bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A080: Target genes in pancreatic cancer cells of the pan-quadruplex clinical candidate compound QN-302 revealed by comparative transcriptome profiling
Authors: Ahmed Ahmed , Arshad Tariq , Roman-Escorza Maria , Neidle Dan M. , Neidle Stephen 
Published: January 2024

Abstract
QN-302 is a tetra-substituted naphthalene derivative designed to have high affinity to quadruplexes in cancer-related genes, which have multiple quadruplex occurrence in their promoter sequences. QN-302 has ca 1 nM in vitro activity against a panel of pancreatic ductal adenocarcinoma (PDAC) cell lines and shows high activity against four distinct PDAC in vivo models, including the KPC genetic model. QN-302 is currently being developed for clinical trials in solid tumors including PDAC. It has also recently been granted orphan drug drug (ODD) status by the FDA. We have previously reported on whole-genome transcriptome studies for QN-302, which show that it selectively targets quadruplex-rich genes in PDAC-related pathways, and thus acts as a pan-quadruplex agent. We have recently extended our analysis to include two closely related analogs of QN-302 as well as data from a gemcitabine-resistant line. QN-302 is consistently ca 10-fold more potent in PDAC cells and in vivo than the second-best analog. RNA-seq whole-cell and comparative bioinformatics analyses have been used to probe these differences. This has resulted in the identification of those target genes that the naphthalene diimide family have in common, many of which are involved in PDAC pathways such as hedgehog, axon guidance, WNT/β-catenin and hippo. It has also been possible to identify a small number of quadruplex target genes that are highly and selectively down-regulated by QN-302, and which are also highly up-regulated in human PDAC. We suggest that these contribute to the exceptional in vivo potency of this compound.
Citation Format: Ahmed Ahmed, Tariq Arshad, Maria Roman-Escorza, Dan M. Neidle, Stephen Neidle. Target genes in pancreatic cancer cells of the pan-quadruplex clinical candidate compound QN-302 revealed by comparative transcriptome profiling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A080.
Abstract A092: Exploiting the neural-like properties of a new pancreatic cancer morpho-biotype for the development of a combinatorial treatment targeting tumor heterogeneity
Authors: Diaferia Giuseppe R. , Di Chiaro Pierluigi , Fiumani Francesca , Nacci Lucia , Zerbi Alessandro , Spaggiari Paola , Barozzi Iros , Natoli Gioacchino 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers in which high intra-tumor heterogeneity and plasticity makes PDAC poorly responsive to available treatments. Coupling transcriptional profiling with laser capture microdissection of groups of cancer cells defined by distinct histological patterns, we were able to describe three PDAC “morpho-biotypes”. Such morpho-biotypes represent the combined morphological, molecular and functional properties of PDAC cells that coexist, in various proportions, in nearly all patients analyzed. Compared to single cells, our approach, that integrates morphological and spatial features, was able to clearly identify a novel morpho-biotype, primed toward a neural-like lineage differentiation. Only combining the expression of those genes able to discriminate all three morpho-biotypes, we achieved high prognostic power, underscoring the relevance of the co-existence of different cancer populations for clinical assessment. We therefore hypothesize that only combinatorial therapies, that target all the different biotypes simultaneously, can result in an effective cancer treatment. We identified an antiepileptic drug to be the best candidate to interfere with the neuronal-like program we unexpectedly found enriched in one of the PDAC morpho-biotypes. Using this drug with other oncogenic inhibitors specific for the other morpho-biotypes we obtained a complete stop of the tumor progression in a mouse model of xenografted human tumor fragments that maintained tumor heterogeneity. A similar neural progenitor-like signature was recently found enriched in single cell data form neo-adjuvant treated patients. This founding indirectly suggests that the new morpho-biotype we described in treatment-naïve patients could be responsible for the failure of the available treatments. This study not only contributes to our understanding of the effects of the combinatorial treatment, but also provides valuable molecular data for development of improved treatment schemes and histological maps that can guide pathologists’ diagnosis.
Citation Format: Giuseppe R. Diaferia, Pierluigi Di Chiaro, Francesca Fiumani, Lucia Nacci, Alessandro Zerbi, Paola Spaggiari, Iros Barozzi, Gioacchino Natoli. Exploiting the neural-like properties of a new pancreatic cancer morpho-biotype for the development of a combinatorial treatment targeting tumor heterogeneity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A092.
Abstract A107: MAPK signaling is a conserved mechanism explaining phenotypic heterogeneity across diverse drivers of epithelial-mesenchymal transition in pancreas cancer
Authors: Barbeau Michelle C. , Lazzara Matthew J. 
Published: January 2024

Abstract
Epithelial-mesenchymal transition (EMT) is a developmental process that is aberrantly activated in cancers such as pancreatic ductal adenocarcinoma (PDAC) to promote disease progression and chemoresistance. EMT occurs heterogeneously among PDAC ductal cells, which frustrates efforts to identify the underlying signaling regulatory mechanisms. We hypothesize that cell-to-cell variation in the activities of specific signaling pathways explains EMT heterogeneity. To test this, we developed a workflow integrating: 1) iterative indirect immunofluorescence imaging (4i) to quantify the activities of up to seven purported EMT-regulating pathways with single-cell resolution and 2) a multivariate mutual information computational model to predict the pathways that are most informative of the EMT phenotype. In cultured PDAC cells, EMT was induced by treating cells with growth factors present in the tumor microenvironment (hepatocyte growth factor, epidermal growth factor, transforming growth factor β1, or two combinations) or with chemotherapeutics (gemcitabine or 5-fluorouracil). EMT phenotypic markers and signaling pathway proxies were assessed daily for up to 96 hr. A mutual information analysis of the aggregated data identified ERK as the most important signaling node explaining EMT heterogeneity across the diverse set of agonists investigated. Kinase inhibition and siRNA studies confirmed the implied role of ERK but also revealed a compensatory, EMT-driving JNK activation in the context of MEK inhibition that explains a cooperative effect of simultaneous MEK and JNK inhibition on EMT antagonism. Importantly, a model based on cell population-level measurements nominated JNK as more informative than ERK for determining EMT state in response to growth factors. We are implementing this approach in vivo using pancreas cancer tissue sections to determine generalizability of these findings in different microenvironmental contexts. Overall, our results demonstrate the pervasive importance of ERK for diverse drivers of EMT and the need to account for the effects of heterogeneous signaling pathway activation in the determination of EMT.
Citation Format: Michelle C. Barbeau, Matthew J. Lazzara. MAPK signaling is a conserved mechanism explaining phenotypic heterogeneity across diverse drivers of epithelial-mesenchymal transition in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A107.
Abstract A115: Collective invasion facilitates liver metastasis in pancreatic ductal adenocarcinoma
Authors: Eng Jennifer R. , Pelz Carl , Chin Koei , Sivagnanam Sam , Jason Link M. , Keith Dove , Coussens Lisa , Sears Rosalie C. 
Published: January 2024

Abstract
Fifty percent of PDAC patients present with distant metastasis and face a dismal prognosis of 8 to 11 months. However, patients with lung metastases have better prognosis than patients with metastatic spread to other sites. In our PDAC metastasis cohort, patients with lung-only metastasis survived longer than patients with liver metastasis, despite sharing the same tumor subtype. To understand features of the primary tumor linked to metastatic site, we generated a novel gene signature for primary organotropism (pORG) that distinguishes primary tumors that developed liver metastasis from those that developed lung metastasis, independent of known tumor subtypes. Our pORG signature predicts survival independently of transcriptional subtype, genetic alterations and clinicopathological variables and in a validation cohort consisting of TCGA pancreatic cancer. Primary tumors with high pORG scores, i.e., liver-tropic primaries, have increased transcriptomic signatures of proliferation and replication stress whereas low pORG tumors have increased lymphocyte gene expression. To validate our findings, we generated cyclic immunofluorescence multiplex imaging data from 34 primary tumors. As anticipated, single cell image analysis revealed high B and T cell infiltration in low-pORG tumors, and increased proliferation and replication stress foci in high-pORG tumors. Intriguingly, malignant cells from high pORG tumors had an increased fraction KRT19-high tumor cells relative to low pORG tumors and were distinctly epithelial in appearance. To reconcile the metastatic behavior of high pORG tumors with their apparent enrichment for epithelial-state cells, we hypothesized that liver-tropism was associated with a partial epithelial-to-mesenchymal transition (EMT) state and metastasis via collective invasion. Bulk transcriptional analysis of 200 PDAC primary tumors revealed a distinct subset of high pORG tumors have increased expression of markers linked to partial EMT and collective invasion, including RAB11a, Rho-like GTPases, and proteases MMP7 and KLK7. Our results support a model of E-cadherin internalization facilitating partial EMT and collective invasion. Current efforts include in-vitro characterization of migration modes in patient-derived cell lines and organoids. Our work suggests unique and targetable tumor intrinsic features linked to organotropism in PDAC.
Citation Format: Jennifer R. Eng, Carl Pelz, Koei Chin, Sam Sivagnanam, Link M. Jason, Dove Keith, Lisa Coussens, Rosalie C. Sears. Collective invasion facilitates liver metastasis in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A115.
Abstract B009: Identifying of a novel diagnostic markers for pancreatic neuroendocrine tumors by proteomics with patient blood
Authors: Koh Eun-Young , Jeong Ji Hye , Ahn Hee-Sung , Kim Kyunggon , Jun Eunsung 
Published: January 2024

Abstract
Neuroendocrine tumors are tumors originating from endocrine cells in various organs, and present very heterogeneous characteristics, and the incidence rate is gradually increasing. Among them, neuroendocrine tumors originating from pancreas are divided into functional tumors and non-functional tumors according to the presence hormone secretion function. Since non-functional tumors are often asymptomatic, early diagnosis is not easy, and differential diagnosis from pancreas ductal adenocarcinoma (PDAC) is difficult, making it difficult to determine the direction of treatment. Therefore, we aimed to find protein biomarkers for the diagnosis and differential diagnosis of pancreatic neuroendocrine tumors (PNET) through proteomic analysis of human blood. First, a total of 60 human plasma samples were obtained from 17 PNETs, 23 PDACs, and 20 Healthy donors (HD), and liquid chromatography-mass spectrometry (LC-MS) proteomics analysis was performed. For 60 cases of raw data obtained through LC-MS analysis, identification and label-free quantification were performed through the Human swissprot protein sequence database. Through pre-processing and normalization, an average of 549 protein lists for each sample were obtained. And through quantitative evaluation, the proteomes that were increased or decreased for each disease were analyzed and classified, and ACTR3, CD163, and LECT2, which were increased in PNET, were selected as diagnostic biomarker candidates. The diagnostic AUC for distinguishing PNET from HD was 0.706 for ACTR3, 0.971 for CD163, and 0.541 for LECT2. The diagnostic AUC to distinguish PNET from PDAC was 0.821 for ACTR3, 0.870 for CD163, and 0.783 for LECT2. We selected three candidates, ACTR3, CD163, and LECT2, as blood biomarkers for the accurate diagnosis of PNET. And through the combination of markers, it is expected that the sensitivity and accuracy of the diagnosis can be further increased. In the future, we will study the function as a marker that can simultaneously predict diagnosis and treatment response by identifying the molecular biological mechanism for the generation and progression of PNET through these three markers.
Citation Format: Eun-Young Koh, Ji Hye Jeong, Hee-Sung Ahn, Kyunggon Kim, Eunsung Jun. Identifying of a novel diagnostic markers for pancreatic neuroendocrine tumors by proteomics with patient blood [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B009.
Abstract B025: IL-1 blockade prevents cardiac toxicity and improves immunotherapy efficacy in mouse models of pancreatic cancer
Authors: Talele Nilesh P. , Kumra Heena , Gomes-Santos Igor L. , Roberge Sylvie , Ho William W. , Andersson Patrick , Chatterjee Sampurna , Siwicki Marie , Duda Dan G. , Pittet Mikael J. , Fukumura Dai , Jain Rakesh K. 
Published: January 2024

Abstract
Background: Immune checkpoint blockers (ICBs) have revolutionized cancer treatment, but they are often associated with severe immune related adverse events (irAEs). These severe irAEs are more often seen in patients with obesity or concomitantly treated with cytotoxic therapies. Methods: We aimed to understand the mechanisms of ICB-induced irAEs, in the context of obesity and ICB/chemotherapy combinations. We developed a mouse model of cardiac irAEs, which is the most fatal type of irAE in ICB-treated cancer patients, with clinically relevant features: (i) an ICB-resistant cancer (pancreatic ductal adenocarcinoma or PDAC), (ii) obesity induced with high-fat diets, and (iii) a combination treatment of ICB (α-PD1 + α-CTLA4) and chemotherapy (FOLFIRINOX). Results: Our FDA and single institution retrospective analyses indicate that patients treated with ICB had greater relative risk of developing myocarditis as compared to other anti-cancer therapies. Mice with orthotopic PDAC and obesity developed irAEs after treatment with ICB and chemotherapy as compared to chow diet. These irAEs recapitulated those observed in patients with cancer and obesity, including cardiac dysfunction consistent with myocarditis, cardiac fibrosis, and increased circulating levels of interleukin-1 beta (IL-1b). IL-1β blockade prevented myocarditis and reduced cardiac fibrosis after immunotherapy. Importantly, IL-1β blockade also enhanced the anti-tumor effects of ICB + FOLFIRINOX combination therapy, and increased mouse survival. Conclusions: We developed a translationally relevant 'triple hit' mouse model and discovered that IL-1β mediates ICB-induced cardiotoxicity. In addition, we found that IL-1β blockers, which are already used in the clinic for cardiology indications, both reduce adverse events and simultaneously enhance the antitumor effects triggered by immunotherapy.
Citation Format: Nilesh P. Talele, Heena Kumra, Igor L. Gomes-Santos, Sylvie Roberge, William W. Ho, Patrick Andersson, Sampurna Chatterjee, Marie Siwicki, Dan G. Duda, Mikael J. Pittet, Dai Fukumura, Rakesh K. Jain. IL-1 blockade prevents cardiac toxicity and improves immunotherapy efficacy in mouse models of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B025.
Abstract B033: Tumor cell-intrinsic mPGES-1-PGE2-EP4 signaling is a major immunosuppressive pathway in pancreatic cancer
Authors: Markosyan Nune , Kim Il-Kyu , Arora Charu , Quinones Liz , Cheng Noah , Stanger Ben Z. , Vonderheide Robert H. 
Published: January 2024

Abstract
Pancreatic adenocarcinoma (PDA) is the 4th leading cause of cancer-related deaths in the US partly because of its resistance to conventional chemotherapies. Immunotherapies that improve survival in many cancers, almost universally fail in PDA. The resistance to immune checkpoint blockade is at least partially explained by the lack of T cells in the tumor microenvironment (TME) in PDA. As demonstrated previously, tumor cell-derived prostaglandin E2 (PGE2) is one of the tumor intrinsic factors that creates/supports immunosuppressive TME in PDA. The current study investigates how depleting tumor cell-derived PGE2 or disrupting its autocrine signaling through the cognate EP4 receptors on tumor cells reverses the T cell low, myeloid cell rich PDA TME and suppresses the tumor growth. Pharmacological blockade of EP4 receptors combined with anti-PD-1 and agonistic CD40 antibodies induced complete tumor regressions with a lasting vaccine effect. Knockout (KO) of Ptges, the gene encoding PGE2 synthesis enzyme mPGES-1, or EP4 receptor gene, Ptger4, in KrasG12D/P53R172H/Yfp/PdxCre (KPCY) pancreatic tumor cells was sufficient to abolish the growth of implanted tumors (p&lt;0.0001 both). The rejection of the primary KO and rechallenge control tumors was T cell-dependent as it did not happen in hosts depleted of CD4+ and CD8+ T cells. Both KO tumor cells were more susceptible to TNF-a killing while their TMEs were enriched with central memory T cells and phagocytic macrophages and depleted of granulocytic myeloid-derived suppressor cells (gMDSC). Further analysis of Ptger4 tumors revealed changes in CCL2, CXCL9, and GM-CSF production probably causing the changes in TME. In addition, in both Ptges and Ptger4 KO tumors, the adenosine synthesis pathway was significantly downregulated probably due to decreased TGF-b signaling in tumor cells. When cultured ex vivo in hypoxic conditions, Ptger4 KO tumors made significantly less immunosuppressive adenosine (p&lt;0.001). Consequently, 57% of Ptger4 KO tumors in adenosine deaminase inhibitor treated hosts accumulated enough adenosine to suppress the anti-tumor immune response and grow out. The study demonstrates a primary role for the tumor cell-intrinsic mPGES1-PGE2-EP4 signaling in creating immune-suppressive TME in PDA, suggesting EP4 blockade as a novel approach in the treatment of pancreatic cancer.
Citation Format: Nune Markosyan, Il-Kyu Kim, Charu Arora, Liz Quinones, Noah Cheng, Ben Z. Stanger, Robert H. Vonderheide. Tumor cell-intrinsic mPGES-1-PGE2-EP4 signaling is a major immunosuppressive pathway in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B033.
Abstract B053: Physical activity regulates targetable transcriptomic changes in the adipose tissue of obese PDAC mice
Authors: Hsueh Hsiang-Yin , Pita-Grisanti Valentina , Vélez-Bonet Ericka , Cao Lei , Huang Wei , Cruz-Monserrate Zobeida 
Published: January 2024

Abstract
Background: Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a highly aggressive cancer with a low 5-year survival rate. The association between obesity and PDAC could be attributed to the inflammatory effects of obesity and its impact on the adipose microenvironment. Physical activity (PA) is a potential approach to counteract obesity and its associated inflammation. Moreover, a recent study revealed that exercise-induced interleukin (IL)-15 in tumors has an anti-tumor response. However, there is still limited understanding of the mechanisms underlying how PA impacts the adipose-tumor microenvironments in PDAC. In this study, we hypothesized that PA could upregulate anti-inflammatory signaling in the adipose tissue and that targeting some of these signaling pathways could be a novel therapy for obesity-associated PDAC. Methods: Transcriptomic analysis was performed on adipose tissue obtained from a genetically engineering mouse model of obesity-associated PDAC. The mice were fed an obesogenic high-fat diet and divided into groups with and without PA intervention for one month. An adipose-specific recombinant adeno-associated vector (rAAV) was generated and mouse IL-15 cDNA was subcloned into the vector. C57BL/6J mice were administered intraperitoneal injections of either the rAAV/empty or rAAV/IL-15 vectors. Three weeks after rAAV intraperitoneal injection, mice were orthotopically injected with mouse KRasG12D/Trp53−/−/PDX-1-CRE cells expressing firefly luciferase to monitor growth in vivo and expression of IL-15 in the adipose tissue was confirmed via qPCR. Results: PA intervention increased the expression of genes related to metabolic and inflammation-related pathways. The administration of a novel adipose-targeted rAAV resulted in the upregulation of IL-15 within the adipose tissue and not the tumor. Increasing IL-15 expression in the adipose tissue led to a notable delay in tumor growth in an orthotopic mouse model. Conclusions: Here, we show that PA modulates gene expression in the adipose tissue and the beneficial impact of adipose tissue molecular remodeling on anti-tumor effects. However, more studies are needed to characterize the full extent of the adipose-tumor interactions and how they can be effectively targeted for therapeutic interventions.
Citation Format: Hsiang-Yin Hsueh, Valentina Pita-Grisanti, Ericka Vélez-Bonet, Lei Cao, Wei Huang, Zobeida Cruz-Monserrate. Physical activity regulates targetable transcriptomic changes in the adipose tissue of obese PDAC mice [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B053.