A member 1 (ABCA1). It also increased the binding of co-repressor peptides such as nuclear receptor co-repressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) to the LXRβ ligand binding domain, whereas it decreased the binding of the co-activator peptide as demonstrated by the time-resolved fluorescence energy transfer (TR-FRET) assay, thereby inhibiting the transcriptional activity of LXRβ. Therefore, 1E5 acts as an LXRβ inverse agonist. Furthermore, the metabolomics study revealed that 1E5 disrupts glutamine metabolism in PDAC cells by downregulating the glutamine, aspartate, and alpha-ketoglutarate levels in cells. Gene expression analysis showed that it significantly downregulated GLS1 expression. These results demonstrate that the novel inverse agonist is a candidate agent in the treatment of PDAC by targeting glutamine metabolism.
Citation Format: Shivangi Srivastava, Scott Widmann, Chin-Yo Lin. Liver X receptor ligand targets glutamine metabolism 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 C53.