bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B051: Design, synthesis, and in vitro evaluation of enedione derivatives as promising selective COPZ1 inhibitor
Authors: Martins Allana Cristina F. , Barbosa Barbara M. , Badenoch Bretton , Gomes Roberto S. 
Published: November 2022

Abstract
Pancreatic cancer is a disease with a rising incidence and low survival rate. Anticancer drugs are effective, but are not selective, leading to serious side effects, as pain, loss of taste bud, and hair loss. The available treatments are involved in target cell proliferation, but are ineffective against nonproliferating tumor cells, which could lead to a relapse. COPZ1 and its paralogous COPZ2 are involved in intracellular trafficking and autophagy. They were identified as essential for healthy and tumor cell survival. Both COPZ1 and COPZ2 are expressed in almost the same level in normal cells. Interestingly, in tumor cells, COPZ2 is downregulated. In normal cells, the simultaneous depletion of both COPZ1 and COPZ2 leads normal cells to apoptosis, but the depletion of only one of the proteins does not affect cell cycle. This fact led us to the hypothesis that tumor cells are COPZ1 dependent, and the inhibition of this protein could lead tumor cells to apoptosis selectively once COPZ2 is naturally downregulated. Once these proteins are involved in intracellular trafficking, the inhibition of COPZ1 in COPZ2-defficient tumor cells could cause Golgi apparatus collapse, block autophagy, and induce apoptosis in both proliferating and dormant cells. This suggests that the COPZ1 knockdown may suppress tumor growth selectively, making it a promising cancer therapy target. We used molecular docking, synthesis and cell biology to prove our hypothesis. To obtain the 3D structure of COPZ2 for in silico studies purpose, a homology modeling was performed using the amino acids sequence. A set of 84 molecules were submitted to molecular docking, and 4 compounds containing the active metabolite 4-aminoantipyrine and enedione fragment were selected for synthesis and in vitro evaluation. The selection was based on the interactions between the inhibitor and the amino acids within the binding site of the enzyme. Interestingly, the selected 1-4 compounds showed cellular growth inhibition of MIA PaCa-2 and AsPC-1 cell lines, but not for normal cell line. Our new drug prototypes based on 4-aminoantipyrine and enedione moieties showed quite good anti-cancer properties, therefore deserving to be considered in further studies with the aim of understanding the role of COPZ1 in tumor development, as a target for selective treatment.
Citation Format: Allana Cristina F. Martins, Barbara M. Barbosa, Bretton Badenoch, Roberto S. Gomes. Design, synthesis, and in vitro evaluation of enedione derivatives as promising selective COPZ1 inhibitor [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B051.
Abstract B063: Differential pathway engagement and the biological consequences of KRAS variants in cancer
Authors: Avilés Yanixa Quiñones , Singh Jaffarguriqbal , Li Wenxue , Kong Yong , Liu Yansheng , Muzumdar Mandar Deepak 
Published: November 2022

Abstract
KRAS is a proto-oncogene found mutated in &gt;90% of pancreatic ductal adenocarcinomas (PDAC) and encodes for a GTPase that mediates signaling transduction through the mitogen-activated protein kinase (MAPK) and PI3K/AKT pathways. Mutations in amino acids G12, G13, and Q61 prevent its inactivation by regulatory GTPase-activating proteins (GAPs), resulting in its constitutive activation. Previous work indicates that KRAS mutants possess unique biochemical differences that could result in divergent allele-specific signaling networks, underscoring unique vulnerabilities and response to treatment. Furthermore, preclinical and clinical data reveal allele-specific differences in tumor initiation capacity and patient prognosis in PDAC. Therefore, dissecting the biochemical and biological differences among KRAS variants would allow the identification of new allele-specific strategies for therapy. We hypothesize that the biochemical differences between KRAS variants result in differential signaling pathway engagement, affecting cellular behavior and tumorigenic properties. To study the biology of KRAS mutant variants in PDAC, we used CRISPR-Cas9 to generate KRAS-deficient PDAC cell lines which survived KRAS ablation through adaptive and reversible signaling rewiring. Our initial observations suggested that, at comparable expression levels, KRAS mutants diverge in their baseline signaling through the canonical MAPK and PI3K pathways. Therefore, we leveraged this unique isogenic system to uncover allele-specific differences between KRAS variants in global gene expression (by RNA-seq) and phosphoproteomic signaling networks (by data-independent acquisition mass spectroscopy; DIA-MS). We further employed a multiplexed competitive fitness approach using a sequence-based readout to assess changes in cellular fitness in response to drug perturbations (KRASi, PI3Ki, SHP2i, ERKi, RTKi and MEKi). Our findings suggest that KRAS mutants cluster into groups that diverge in downstream pathway engagement and gene expression, leading to cluster-specific differences in drug sensitivity. Our findings suggest that elucidating the signaling differences between KRAS alleles and their biological functions could translate to novel therapeutic strategies in PDAC and other KRAS mutant cancers.
Citation Format: Yanixa Quiñones Avilés, Jaffarguriqbal Singh, Wenxue Li, Yong Kong, Yansheng Liu, Mandar Deepak Muzumdar. Differential pathway engagement and the biological consequences of KRAS variants in cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B063.
Abstract B067: Genetic and pharmacological inhibition of phospholipase D1 reduces pancreatic carcinogenesis in mice
Authors: Addassi Hala A. , Mackenzie Gerardo G. 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer-related death in the United States and is characterized by its sudden manifestation, poor prognosis, high incidence of metastasis, and aggressive tumor growth. Phospholipase D1 (PLD1) is a lipid-signaling enzyme that plays a role in signaling pathways that lead to cell proliferation, survival/apoptosis as well as downstream oncogenic transformation involved in cancer progression. PLD1 activity has been shown to promote tumor progression in other cancer types, however, the role and mechanisms of PLD1 in pancreatic cancer is not yet understood. The objective of this study is to determine the role of PLD1 regulation in pancreatic carcinogenesis through genetic-ablation and pharmacological inhibition of PLD1. In this study, we crossed the LSL-KrasG12D/+;Ptf1Cre/+ (KC) mice into PLD1 knockout (Pld1-/-) mice to generate KC; Pld1-/- mice in the C57BL/6 background to examine whether PLD1 is required for pancreatic tumorigenesis. Cohorts of male and female KC and KC; Pld1-/- mice, (8-12 mice per group), were euthanized at 4 and 8 months old and the pancreas was carefully resected. At 8 months of age, there was a significant difference (p&lt;0.05) in the pancreas weight at sacrifice between the KC mice and the KC; Pld1-/- mice in a sex-dependent manner. This was due, in part, by a reduction in tumor proliferation as determined by Ki67 expression. To assess whether pharmacological inhibition of PLD could prevent pancreatic carcinogenesis in KC mice, cohorts of 9-12 male 7-month-old KC mice received daily intraperitoneal injections of a small molecule inhibitor of PLD (FIPI) at a dosage of 3 mg/kg of body weight for a duration of 5 weeks. The mice were euthanized at 8.5 months of age and the pancreas was carefully resected. Histological analysis indicated that FIPI-treated KC mice displayed less acinar cell loss compared to vehicle-treated KC controls. Moreover, treatment with FIPI significantly reduced cell proliferation (p&lt;0.01) in KC mice in comparison to vehicle-treated KC mice. In summary, these results indicate that PLD1 plays a critical role in pancreatic carcinogenesis and may represent a novel therapeutic target. Additional studies are underway to explore the cellular mechanisms of how PLD1 inhibition modulates pancreatic carcinogenesis.
Citation Format: Hala A. Addassi, Gerardo G. Mackenzie. Genetic and pharmacological inhibition of phospholipase D1 reduces pancreatic carcinogenesis in mice [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B067.
Abstract B070: Deletion of NEMO inhibits PanIN development but accelerates PanIN progression towards PDAC
Authors: Tsesmelis Miltiadis , Gerstenlauer Melanie , Manfras Uta , Barth Thomas F.E. , Maier Harald Jakob , Chan Lap Kwan , Wirth Thomas 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest types of cancer with a 5-year survival rate of less than 10%. Importantly, the canonical NF-κB pathway, which regulates critical cellular functions including inflammation, is active in the majority of PDAC cases as well as in pancreatic intraepithelial neoplasias (PanINs). Our study investigated the role of NF-κB signaling in the development and progression of PanINs and PDAC by deleting NF-κB essential modulator (NEMO), an essential protein for the activation of the NF-κB pathway. We used genetically-modified mice with pancreas-specific expression of oncogenic KRAS (KC mouse model). To blunt the canonical NF-κB pathway, KC mice were crossed to NEMO-floxed mice, allowing pancreas-specific deletion of NEMO (KNeC mouse model). The mice were injected with cerulein to promote the development of pancreatitis and accelerate the development of PDAC. Analysis of the pancreata at the time point of 8 weeks revealed that NEMO deletion reduced the infiltration of immune cells and the collagen deposition in the pancreas. However, no significant difference in the number of PanINs between the KC and KNeC mice was observed. In contrast, analysis at the time point of 10 months demonstrated that NEMO deletion drastically reduced the total number of PanINs and the field covered by desmoplasia. In addition, KNeC pancreata exhibited reduced inflammation compared to KC pancreata. Strikingly, however, NEMO deletion accelerated the progression of low-grade to high-grade PanINs and eventually to PDAC and reduced the lifespan of the mice. Mechanistically, NEMO deletion blocked the oncogene-induced senescence (OIS) that is active in low-grade PanINs. RNA-seq analysis revealed that inhibition of OIS resulted in reduced expression of the senescence-associated secretory phenotype (SASP). Finally, NEMO deletion increased the proliferation rate and the accumulation of DNA damage in precancerous lesion cells, supporting their progression to high-grade PanINs. Collectively, our study gives a mechanistic insight of the role of NF-κB in the development and progression of precancerous lesions. It underscores that NEMO exerts oncogene properties by supporting the development of new low-grade PanINs, but at the same time, it exerts tumor-suppressor properties by maintaining OIS in PanINs.
Citation Format: Miltiadis Tsesmelis, Melanie Gerstenlauer, Uta Manfras, Thomas F.E. Barth, Harald Jakob Maier, Lap Kwan Chan, Thomas Wirth. Deletion of NEMO inhibits PanIN development but accelerates PanIN progression towards PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B070.
Abstract B078: PP2A activation drives alternative EGFR activation in PDAC
Authors: Pfeffer Claire M. , Clifford Sydney J. , Hoffman Elizabeth G. , Mall Gagan K. , Baral Garima , Allen-Petersen Brittany L. 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) stands to become the 2nd most deadly cancer by 2030. Over 90% of PDAC patients have oncogenic KRAS mutations with the most prevalent being KRASG12D which have proven difficult to therapeutically target. Several studies have implicated EGFR signaling as critical for PDAC tumorigenesis in KRAS mutant tumors. Consistent with these findings, the first FDA-approved targeted therapeutic for PDAC was the EGFR inhibitor, Erlotinib. However, single agent use of Erlotinib has shown minimal efficacy in the clinic suggesting that this signaling is complex and needs further interrogation. Studies have shown the serine/threonine phosphatase, Protein Phosphatase 2A (PP2A), negatively regulates several downstream targets of EGFR and KRAS. Our previous studies using small molecule activators of PP2A demonstrate a heterogeneous response to PP2A activation, with some PDAC cell lines downregulating oncogenic signals and others maintaining the oncogenic signaling. Using pharmacological activation of PP2A, as well as overexpression and knockdown studies, we have identified a novel signaling cascade in which PP2A activation leads to increased expression and secretion of EGFR ligands and EGFR activation in a subset of PDAC cell lines. Given this unique feedback mechanism, we combined EGFR inhibitors with PP2A activation and found that the combination killed more cells than either agent alone. Together, our studies identify a novel role for PP2A in regulating EGFR signaling and support the combined use of EGFR inhibitors and PP2A activators to increase efficacy of both agents.
Citation Format: Claire M. Pfeffer, Sydney J. Clifford, Elizabeth G. Hoffman, Gagan K. Mall, Garima Baral, Brittany L. Allen-Petersen. PP2A activation drives alternative EGFR activation in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B078.
Abstract C023: A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer
Authors: Mirji Gauri , Worth Alison , Bhat Sajad , Sayed Mohamed , Kannan Toshitha , Goldman Aaron , Tang Hsin-Yao , Liu Qin , Auslander Noam , Dang Chi , Abdel-Mohsen Mohamed , Kossenkov Andrew , Stanger Ben , Shinde Rahul 
Published: November 2022

Abstract
The composition of the gut microbiome controls innate and adaptive immunity and has emerged as a key regulator of tumor growth and the success of immune checkpoint blockade (ICB) therapy. However, the underlying mechanisms remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory to therapy, including ICB. We found that the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) enhances anti-tumor immunity to PDAC. Delivery of TMAO given intraperitoneally or via dietary choline supplement to PDAC-bearing mice reduces tumor growth and is associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype and activated effector T cell response in the tumor microenvironment. Mechanistically, TMAO signals through potentiating type-I interferon (IFN) pathway and confers anti-tumor effects in a type-I IFN dependent manner. Notably, delivering TMAO-primed macrophages alone produced similar anti-tumor effects. Combining TMAO with ICB (anti-PD1 and/or anti-Tim3) significantly reduced tumor burden and improved survival beyond TMAO or ICB alone. Finally, the levels of trimethylamine (TMA)-producing bacteria and of CutC gene expression correlate with improved survivorship and response to anti-PD1 in cancer patients. Together, our study identifies the gut microbial metabolite TMAO as an important driver of anti-tumor immunity and lays the groundwork for new therapeutic strategies.
Citation Format: Gauri Mirji, Alison Worth, Sajad Bhat, Mohamed Sayed, Toshitha Kannan, Aaron Goldman, Hsin-Yao Tang, Qin Liu, Noam Auslander, Chi Dang, Mohamed Abdel-Mohsen, Andrew Kossenkov, Ben Stanger, Rahul Shinde. A microbiome-produced metabolite drives immunostimulatory macrophages and boosts response to immune checkpoint inhibitors in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C023.
Abstract C035: Biotherapeutic strategies targeting the CXCR2 axis for depletion of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma
Authors: Christopher Ben N. , Robinson Reeder , Reyes Leticia , Golick Lena , Basar Ashton , Dolloff Nathan 
Published: November 2022

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) has a 5-year survival rate of only 10%, and limited treatment options exist. Immune checkpoint inhibitors are effective in a variety of cancer types; however, the complex immunosuppressive tumor microenvironment (TME) of PDAC is a significant barrier to immunotherapy. Myeloid-derived suppressor cells (MDSCs) are abundant in PDAC tumors from humans and mouse models. MDSCs suppress effector T cell function, leading us to hypothesize that targeting tumor MDSCs would be an effective therapeutic strategy for PDAC and enhance the efficacy of T cell-based immunotherapy. Our preliminary data and the work from others shows that CXCR2 ligands such as CXCL8/IL-8, CXCL5/ENA78, and CXCL1/GROα are the most abundant soluble factors secreted by PDAC cells. CXCR2 ligands are critical for the homing of myeloid cells to sites of injury in cutaneous wound healing, suggesting that dysregulated secretion of CXCR2 chemokines in PDAC may mimic a wound healing response that attracts myeloid cells and promotes the expansion of MDSCs and an immunosuppressive TME. To test this hypothesis, we have designed multiple biotherapeutic molecules that exploit CXCL5/ENA78 and CXCL1/GROa to target and eliminate MDSCs from PDAC tumors. Specifically, we have generated Pseudomonas aeruginosa exotoxin (ExoA) and IgG-Fc fusion proteins that will be used to deliver cytotoxic payloads to MDSCs. A variety of CXCR2 knockout and knock-in models will be used to demonstrate CXCR2 dependence and elimination of MDSCs in vitro. In vivo, we are utilizing the KPC (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre) mouse model of PDAC, which we've shown in preliminary studies to, like human PDAC, support an abundance of MDSCs in tumors as well as secondary lymphoid organs such as the spleen. We anticipate that this study will demonstrate the therapeutic potential and actionability of targeting MDSCs and will provide novel biotherapeutic drug candidates that will ultimately improve immunotherapy outcomes in patients with PDAC.
Citation Format: Ben N. Christopher, Reeder Robinson, Leticia Reyes, Lena Golick, Ashton Basar, Nathan Dolloff. Biotherapeutic strategies targeting the CXCR2 axis for depletion of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C035.
Abstract C039: An EGFR-activated subset of myofibroblastic cancer-associated fibroblasts supports local metastatic dissemination in pancreatic ductal adenocarcinoma
Authors: Mucciolo Gianluca , Henríquez Joaquín Araos , Teles Sara Pinto , Manansala Judhell , Li Wenlong , Lloyd Eloise G. , Cheng Priscilla , Biffi Giulia 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and new therapies are needed. Cancer-associated fibroblasts (CAFs) can promote PDA progression and are recognized promising therapeutic targets. However, the ongoing characterization of PDA CAF heterogeneity and plasticity and the identification of potential tumor-restraining CAF populations have highlighted the need to further dissect the diverse biology of PDA CAFs to develop effective combination therapies. Using pancreatic organoid/fibroblast co-cultures and organoid-derived transplantation mouse models of PDA, we mechanistically investigated the signaling cascade downstream TGF-beta activation, which is a main driver of myofibroblastic CAF (myCAF) formation. We find that the EGFR/ERBB2 pathway is activated by TGF-beta in a subset of myCAFs, in both murine and human PDA, via amphiregulin induction and autocrine signaling. ERBB activation is important for the maintenance of this myCAF subset, with genetic and pharmacological inhibition of this pathway differentially affecting PDA CAF composition both in culture and mouse models. Importantly, analysis of lung cancer and breast cancer patient samples suggests that our observations in PDA are also relevant to these malignancies. Finally, we reveal a role of this EGFR-activated myCAF subset in promoting local metastatic dissemination in PDA and indicate new potential combination strategies. Our study highlights the need to better dissect PDA CAF heterogeneity also in populations typically considered to be tumor-restraining, in order to develop effective combination strategies for future clinical intervention. Our work also reveals how cancer-targeting therapies can directly affect the surrounding microenvironment with potential clinical implications for various malignancies.
Citation Format: Gianluca Mucciolo, Joaquín Araos Henríquez, Sara Pinto Teles, Judhell Manansala, Wenlong Li, Eloise G. Lloyd, Priscilla Cheng, Giulia Biffi. An EGFR-activated subset of myofibroblastic cancer-associated fibroblasts supports local metastatic dissemination in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C039.
Abstract C042: Deletion of Gα13 promotes inflammation in the KPC mouse model of pancreatic cancer
Authors: Shields Mario A. , Metropulos Anastasia E. , Spaulding Christina , Pham Thao ND , Munshi Hidayatullah G. 
Published: November 2022

Abstract
G protein-coupled receptor (GPCR) signaling regulates many aspects of tumor biology, including inflammation, angiogenesis, and metastasis. However, the tumor-specific functions of G proteins, immediate downstream signaling partners of GPCRs, are not well understood. Counter to previous reports in epithelial cancer cell lines, we recently showed that Gα13, a member of the G12 family of heterotrimeric G proteins, is a tumor suppressor in the genetically engineered KPC (Pdx1-Cre; KrasG12D/+; Tp53R172H/+) mouse model of pancreas cancer (Shields et al., Cell Rep, 2022). Mechanistically, we found that Gα13 loss increases mTOR signaling in mouse and human pancreas tumors and that Gα13-deficient tumors are susceptible to rapamycin. We now show that Gα13 loss in the KPC mouse model is also associated with increased expression of inflammatory cytokines. Moreover, loss of Gα13 also promotes NF-κB signaling and inflammatory cytokines expression in cerulein-driven pancreatitis. Consistently, we find that loss of Gα13 increases the recruitment of macrophages and promotes acinar-ductal metaplasia in cerulein-driven pancreatitis. In our ongoing studies, we are evaluating the role of mTOR signaling in mediating the increased inflammation seen following the loss of Gα13 in our mouse models. Together, our studies show that the tumor-suppressive function of Gα13 is related to the regulation of mTOR signaling and inflammation in pancreas cancer.
Citation Format: Mario A. Shields, Anastasia E. Metropulos, Christina Spaulding, Thao ND Pham, Hidayatullah G. Munshi. Deletion of Gα13 promotes inflammation in the KPC mouse model of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C042.