bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A079: The quadruplex-binding compound QN-302 in the MIA-PaCa2 pancreatic adenocarcinoma model shows no evidence of cardiac or neurological liabilities at therapeutic doses
Authors: Ahmed Ahmed , Arshad Tariq , Neidle Stephen 
Published: November 2022

Abstract
The human genome contains multiple sites of quadruplex (G4) arrangements, with over-representation in promoter regions of many oncogenes. Small molecule G4 stabilization down-regulates the transcription of these genes, leading to selective inhibition of cancer cell growth and anti-tumor activity. We have developed a number of novel G4-binding small molecules. QN-302, the most potent, has significant in vivo activity in animal models for pancreatic cancer and is currently in pre-clinical development with Qualigen Therapeutics. The effects of QN-302 have been examined on (1) a panel of cardiac function receptors, (2) heart rate in vivo, and (3) on the histopathology of organs from treated animals. QN-302 was initially screened in a series of in vitro industry-standard CEREP receptor binding assays. The few apparent indications of significant receptor binding were examined in vivo by means of ELISA assays. Cardiac function was examined using a cardiac heart-beat monitor attached to animals treated with QN-302 and compared to animals dosed with a vehicle control. QN-302 gave negative results in CEREP assays, apart from micromolar inhibition of acetylcholinesterase (ACE) and muscarinic (MUSC) receptors. There was no significant hERG receptor inhibition. There was no significant inhibition of ACE and MUSC receptors in vivo. Heart rate experiments, run at both the proposed therapeutic dose of 1mg/kg and at elevated levels, did not show significant deviations from values for the vehicle control arm. Histopathology of heart, liver and brain tissues from QN-302 treated animals, did not show any deleterious effects from the drug. The lack of effects on ACE and MUSC receptors in vivo, together with the absence of effects on heart, liver and brain tissue from treated animals and the normality of heart rate during treatment, demonstrate that treatment of MIA-Paca2 tumor-bearing mice with QN-302 does not have a cardio-, nephro- or neurotoxic burden at therapeutic doses. QN-302 is bio-available at therapeutic doses and is currently in pre-clinical development with Qualigen Therapeutics Inc
Citation Format: Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The quadruplex-binding compound QN-302 in the MIA-PaCa2 pancreatic adenocarcinoma model shows no evidence of cardiac or neurological liabilities at therapeutic doses [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 A079.
Abstract B003: Pancreatic cancer cells activate arginine biosynthesis to adapt to myeloid-driven amino acid stress in the tumor microenvironment
Authors: Saab Juan J. Apiz , Dzierozynski Lindsey N. , Jonker Patrick B. , Zhu Zhou , Chen Riona N. , Oh Moses , Sheehan Colin , Macleod Kay F. , Weber Christopher R. , Muir Alexander 
Published: November 2022

Abstract
Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs to maintain survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors. We have used this information to develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling study of PDAC metabolism under physiological nutrition. By transcriptomic analysis, we show that PDAC cells cultured in TIFM, compared to standard culture models, adopt a cellular state more similar to PDAC cells in tumors. Using the TIFM model, we then identified arginine biosynthesis as a critical metabolic adaptation PDAC cells engage to cope with microenvironmental nutrition. We further find that arginine biosynthesis enables PDAC cells to cope with microenvironmental arginine starvation, which we show is driven by myeloid cells in PDAC tumors. Altogether, these data show that nutrient availability in the microenvironment is an important determinant of PDAC metabolism and behavior, and models incorporating tumor nutrition enable detailed and mechanistic study of microenvironmentally-programmed PDAC cell states and phenotypes. Further, through use of the TIFM model, we identified both myeloid-driven arginine starvation as a major metabolic stress prevalent in the PDAC microenvironment, and the metabolic adaptations PDAC cells use to counter this nutritional challenge.
Citation Format: Juan J. Apiz Saab, Lindsey N. Dzierozynski, Patrick B. Jonker, Zhou Zhu, Riona N. Chen, Moses Oh, Colin Sheehan, Kay F. Macleod, Christopher R. Weber, Alexander Muir. Pancreatic cancer cells activate arginine biosynthesis to adapt to myeloid-driven amino acid stress in the tumor microenvironment [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 B003.
Abstract B007: Enhancing autophagy inhibition as a therapeutic strategy for pancreatic cancer
Authors: DeLiberty Jonathan M. , Robb Ryan , Gates Claire E. , Pieper Noah L. , Yang Runying , Stalnecker Clint A. , Bryant Kirsten L. 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth. We determined the role of mutationally activated KRAS, found in ~95% of PDAC, in supporting autophagy. Surprisingly, acute KRAS suppression was associated with increased autophagic flux. Pharmacologic inhibition of ERK MAPK phenocopied the genetic silencing of KRAS and increased autophagic flux. We speculated that the loss of ERK-driven metabolic processes may induce compensatory mechanisms to increase autophagy. We then addressed whether ERK inhibition increased PDAC dependence on autophagy. Supporting this possibility, we found that cotreatment with the autophagy inhibitor chloroquine (CQ) synergistically enhanced ERK inhibitor-mediated anti-proliferative activity. Our findings, together with similar observations by others, provided the rationale for our initiation of Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT04132505) or ERKi (LY3214996; NCT04386057) with hydroxychloroquine (HCQ) in PDAC. Our ongoing studies are centered on developing additional combinations for targeting autophagy. First, we performed a CRISPR/Cas-9 mediated genetic loss-of-function screen in the presence of CQ to determine additional sensitizers as well as mediators of resistance to autophagy inhibition. Top sensitizers included multiple facilitators of the DNA damage response, mTOR pathway components, and genes involved in the upstream regulation of the autophagy pathway. Second, we determined that autophagic signaling is temporally regulated following RAS pathway inhibition and hypothesize that further dissection of this regulation will improve current anti-nutrient scavenging treatment strategies. We conclude that concurrent suppression of multiple metabolic processes, to block compensatory rebound activities, will be needed for effective PDAC treatment.
Citation Format: Jonathan M. DeLiberty, Ryan Robb, Claire E. Gates, Noah L. Pieper, Runying Yang, Clint A. Stalnecker, Kirsten L. Bryant. Enhancing autophagy inhibition as a therapeutic strategy for 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 B007.
Abstract B019: Inflammatory response to dietary carbohydrates contributes to the formation of hepatic metastatic niche
Authors: Surumbayeva Aizhan , Williams Riley , Kotliar Michael , Taylor Maryclare , Costa Débora B. Vendramini , Ogier Charline , Restifo Diana , Cai Kathy Q. , He Xueyang , Boutz Paul , Balachandran Siddharth , Astsaturov Igor 
Published: November 2022

Abstract
Mortality from colon and pancreatic cancers arises from cancer metastatic dissemination to the liver. The glycemic load from carbohydrates (carbs) has been specifically linked to the risk of metastatic recurrence of stage 3 colorectal cancer, but the mechanism of how dietary carbs contribute to the formation of liver metastases remains poorly understood. Our analyses now demonstrate that feeding mice a high carb diet (HCD) promotes liver colonization by tumor cells, and supports the survival of these cells, once in the liver. HCD also induces expression of a Type I interferon (IFN) inflammatory gene signatures which may contribute to its ability to promote metastatic seeding of the liver. Notably, this inflammatory phenotype in hepatocytes was completely abolished if animals are fed a diet enriched in fats (75% of calories), indicating a direct link between liver inflammation and consumption of carbohydrates. Specifically, we have discovered that: 1) dietary carbohydrates, but not a high-fat ketogenic diet, activate multiple independent inflammatory cascades in hepatocytes, including Type-I IFN/STAT1, NFkB, and IL6-STAT3 pathways; 2) the inflammatory signaling in hepatocytes is retained in Scid and NSG mice, indicating that it occurs in the absence of adaptive immunity; 3) HCD, but not fasting or ketogenic diet, markedly increases abundance of retained intronic sequences and formation of double-stranded RNA (dsRNAs). We nominate these yet uncharacterized dsRNAs as potential viral mimics which may trigger the Type I IFN signature observed in HCD-fed livers; and (4) a ketogenic diet showed a trend to reduce liver metastatic colonization, but was associated with mild hepatic steatosis. Overall, this study establishes a new paradigm in nutrient sensing by normal hepatocytes and nominates alternative RNA splicing as the potential trigger of inflammatory responses to HCDs via accumulation of dsRNAs. We suggest that a reduction of dietary carbohydrates, by suppressing the diet-induced hepatic inflammation, will improve the survival of cancer patients, and reduce the risk of liver metastases.
Citation Format: Aizhan Surumbayeva, Riley Williams, Michael Kotliar, Maryclare Taylor, Débora B. Vendramini Costa, Charline Ogier, Diana Restifo, Kathy Q. Cai, Xueyang He, Paul Boutz, Siddharth Balachandran, Igor Astsaturov. Inflammatory response to dietary carbohydrates contributes to the formation of hepatic metastatic niche [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 B019.
Abstract B045: Evaluating the role of altered RNA metabolism in pancreatic cancer therapy resistance
Authors: Siraj Md Afjalus , Shan Xinning , Tseng Robert , Escobar-Hoyos Luisa 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinomas (PDACs) are highly lethal, mostly because they quickly develop resistance to current chemotherapies: Gemcitabine (GEM)/paclitaxel or cocktail FOLFIRINOX. Both chemotherapies rely on nucleoside analogues (GEM and 5-fluorouracil [5-FU], and resistance is developed without acquiring mutations, suggesting the role of non-mutational mechanisms for therapy resistance. Our recent findings demonstrated that PDACs depend on RNA splicing proteins to maintain tumors and are exquisitely susceptible to a range of therapies directed at RNA splicing, supporting the role of aberrant RNA splicing in PDAC therapy resistance. Here we evaluated the role of altered RNA splicing in PDAC therapy resistance. Three murine and human isogenic lines with either sensitivity or resistance to GEM were developed. We performed deep RNA sequencing (RNASeq, 80-100 million reads, traditional is 20-40 million reads), differential gene expression, and splicing analyses. GEM resistant PDAC cells demonstrated &gt;40% of non-canonical RNA splice variants and altered expression of 30% of RNA-binding proteins encoded in the human/murine genome, compared to GEM sensitive ones. Specific alternatively spliced exons with common cis-elements were identified in therapy resistant cells, suggesting that these splicing changes are guided by a splicing factor or other RNA-binding protein(s) (RBPs). Top splicing changes were associated to mRNAs encoding ether lipid and pyruvate metabolism. This finding is important as previous studies have linked these metabolic pathways to therapy resistance, however, they have overlooked if protein isoforms, resulting from aberrant splicing, have different impacts in therapy resistance. In addition, GEM and H3B-8800, a novel spliceosome inhibitor showed higher synergistic activity in GEM resistant PDAC cells compared to GEM sensitive cells, suggesting that the development of resistance in PDAC is highly dependent on RNA splicing. Combinedly, these data strongly suggest that resistance to chemotherapeutic agents in PDAC cells requires altered RNA splicing and aberrant expression of associated proteins. Further investigation is ongoing to identify the splicing events and RBPs related to chemotherapy resistance, which will uncover novel mechanisms of therapy resistance and therapeutic modalities by targeting RNA splicing in pancreatic cancer.
Citation Format: Md Afjalus Siraj, Xinning Shan, Robert Tseng, Luisa Escobar-Hoyos. Evaluating the role of altered RNA metabolism in pancreatic cancer therapy resistance [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 B045.
Abstract B046: Restricted cellular plasticity of human pancreatic ductal cells into a pluripotent state
Authors: Grygoryev Dmytro , Ekstrom Taelor , Link Jason M. , Sears Rosalie C. , Kim Jungsun 
Published: November 2022

Abstract
Cancer cells undergo plasticity against stress for the survival of the fittest. Pancreatic ductal adenocarcinoma (PDAC) also shows intratumoral transcriptional heterogeneity with cell plasticity, which correlates with phenotypical aggressiveness and therapeutic resistance. Cell fates are determined by master transcription factors (TFs, also called “pioneer factors”) and their co-factors by opening up chromatin and establishing competence for gene expression specific to each cell type during normal development. Force expression of various combinations of pioneer factors can switch cell fate into other lineages, including induced pluripotent stem cells (“iPSC”). Since pluripotent stem cells do not have the cancer hallmarks of uncontrolled cell growth and migration, hypothetically, a fully reprogrammed cancer iPSC should regain gene programs to control these hallmarks of cancer. Thus, we and others have reprogrammed cancer cells into pluripotent stem cell-like cells by introducing pluripotent pioneer factors. However, intriguingly, despite the nature of the high plasticity of cancer, complete reprogramming of cancers to a pluripotent state is impeded in most cases, enabling us to study and model cancer progression. Our further studies confirm that, upon reprogramming, most PDAC cells lose the original PDAC phenotypes to some extent but remain in plasticity states during reprogramming. Herein, we further update on our efforts to optimize the reprogramming of normal pancreatic ductal epithelial cell line (PDEC) and PDAC derived from patients through the Sendai virus, which can most robustly transfer genes regardless of cell types. While control cells (e.g., acinar cells and fibroblast) were fully reprogrammed into iPSC cells, both PDEC and PDAC were impeded from being fully reprogrammed into pluripotency. Intriguingly, a subset of normal PDEC cells as well as some PDAC cell acquired a “partial reprogramming marker” upon reprogramming, suggesting that PDEC cells are stalled in early developmental states. Therefore, we now conclude that normal and cancerous pancreatic ductal cell states have an intrinsic mechanism that blocks complete reprogramming into a pluripotent state, and the oncogenic pathway is poised for activation, despite the nature of the high plasticity of PDAC. Identifying the factors responsible for maintaining this impenetrable cancer chromatin landscape is ideal for nominating therapeutic targets for intercepting PDAC plasticity. This work is supported by OHSU/CEDAR project award 68182-939-000.
Citation Format: Dmytro Grygoryev, Taelor Ekstrom, Jason M. Link, Rosalie C. Sears, Jungsun Kim. Restricted cellular plasticity of human pancreatic ductal cells into a pluripotent state [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 B046.
Abstract B060: Investigating the role of ERphagy in pancreatic cancer
Authors: Vogt Sandra L. , Bar-Sagi Dafna 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) harbors mutations in KRAS in greater than 90% of cases and is characterized by a dense, fibrotic stroma that fosters the formation of a hypoxic, nutrient-poor tumor microenvironment. Tumor cells counteract these stresses through the hyperactivation of multiple nutrient scavenging pathways, including macropinoytosis and macroautophagy. Whereas the role of the latter in the regulation of PDAC growth has been extensively studied, much less is known about the role of endoplasmic reticulum (ER)-specific autophagy (ERphagy), a homeostatic mechanism involving ER membrane remodeling which promotes the clearance of misfolded protein aggregates, thereby supporting proteostasis. Using an ERphagy reporter system, we found that pancreatic cancer cells display mutant KRas-dependent suppression of ERphagy both at baseline and in the context of nutrient deprivation, which was partially dependent on the ER-resident receptor CCPG1. Furthermore, direct perturbation of the 26S proteasome with bortezomib enhanced ERphagy, suggesting that the attenuated ERphagy capacity in pancreatic cancer cells may reflect a greater dependence on proteasomal activity for the maintenance of proteostasis. Significantly, the knockdown of CCPG1 but not other ERphagy receptors augmented the growth-suppressive effects of bortezomib in vitro, an effect likely caused by unresolved proteotoxic stress. Overall, our findings implicate CCPG1-mediated ERphagy in pancreatic cancer cell survival and identify a targetable cell-intrinsic vulnerability that can potentiate the cytotoxic effects of bortezomib, which alone is clinically ineffective in treating PDAC.
Citation Format: Sandra L. Vogt, Dafna Bar-Sagi. Investigating the role of ERphagy 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 B060.
Abstract B079: Unfolding the role of cell state on stress granule heterogeneity and function in pancreatic cancer
Authors: Redding Alexandra , Fonteneau Guillaume , Grabocka Elda 
Published: November 2022

Abstract
Phenotypic and functional heterogeneity is a common feature of cancer cells that poses as a major therapeutic challenge. Previous work has implicated the phase-separation organelles, stress granules (SGs), as important mediators of tumorigenesis that function as a mutant KRAS-driven stress-adaptive mechanism to enhance cellular fitness. We have found that mutant KRAS pancreatic cancer cells show a high degree of intra-cellular heterogeneity in SG formation, ranging from no SGs to markedly high levels. Given the function of SGs in cancer cell fitness and the role of cancer cell heterogeneity in tumor progression and therapeutic response, we sought to understand the determinants of SG heterogeneity and its role in KRAS-driven tumorigenesis. Here, we show that the capability of KRAS mutant pancreatic cancer cells to form SGs is dependent on the cell cycle state, with cells in G2 phase showing markedly enhanced SG formation. We demonstrate that this heterogeneity in SG formation is determined by a cell cycle specific interplay between the activator of cell death, Caspase 3, and the SG regulator molecule 15-deoxy-delta-12,14-prostaglandin J2 (15-d-PGJ2). We show that 15-d-PGJ2 production in G2 is driven by calcium-dependent phospholipase A2 (cPLA2) activity and is subject to regulation by Caspase 3. Our results show that the capacity of Caspase 3 to cleave and inactivate the cPLA2 protein is specifically suppressed in G2, thus leading to upregulation of cPLA2 activity and 15-d-PGJ2 levels. As such, we find that 15d-PGJ2 levels are highest in G2 and that the inhibition of cPLA2 blocks SG formation in G2 specifically. Accordingly, exogenous 15d-PGJ2 rescues SG formation in cPLA2-inhibited G2 cells. In addition, we demonstrate that Caspase 3 inhibition increases 15-d-PGJ2 levels and stimulates SG formation in asynchronous cells, mirroring the natural suppression of Caspase 3 seen in G2. Importantly, we show that heterogeneity in SG levels translates into a functional heterogeneity whereby SG inhibition preferentially sensitizes cells in G2 to stress stimuli. Altogether these data support a model whereby SG formation integrates cues from cell death and proliferative signals and indicate that SG levels may be critical to achieve a clear signal for cell cycle progression at the G2/M border. Furthermore, our findings suggest that cancer cells may show differential sensitivity to anti-SG therapy as they progress through the cell cycle, and pairing such therapy with G2-synchronizing chemotherapeutics may increase susceptibility and thus treatment efficacy.
Citation Format: Alexandra Redding, Guillaume Fonteneau, Elda Grabocka. Unfolding the role of cell state on stress granule heterogeneity and function 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 B079.