bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C19: Impaired adaptation to negative energy balance in pancreatic cancer-associated wasting
Authors: Mendez Heike , Zhu Xinxia , Olsen Brennan , Marks Daniel L. , Grossberg Aaron J. 
Published: March 2020

Abstract
Purpose/Objectives: The disease-associated wasting condition cachexia is a common complication of pancreatic ductal adenocarcinoma (PDAC) that impacts quality of life and portends poor survival. Undernutrition is a major driver of wasting in PDAC, yet cachexia remains refractory to nutritional supplementation. By modifying nutritional challenges at different stages of cachexia development, we sought to understand the relative contributions of undernutrition and metabolic reprogramming on adipose and skeletal muscle wasting.
Materials/Methods: Adult mice received orthotopic PDAC tumor injections (KrasG12D; p53R172H/+; Pdx1-cre) or sham injections. Mice were fasted or food restricted at different times during tumor growth in a series of 2x2 factorial studies. Anthropometrics, voluntary wheel running activity, and body composition were measured throughout study. Blood glucose and ketones were measured by glucometer and ketometer. Ketogenic potential was assessed using octanoate challenge after fasting. Liver mRNA levels were measured using qPCR. Hepatic IL-6 signaling was assessed using qPCR and ELISA for plasma IL-6.
Results: PDAC mice maintained food intake and wheel running for 8 days after tumor injection, before progressive decline. Loss of adipose mass in PDAC mice occurred only in the context of decreased nutrition, whereas loss of lean mass preceded decreases in food intake. Overnight fasting mitigated differences in fat mass between groups, whereas the effect of fasting on skeletal muscle loss was similar in PDAC and control mice. Fasting blood glucose and ketogenic potential were lower in PDAC mice, suggesting impaired hepatic response to metabolic stress. In the liver, glycolytic genes were increased, whereas gluconeogenic and ketogenic genes were decreased in PDAC mice. Wasting and hepatic reprogramming occurred independently of hepatic IL-6 signaling.
Conclusions: Undernutrition drives PDAC-associated adipose wasting, yet muscle wasting occurs prior to changes in food intake and in the absence of systemic inflammation. Hepatic macronutrient partitioning and metabolic gene expression are altered in PDAC, implicating impaired adaptive responses to negative energy balance in PDAC-associated cachexia.
Citation Format: Heike Mendez, Xinxia Zhu, Brennan Olsen, Daniel L. Marks, Aaron J. Grossberg. Impaired adaptation to negative energy balance in pancreatic cancer-associated wasting [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 C19.
Abstract C21: KRAS confers resistance to mechanical compression in pancreatic cancer cells
Authors: Brittingham Gregory P. , Holt Liam J. 
Published: March 2020

Abstract
Physical pressure is fundamentally important for cancer biology, but its effects remain poorly understood. When solid tumors grow confined within surrounding tissue, they build up compressive stress. Given that cells evolved to function in a stable mechanical environment, even slight changes in pressure perturb physiology. Normal cells and early-stage cancer cells stop growing when pressure builds up. In contrast, in advanced cancer, compression can change cellular behavior to drive migration or confer resistance to chemotherapy. This difference implies that cancer cells somehow adapt to physical pressure. Pancreatic ductal adenocarcinoma (PDAC) builds the most compressive stress of any tumor because it grows in the context of a stiff fibrotic microenvironment. We have discovered that KRAS activation, present in &gt;90% PDAC, enables survival under pressure. We propose that the prevalence of KRAS mutation in PDAC is partly due to its role in adaption to the compressive microenvironment in pancreatic tumors.
Citation Format: Gregory P. Brittingham, Liam J. Holt. KRAS confers resistance to mechanical compression 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 C21.
Abstract C26: Oncogenic mechanism of soluble keratin 17 offers potential therapeutic vulnerability in pancreatic cancer
Authors: Kawalerski Ryan R. , Roa-Pena Lucia , Torre-Healy Luke A. , Boyle Taryn , Leiton Cindy V. , Snider Natasha T. , Shroyer Kenneth R. , Escobar-Hoyos Luisa F. 
Published: March 2020

Abstract
Clinical Need and Objectives: Our previous reports suggest that keratin 17 (K17), an intermediate filament (IF), is an oncoprotein and biomarker of the most aggressive and treatment-resistant form of pancreatic ductal adenocarcinoma (PDAC). Importantly, K17 transitions from its “insoluble” IF form to a “soluble” form that can regulate cell cycle progression and gene expression, though the mechanisms that mediate K17 solubilization are yet unknown. Determining these mechanisms may uncover new keratin 17-specific PDAC therapeutic vulnerabilities.
Methods and Results: We found that in human and murine PDAC models, the soluble fraction of K17 exists in the full-length form (flK17) and as a caspase-cleaved peptide (ccK17), each with potential roles as biomarkers and/or functional drivers of PDAC aggression. In a PDAC tumor mouse model and human samples, we show, independent of total K17 protein amount, that the percent of soluble and ccK17 in tumor cells is negatively prognostic. We sequenced both the soluble and cytoskeletal insoluble forms of K17 from primary PDACs using liquid chromatography mass spectrometry (LC-MS) and identified that K17 is phosphorylated on several N-terminal serine residues, some of which identify a semiconserved IF motif that may regulate caspase cleavage and solubilization. Serine phosphatase inhibition in vitro demonstrated that phosphorylation is necessary to trigger K17 solubilization followed by nuclear translocation. Mutagenesis of N-terminal serine sites demonstrated that phosphorylation of three serine residues is sufficient to solubilize K17 from its filamentous state, and that phosphorylation of K17 by a PKC-RSK signaling pathway is likely to induce solubilization. In vitro and in vivo experiments are ongoing to address the functional role of this mechanism in regulating PDAC pathogenesis.
Conclusion: Phosphorylation is an important regulator of K17 dynamics in PDAC, promoting solubilization and, in some cases, caspase cleavage. Our results suggest that soluble K17 may have a functional role in promoting tumor aggression. Inhibiting RSK or PKC kinases that phosphorylate K17 could impact tumor growth by blocking K17 solubilization/cleavage, and this line of research could accelerate the development of more effective treatments, coupled to soluble K17 testing as a predictive biomarker for PDAC.
Citation Format: Ryan R. Kawalerski, Lucia Roa-Pena, Luke A. Torre-Healy, Taryn Boyle, Cindy V. Leiton, Natasha T. Snider, Kenneth R. Shroyer, Luisa F. Escobar-Hoyos. Oncogenic mechanism of soluble keratin 17 offers potential therapeutic vulnerability 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 C26.
Abstract C38: HNF4a regulates progression and molecular subtype of pancreatic ductal adenocarcinoma
Authors: Camolotto Soledad A. , Torre-Healy Luke , Belova Veronika , Vahrenkamp Jeffrey , Berrett Kris , Stubben Chris , Gertz Jay , Moffit Richard , Snyder Eric L. 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy in which the vast majority of patients succumb to disease. Transcriptomic analysis has identified two major molecular subtypes of PDAC, classical and basal-like. The classical subtype is associated with an increased response rate to standard-of-care therapies and improved overall survival. Furthermore, classical tumors have higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor HNF4a. We now show that HNF4a expression is functionally tied to induction and maintenance of the classical subtype of PDAC. We used multiple preclinical models to investigate HNF4a in PDAC. We first used the KPC (KrasLSL-G12D/+; Trp53F/+; Pdx1-Cre) mouse model in which we deleted Hnf4a at the time of tumor initiation (KPC-Hnf4aF/F). We then derived cell lines from these HNF4a-negative mouse tumors, rescued HNF4a, and analyzed their proliferation and viability in vitro. Additionally, we used a sequential recombination strategy to derive murine PDAC organoid cultures in which Hnf4a could be deleted in vitro. Finally, in a retrospective analysis, we investigated clinical and molecular associations with HNF4a expression in PDAC patients from TCGA. Our data in genetically engineered mouse models show that loss of HNF4a causes increased tumorigenicity and decreased overall survival. In cell lines, rescue of HNF4a expression impairs proliferation and alters differentiation state. In organoid cultures, Hnf4a deletion changes the in vivo three-dimensional growth pattern, resulting in a more malignant phenotype. In all of these model systems, RNA sequencing shows that loss of HNF4a expression results in a significant loss of classical subtype gene expression. In PDAC patients, HNF4a expression was strongly correlated with classical subtype gene expression (R = .71) and was mildly associated with better survival (p = .088). Taken together, our data suggest that HNF4a is a key lineage specifier within a larger transcriptional network that regulates the growth and molecular subtype of PDAC. Thus, we anticipate that these data will advance the development of novel therapeutics that take advantage of HNF4a’s important role in the classical subtype of this disease.
Citation Format: Soledad A. Camolotto, Luke Torre-Healy, Veronika Belova, Jeffrey Vahrenkamp, Kris Berrett, Chris Stubben, Jay Gertz, Richard Moffit, Eric L. Snyder. HNF4a regulates progression and molecular subtype 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 C38.
Abstract C45: NT219, a novel bispecific inhibitor of STAT3 and IRS1/2, combined with chemotherapy or MEK inhibitor in gemcitabine-resistant pancreatic tumors, induced tumor regression
Authors: Reuveni Hadas , Kupershmidt Lana , Moskovits Neta , Solomonov Evgeny , Stemmer Salomon M , Haviv Izhak 
Published: March 2020

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, with poor outcome of current treatments. Major contributors to therapeutic resistance in PDAC include Kras mutations, a dense desmoplastic stroma, and activation of feedback signaling pathways. STAT3 and Insulin Receptor Substrate 1/2 (IRS1/2) regulate tumor survival and metastasis, the crosstalk of the tumor and its microenvironment, and play major role in drug resistance. NT219 is a novel bispecific inhibitor of IRS1/2 and STAT3, leading to IRS1/2 elimination and STAT3 dephosphorylation. The purpose of this study was to assess NT219 activity in PDAC PDX models and define schedule and regimens and combinations to overcome resistance to optimize future clinical protocols.
Methods: Patient-derived tumor xenograft (PDX) models of mutated KRAS pancreatic cancer were used to test the efficacy of NT219 in combination with gemcitabine, trametinib, and folfirinox. RNAseq was used to analyze the pharmacodynamic effect of NT219. Pharmacokinetic profile of NT219 was tested.
Results: Chemoresistent tumors of 4 PDAC PDX models were exposed to NT219 with gemcitabine demonstrated reversal of pre-existing resistance. One of these models demonstrated complete response in 5 out of 10 mice upon addition of NT219 to gemcitabine. Similar results were observed when NT219 was combined with trametinib (a MEK inhibitor) and with folfirinox (chemotherapy). There was a correlative dose-escalation response of both plasma and tumor levels and the therapeutic effect. NT219 delivered prior to gemcitabine showed a much better response than the inverse schedule/drug administration. RNAseq analysis of the tumors revealed that the combined treatment with NT219 and gemcitabine lowered the levels of IRS1 to 20% of the control group. Similar reductions were observed for STAT3-regulated genes, as well as for Ki67 (a proliferation marker), cyclin D (prognostic marker), and TGFβ (driver of epithelial to mesenchymal transition).
Conclusion: NT219 overcomes gemcitabine acquired resistance in PDAC. The combination of NT219 with modern chemotherapy in pancreatic cancer may enhance efficacy and delay acquired resistance in this fatal disease.
Citation Format: Hadas Reuveni, Lana Kupershmidt, Neta Moskovits, Evgeny Solomonov, Salomon M Stemmer, Izhak Haviv. NT219, a novel bispecific inhibitor of STAT3 and IRS1/2, combined with chemotherapy or MEK inhibitor in gemcitabine-resistant pancreatic tumors, induced tumor regression [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 C45.
Abstract C46: Establishing a living biobank of patient-derived organoids of intraductal papillary mucinous neoplasms
Authors: Reverón Dayana , Beato Francisca , DeNicola Gina , Ortiz Antonio , Centeno Barbara , Jiang Kun , Jeong Daniel , Malafa Mokenge , Hodul Pamela , Deszi Kaleena , Permuth Jennifer , Fleming Jason 
Published: March 2020

Abstract
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. There is an unmet need to develop strategies to detect pancreatic cancer at an early, operable stage and prevent its progression. Intraductal papillary mucinous neoplasms (IPMNs) are cystic pancreatic cancer precursors that comprise nearly 50% of pancreatic cysts detected incidentally via computed tomography (CT) scans. Since IPMNs can progress from low- and moderate-grade dysplasia and invasion, the study of these lesions offers a prime opportunity to develop early detection and prevention strategies. Organoids are an ideal preclinical platform to study IPMNs, and the objective of the current investigation was to establish the first living biobank of IPMN tumor organoids. IPMN tumors and adjacent normal pancreatic tissues were harvested from 15 patients undergoing pancreatic surgical resection at Moffitt Cancer Center & Research Institute (Tampa, FL) between 2017 and 2019. Following immunohistopathologic analysis of primary tissues, organoid cultures were generated, expanded, and cryopreserved. Furthermore, organoid cultures were generated from cryopreserved tissues as well. Count and size of the organoids over time was determined via the Image-Pro Premier 3D Version digital platform. Genomic characterization of the organoids was performed through DNA fingerprinting, and a subset of cases were sequenced. The success rates of organoid generation from IPMN tumor and adjacent normal pancreatic tissues were 81% and 87%, respectively. IPMN organoids derived from different IPMN subtypes tissues showed different morphologies in vitro, with the low- and moderate-grade pancreatobiliary subtypes showing the highest proliferation rates. This model has potential to provide new opportunities to unveil mechanisms of IPMN progression to invasion and to shed insight into novel biomarkers for detection and targets for chemoprevention.
Citation Format: Dayana Reverón, Francisca Beato, Gina DeNicola, Antonio Ortiz, Barbara Centeno, Kun Jiang, Daniel Jeong, Mokenge Malafa, Pamela Hodul, Kaleena Deszi, Jennifer Permuth, Jason Fleming. Establishing a living biobank of patient-derived organoids of intraductal papillary mucinous neoplasms [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 C46.
Abstract C61: Dysregulation of HNF1B/Clusterin axis enhances disease progression in a highly aggressive subset of pancreatic cancer
Authors: Yang Shouhui , Tang Wei , He Peijun , Wang Limin , Gaedcke Jochen , Ghadim B. Michael , Ströbel Philipp , Azizian Azadeh , Gaida Matthias M. , Bergmann Frank , Alexander H. Richard , Hanna Nader , Hussain S. Perwez 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is largely refractory to available treatments with heterogenous chemotherapeutic response in subsets of patients. Identifying key pathways associated with disease aggressiveness and therapeutic resistance may characterize candidate targets to improve patient outcome. We used a strategy of examining the molecular subset of PDAC patients with worst survival to understand the underlying mechanisms of disease progression and to identify candidate molecular targets with potential therapeutic significance. Non-negative matrix factorization (NMF) clustering using gene expression profile revealed three patient subsets. A 142-gene signature specific to the subset with the worst patient survival predicted prognosis and stratified patients in two clusters in a test (N=126) and validation (N=176) cohorts with significantly different survival. Gene-network and pathway analysis of the 142-gene signature revealed dysregulation of hepatocyte nuclear factor 1-B (HNF1B)/Clusterin (CLU) axis in the highly aggressive patient subset. HNF1B positively regulated CLU and a lower expression of HNF1B and CLU was associated with poor patient survival. Mechanistic and functional analyses revealed that CLU inhibits proliferation, migration, invasion, and 3D spheroid growth and epithelial-to-mesenchymal transition in pancreatic cancer cells. Furthermore, CLU enhanced sensitivity of pancreatic cancer cells, representing the aggressive patient subset, to the chemotherapeutic drug gemcitabine. Taken together, targeting HNF1B/CLU axis may attenuate disease progression with potential therapeutic implication in a subset of pancreatic cancer.
Citation Format: Shouhui Yang, Wei Tang, Peijun He, Limin Wang, Jochen Gaedcke, B. Michael Ghadim, Philipp Ströbel, Azadeh Azizian, Matthias M. Gaida, Frank Bergmann, H. Richard Alexander, Nader Hanna, S. Perwez Hussain. Dysregulation of HNF1B/Clusterin axis enhances disease progression in a highly aggressive 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 C61.
Abstract I07: Multimodal evolutionary dynamics of pancreatic cancer
Authors: Iacobuzio-Donahue Christine 
Published: March 2020

Abstract
The pancreatic cancer genome has been well annotated through multiple large-scale efforts. However, the extent to which specific genes correspond to specific subtypes of PDA or to specific patterns of failure remains a work in progress. Transcriptional subtypes of PDA have also emerged as an important variable for this disease, with classical-type and basal-like profiles now recognized as potential extremes of a range of phenotypes. We integrated evolutionary analysis and expression profiling in multiregion sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq defined basal-like subtype. In patients with coexisting basal/squamous and classical/glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical/glandular tumor. Cancers with squamous features were notable for MYC amplification. We also identify entosis, a unique form of cell competition in which one cancer cell engulfs another, as a predominant feature of squamous morphology in PDAC. Entosis is associated with profound intercellular heterogeneity for MYC copy number, suggesting a mechanistic link between MYC amplification, cell competition and the microenvironment in squamous features. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology, and genomic alterations in the context of clonal evolution of pancreatic cancer.
Citation Format: Christine Iacobuzio-Donahue. Multimodal evolutionary dynamics 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 I07.
Abstract I12: CD40 immunotherapy for pancreatic cancer
Authors: Vonderheide Robert H. 
Published: March 2020

Abstract
CD40 is a cell-surface member of the TNF receptor superfamily that upon activation can license dendritic cells (DC) to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Mechanistically, the combination of chemotherapy followed by CD40 mAb functions as an “in situ” vaccine; in addition, destruction of stroma by CD40-activated macrophages may enhance chemotherapy delivery. In a recent study sponsored by the Parker Institute of Cancer Immunotherapy of gemcitabine and nab-paclitaxel chemotherapy plus CD40 mAb APX005M, with or without PD-1 nivolumab mAb, we found the objective response rate among 30 patients with untreated, metastatic pancreatic cancer was more than 50% in the DLT-evaluable population. 13 patients experienced an AE leading to discontinuation, and 10 patients experienced a treatment-related serious AE. Two DLTs were observed, grade 3 and 4 febrile neutropenia, respectively. A three-arm randomized study of gemcitabine, nab-paclitaxel with APX005M, or with nivolumab, or with both APX005M and nivolumab has completed enrollment. Evidence to date suggests that CD40 activation is a critical and nonredundant mechanism to convert “cold” tumors to “hot” (with prominent tumor infiltration of T cells), sensitizing them to checkpoint inhibition.
Citation Format: Robert H. Vonderheide. CD40 immunotherapy for 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 I12.