bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO-026: CircMYOF acts as a miR-4739 sponge to promote progression and facilitate glycolysis via VEGFA/PI3K/AKT pathway in pancreatic ductal adenocarcinoma
Authors: Zheng Dandan , Huang Xianxian , Peng Juanfei , Zhuang Yanyan , Li Yuanhua , Qu Junchi , Zhang Shineng , Huang Fengting 
Published: November 2021

Abstract
Emerging evidences has revealed that circular RNAs (circRNAs) participate in the initiation and development of pancreatic ductal adenocarcinoma (PDAC), a deadly malignancy with extremely low 5-year survival rate. Reprogrammed glucose metabolism is a key feature of tumor development, including PDAC. In this study, we aimed to investigate the role of circRNAs in reprogrammed glucose metabolism in PDAC. RNA sequencing under various glucose incubation circumstance was performed. A new circMYOF was identified. Sanger sequencing and RNase R treatment confirmed its circular RNA characteristics. Real time PCR indicated that it was overexpressed in PDAC tissues and cell lines. Gain-of and loss-of function assay implied that circMYOF promoted progression in PDAC. Mechanically, RNA pull down and luciferase reporter assay suggested that circMYOF, exhibiting as a competing endogenous RNA (ceRNA) for miR-4739, facilitated glycolysis via VEGFA/PI3K/AKT pathway. Taken together, our finding indicates that circMYOF may be a potential biomarker and therapeutic target for PDAC patients.
Citation Format: Dandan Zheng, Xianxian Huang, Juanfei Peng, Yanyan Zhuang, Yuanhua Li, Junchi Qu, Shineng Zhang, Fengting Huang. CircMYOF acts as a miR-4739 sponge to promote progression and facilitate glycolysis via VEGFA/PI3K/AKT pathway in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-026.
Abstract PO-028: Pancreatic ductal adenocarcinoma is dependent on an unconventional pathway for polyamine synthesis
Authors: Lee Min-Sik , Naqvi Insia , Dennis Courtney , Dailey Lucas , Lorzadeh Alireza , Zaytouni Tamara , Adler Ashley , Hitchcock Daniel S. , Lin Lin , Jadhav Unmesh , Clish Clary B. , Kalaany Nada Y. 
Published: November 2021

Abstract
Targeting altered metabolism in pancreatic ductal adenocarcinoma (PDAC) has been an area of extensive investigation for over a decade now. A major hurdle however, for most anti-tumor metabolic strategies, is the high risk for toxicity, given the essential roles of metabolic pathways in the maintenance of normal tissue homeostasis. Indeed, this has been the case for targeting polyamines in cancers. Polyamines are small, highly positively charged molecules involved in multiple fundamental processes of cell growth and survival, including the synthesis of nucleic acids, modifications of chromatin structure, gene transcription and mRNA translation. Polyamine levels are significantly increased in many cancers, including PDAC. Prior anti-tumor strategies focused on pharmacological inhibition of the rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC1) with little success, partially due to risk of harming normal tissues at higher drug doses. In this project, using both in vitro and in vivo mouse models of PDAC, we identified a dependency of PDAC on an unconventional way for the synthesis of the polyamine precursor ornithine, specifically from glutamine via ornithine aminotransferase (OAT); this is in contrast to its synthesis in most adult normal tissues from arginine via arginase (ARG) activity. We also identified potential key players mediating the induction of this metabolic pathway via KRAS, the main oncogenic driver in PDAC and are currently characterizing the downstream effects of polyamines on pancreatic tumor cells. The high dependency of PDAC, compared to normal tissue, on de novo ornithine synthesis via OAT provides an attractive therapeutic window for treating pancreatic cancer patients with minimal toxicity.
Citation Format: Min-Sik Lee, Insia Naqvi, Courtney Dennis, Lucas Dailey, Alireza Lorzadeh, Tamara Zaytouni, Ashley Adler, Daniel S. Hitchcock, Lin Lin, Unmesh Jadhav, Clary B. Clish, Nada Y. Kalaany. Pancreatic ductal adenocarcinoma is dependent on an unconventional pathway for polyamine synthesis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-028.
Abstract PO-045: Targeting HNF1A-dependent cell proliferation and stemness in PDAC using BET inhibitors
Authors: Muppavarapu Bharani , Abel Ethan , Mayberry Melanie 
Published: November 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a disease with poor prognosis, with an overall survival rate of only 10%. Standard of care involves chemotherapy which improves survival by only a few weeks. Several barriers to therapeutic efficacy impede increasing survival outcome, including intrinsic resistance, owing to presence of therapy-resistant pancreatic cancer stem-like cells (PCSCs). Therefore, developing therapeutics to target molecular networks that maintain PCSC populations is critical. Microarray analysis from our lab previously established that pancreas lineage transcription factor HNF1A and its targets are enriched in CD44+CD24+EPCAM+ human PCSCs and that genetic depletion of HNF1A ablates this population and importantly, diminished tumor growth in primary PDAC xenografts. However, there are no therapeutics to directly target HNF1A. In this project, we propose to indirectly ablate HNF1A and its network by targeting epigenetic readers, bromodomain and extra-terminal domain protein family (BET) that maintain expression of transcription factor networks. We hypothesize that BET inhibitors decrease stemness and tumor growth in a HNF1A-dependent manner. Studies in our lab established that BET inhibitors decrease colony-formation, tumorsphere formation and cell-cycle progression in PDAC cells, that is rescued by overexpressing HNF1A. These results indicate that BET inhibitors decrease stemness and proliferation in pancreatic cancer cells in a HNF1A-dependent manner. These results suggest that BET inhibitors target multiple HNF1A-dependent tumor-promoting programs, such as stemness and tumor growth which could impact utilization of these drugs in clinical settings. The ultimate goal of our project is to provide rationale for the use of BET inhibitors in clinical setting in pancreatic cancer.
Citation Format: Bharani Muppavarapu, Ethan Abel, Melanie Mayberry. Targeting HNF1A-dependent cell proliferation and stemness in PDAC using BET inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-045.
Abstract PO-065: SIWA318H, an advanced glycation end product (AGE) targeting antibody, is efficacious in a humanized mouse xenograft model for pancreatic cancer
Authors: Jensen Ashley , Rossi Gabriela R. , Muñoz Ruben , Brothers Kimberly , Gruber Lewis , Gruber Misty , Han Haiyong 
Published: November 2021

Abstract
SIWA318H is a novel monoclonal antibody that selectively targets a biomarker (an advanced glycation end product) found on the surface of cells exhibiting a combination of: (a) an abnormally high level of aerobic glycolysis, a process known to be associated with initiation and progression of cancer as well as metastasis; and (b) oxidative stress. Cells with this biomarker are often dysfunctional and associated with aging, cancer, and infectious diseases. In this study, we evaluated the antitumor activity of SIWA318H in a humanized xenograft model for pancreatic cancer. SIWA318H was found to react to pancreatic cancer cells (PSN1) and cancer associated fibroblasts (CAF08) using immunofluorescent staining. SIWA318H also showed strong reactivity with tumor xenografts derived from patients with pancreatic cancer as demonstrated by immunohistochemistry. Humanized CD34+ NSG mice were injected subcutaneously with PSN1 pancreatic cancer tumor cells. Ten days later, mice were randomized and enrolled in one of the following groups (n=16/group): 1) IgG1 isotype control (20mg/kg, BIWx1 followed by 10 mg/kg, BIWx2); 2) high dose SIWA318H (20mg/kg, BIWx1 followed by 10 mg/kg, BIWx2); and 3) low dose SIWA318H (10 mg/kg, BIWx1 followed by 5mg/kg, BIWx2). Tumors in mice treated with SIWA318H grew significantly slower than those in mice treated with isotype control antibody (p&lt;0.001). After 3 weeks of treatment with the high dose or the low dose of SIWA318H, the tumor growth was suppressed by 68.8% and 61.5%, respectively, when compared to the isotype antibody control (ANOVA p&lt;0.002). Moreover, a significant increase in complete remission (CR) rate was observed in mice receiving high (60%, p&lt;0.05) or low dose (77.8%, p&lt;0.02) of SIWA318H treatment compared with the control mice (6.7%). No significant antibody treatment related weight loss in mice was observed. These results provide compelling evidence that SIWA318H is a promising novel therapeutic for pancreatic cancer. Additional studies to better understand the mechanism of action of this novel immunotherapy agent are underway.
Citation Format: Ashley Jensen, Gabriela R. Rossi, Ruben Muñoz, Kimberly Brothers, Lewis Gruber, Misty Gruber, Haiyong Han. SIWA318H, an advanced glycation end product (AGE) targeting antibody, is efficacious in a humanized mouse xenograft model for pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-065.
Abstract PO-073: Inactivation of Notch4 attenuated pancreatic tumorigenesis in mice
Authors: Saeki Kiyoshi , Qiu Wanglong , Friedman Richard , Shawber Carrie , Kitajewski Jan , Hu Jianhua , Su Gloria H. 
Published: November 2021

Abstract
Expression of the Notch family of receptors are often upregulated in pancreatic ductal adenocarcinoma (PDAC), however, the functional impacts of the Notch signaling network on pancreatic tumorigenesis remain unresolved. In this study, we focused on Notch4, which had not been investigated in PDAC. Leveraging the conventional Notch4 deficient mouse line and previously established genetically engineered mouse models (GEMM) for PDAC, we generated KC (LSL-KrasG12D;p48-Cre), N4−/−KC (Notch4−/−;LSL-KrasG12D;p48-Cre), PKC (p16flox/flox;LSL-KrasG12D;p48-Cre), and N4−/−PKC GEMMs (Notch4−/−; p16flox/lox;LSL-KrasG12D;p48-Cre). We performed caerulein treatment in both KC and N4−/−KC mice, and compared the development of acinar to ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) between them. The ADM/PanIN lesions were significantly smaller in the N4−/−KC than in the KC GEMM (p=0.01), suggesting that Notch4 deficiency attenuated early pancreatic tumorigenesis. This in vivo result was confirmed by in vitro ADM induction of the explant cultures of mouse pancreatic acinar cells. The number of ADM structures in the N4−/−KC acinar cultures was significantly lower than the KC acinar cultures (p&lt;0.001). To evaluate the role of Notch4 in the later stage of pancreatic tumorigenesis, we compared the histological progression and overall survival between the PKC and N4−/−PKC mice. We found that N4−/−PKC mice had better prognosis (p=0.012) and less tumor burden (PanIN: p=0.018 (2 months), PDAC: p=0.039 (5 months)) compared to the PKC GEMM. RNA-Seq analysis of pancreatic tumor cell lines derived from the PKC and N4−/−PKC GEMMs revealed 408 genes were differentially expressed (FDR&lt;0.05) and the genes related to the NGF processing as novel downstream effectors of the Notch4 signaling pathway(p&lt;0.001). Our study is a novel biological investigation that demonstrated that Notch4 signaling possesses tumor promoting function in pancreatic tumorigenesis. Our study revealed a novel association between the NGF processing pathway and Notch4 signaling in PDAC.
Citation Format: Kiyoshi Saeki, Wanglong Qiu, Richard Friedman, Carrie Shawber, Jan Kitajewski, Jianhua Hu, Gloria H. Su. Inactivation of Notch4 attenuated pancreatic tumorigenesis in mice [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-073.
Abstract PO-074: Identification of C-MET receptor as a therapeutic target in patient-specific tumoroid models of metastatic pancreatic adenocarcinoma allows identification of a new mode of action for its inhibitors
Authors: Deems Liam , Ivanova Maria , Murphy Cheryl , Shahar Amit , Deems David , Shvartsman Dmitry 
Published: November 2021

Abstract
Creating patient-specific models with a high level of characterization and functionality in tumoroid modeling enables a better understanding of the disease drivers in metastatic cancers. It presents the opportunity for personalized treatment with novel therapeutic reagents in underrepresented cancers such as pancreatic ductal adenocarcinoma. Using a defined and treatment-naive patient-specific model cohort of nine patients diagnosed with pancreatic adenocarcinoma, we aimed to represent the diversity of progression grade and assay profiles. These models were tested with a panel of common, broad-range chemotherapeutic agents and characterized for genetic, proteomic, and tumoroid drug response profiles. A detailed analysis of gene expression values from the original tissue specimen, compared with cancer cultures in hypoxic, normoxic planar, and spheroid (3D) culture conditions, enabled the identification of C-MET as a critical gene that shows upregulation closely resembling the expression profile observed in the original patient biopsy and was modulated by tissue culture format. Once this potential target was identified, the pancreatic models were treated with five C-MET-targeting chemotherapeutic agents with different modes of action. Proto-oncogene receptor C-MET (HGF receptor) is a potential therapeutic target in many metastatic cancers due to its integral role in angiogenesis, proliferation, and cancer cell survival¹. We propose that these reproducible and easily scaled tumoroid models can be used to find new therapeutic targets in-vitro and provide the example of C-MET in our pancreatic cancer patient cohort. Moreover, only 3D hypoxic models closely resembled original patient tissues in their genomic expression profiles. Using these model formats, we distinguished differences between various C-MET targeting compounds and their ability to induce cell death, which correlated with their mode of action on C-MET neutralization. Identifying these targets in 3D produces new and potentially more effective drug targets where they may not have been observed solely in planar conditions with legacy cell lines. Our models of metastatic pancreatic cancer tumoroids can be readily utilized to benefit researchers and clinicians seeking new targets for patient treatment.
Citation Format: Liam Deems, Maria Ivanova, Cheryl Murphy, Amit Shahar, David Deems, Dmitry Shvartsman. Identification of C-MET receptor as a therapeutic target in patient-specific tumoroid models of metastatic pancreatic adenocarcinoma allows identification of a new mode of action for its inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-074.
Abstract PO-081: Studying MYC's contribution to replication stress at the nuclear pore
Authors: Cohn Gabriel M. , Daniel Colin J. , Liefwalker Daniel F. , Sears Rosalie C. 
Published: November 2021

Abstract
Genomic instability is a hallmark of cancer which promotes oncogenic mutations in pancreatic ductal adenocarcinoma (PDAC), leading to more aggressive tumors with greater potential for drug resistance. Deregulation of the master transcription factor, MYC, is found in virtually all PDAC tumors and promotes genomic alterations by increasing replication stress, augmenting DNA repair pathways, and promoting cell survival. To resolve replication stress, stalled forks are trafficked to the nuclear pores where the necessary machinery accumulates. Activated MYC is spatially reorganized to the nuclear pores as well, a mechanism that is exacerbated in cancer. Whether MYC activity at the nuclear pores contributes to resolving replication stress in PDAC remains to be known. To investigate this mechanism, we are creating genomic and proteomic tools to determine MYC’s function at the nuclear pores during replication stress induced by olaparib treatment in PDAC cells. We found that olaparib significantly increases MYC accumulation at the nuclear pore in low-passage cell lines we established from PDAC patient tumors. Furthermore, we showed that MYC interacts with the nuclear pore resident SUMO protease, SENP1, which plays a key role in resolving stalled forks. Our preliminary data suggest a role for MYC resolving replication stress at nuclear pores, and could indicate MYC activity as a therapeutic target in olaparib-resistant PDAC.
Citation Format: Gabriel M. Cohn, Colin J. Daniel, Daniel F. Liefwalker, Rosalie C. Sears. Studying MYC's contribution to replication stress at the nuclear pore [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-081.
Abstract PO-094: Gα13 loss in KPC mouse model promotes well-differentiated pancreatic tumors that are susceptible to mTOR inhibition
Authors: Shields Mario A. , Spaulding Christina , Khalafalla Mahmoud G. , Pham Thao N. D. , Munshi Hidayatullah G. 
Published: November 2021

Abstract
Gα13 transduces signals from G protein-coupled receptors. Gα13 is pro-tumorigenic in epithelial cancer cell lines, which contrasts with its tumor-suppressive function in transgenic mouse models of lymphomas. We investigated the role of Gα13 in pancreatic tumor development and progression in a transgenic mouse model. Here we show that while loss of Gα13 in pancreatic cell lines decreases tumor growth in vivo, Gα13 loss in the Kras-driven (KC) mouse model of pancreatic tumor initiation does not affect tumor development or survival. Instead, Gα13 loss in the Kras/Tp53 (KPC) transgenic mouse model of advanced pancreatic cancer promotes well-differentiated tumors with increased tumor burden and reduced survival. Mechanistically, Gα13 loss in the KPC mouse model enhances E-cadherin-mediated cell-cell junctions and mTOR signaling. Gα13-deficient pancreatic cancer cell lines derived from these mice form well-differentiated tumors, which are susceptible to mTOR inhibition with rapamycin. Importantly, human pancreatic cancers with low Gα13 expression also exhibit increased E-cadherin protein expression and mTOR signaling. This work establishes a context-dependent role of Gα13 in pancreatic tumorigenesis, demonstrating a tumor-suppressive role in transgenic mouse models of advanced pancreatic cancer.
Citation Format: Mario A. Shields, Christina Spaulding, Mahmoud G. Khalafalla, Thao N. D. Pham, Hidayatullah G. Munshi. Gα13 loss in KPC mouse model promotes well-differentiated pancreatic tumors that are susceptible to mTOR inhibition [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-094.
Abstract PO-126: Loss of HIF1A decreases resistance to radiation and invasiveness in pancreatic ductal adenocarcinoma
Authors: Tu Kevin J. , Roy Sanjit K. , Bhandary Binny , Sawant Amit , Shukla Hem D. 
Published: November 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most lethal cancer in the United States with an estimated 60,430 new cases and 48,220 deaths in 2021. PDACs are characterized by extensive desmoplastic stroma and severe hypovascularity, resulting in an intra-tumoral hypoxic microenvironment. In response to hypoxic stress, cancer cells set off many adaptive responses including metabolism regulation, cell survival, and inflammation through the stabilization and activation of the hypoxia-inducible factor (HIF) family of transcription factors. In this study, we used the gene-editing tool CRISPR-cas9 to knock out HIF1A and investigate whether HIF1A affects the radioresistant and invasive characteristics of PDACs in a KPC cell line model. To first observe how HIF1A affects PDAC radioresistance, we performed a clonogenic survival assay with increasing doses of radiation on both wild-type and HIF1A knockout (KO) cells treated and untreated with CoCl2-induced hypoxia conditions (100 uM and 200 uM CoCl2). Our data showed that under hypoxia, KO cells exhibited significant cell death when treated with 6, 8, and 10 Gy of radiation as compared to wild-type KPC cells, emphasizing the role of HIF1A in radiation resistance. In addition, to understand the role of HIF1A in regulating the invasive behavior of PDACs, we performed a cell proliferation assay on wild-type and KO KPC cells. HIF1A KO cells treated with CoCl2 exhibited significantly reduced proliferation compared to wild-type cells also treated with CoCl2 (p&lt;0.01), though no significant difference was observed between untreated HIF1A KO and untreated wild-type cells (p&gt;0.05). Because western blot demonstrated increased HIF1A expression in wild-type cells following CoCl2 treatment, our results provided evidence for the role of HIF1A activation in promoting PDAC invasiveness. Through western blot, we also confirmed the association between HIF1A expression with p53 degradation in PDAC. We used COREMINE, a literature mining tool, to map a direct interaction between HIF1A with KRAS in PDACs (p=0.000016). We propose HIF1A as a switch to activate KRAS and degrade p53 under hypoxic conditions in PDAC proliferation. Thus, modulating the HIF1A switch may be an important mechanism to reduce the tumor-promoting microenvironment and inhibit cancer growth.
Citation Format: Kevin J. Tu, Sanjit K. Roy, Binny Bhandary, Amit Sawant, Hem D. Shukla. Loss of HIF1A decreases resistance to radiation and invasiveness in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-126.