bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting STAT3 with Proteolysis Targeting Chimeras and Next-Generation Antisense Oligonucleotides
Authors: Shiah Jamie V. , Grandis Jennifer R. , Johnson Daniel E. 
Published: November 2020

AbstractSTAT3 has been recognized for its key role in the progression of cancer, where it is frequently upregulated or constitutively hyperactivated, contributing to tumor cell proliferation, survival, and migration, as well as angiogenesis and suppression of antitumor immunity. Given the ubiquity of dysregulated STAT3 activity in cancer, it has long been considered a highly attractive target for the development of anticancer therapies. Efforts to target STAT3, however, have proven to be especially challenging, perhaps owing to the fact that transcription factors lack targetable enzymatic activity and have historically been considered “undruggable.” Small-molecule inhibitors targeting STAT3 have been limited by insufficient selectivity and potency. More recently, therapeutic approaches that selectively target STAT3 protein for degradation have been developed, offering novel strategies that do not rely on inhibition of upstream pathways or direct competitive inhibition of the STAT3 protein. Here, we review these emerging approaches, including the development of STAT3 proteolysis targeting chimera agents, as well as preclinical and clinical studies of chemically stabilized antisense molecules, such as the clinical agent AZD9150. These therapeutic strategies may robustly reduce the cellular activity of oncogenic STAT3 and overcome the historical limitations of less selective small molecules.
Abstract IA-05: Immune health and intratumoral immune heterogeneity: Barriers to the efficacy of immunotherapy in pancreatic cancer
Authors: Beatty Gregory 
Published: November 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has shown remarkable resistance to immunotherapy including immune checkpoint blockade, vaccines, and other immunomodulatory agents. In cancer, immunosurveillance can be regulated at both the priming and effector phases of an immune response. Based on this reasoning, we investigated a role for the CD40 pathway in mice and humans as a strategy to prime for tumor-reactive T cells. Our studies showed that systemic CD40 activation triggers productive innate immunosurveillance that sensitizes PDAC tumors to chemotherapy but is insufficient to provoke T cell dependent anti-tumor immunity. However, CD40 activation can restore the functional capacity of peritumoral T cells. Consistent with this, PDAC development associates with progressive loss in T cell priming capacity along with a deficiency in circulating dendritic cells. This biology observed in mouse models is mirrored in humans where patients with PDAC show a decrease in circulating dendritic cells and an increase in T cell dysfunction. To overcome these defects in T cell priming and deficiencies in immune health, we studied adoptive transfer of tumor-reactive chimeric antigen receptor (CAR)-modified autologous T cells in patients. Our findings show that the persistence of adoptively transferred T cells is markedly impaired in patients with PDAC compared to hematologic malignancies. In addition, CAR-T cells show limited anti-tumor activity in PDAC. This lack of efficacy has prompted our investigation into the biology of the tumor microenvironment which displays remarkable spatial heterogeneity in immune cell infiltrates. In our studies, we have identified phenotypically distinct cellular communities marked by weak (“cold”) and strong (“hot”) infiltration of T cells. We find that these distinct regions of PDAC tumors are orchestrated by unique immunoregulatory mechanisms with therapeutic implications. Overall, our findings demonstrate that immunological barriers residing both within and outside the tumor microenvironment have the potential to impair the efficacy of immunotherapy in PDAC. In addition, our data suggest that the immunogenicity of PDAC varies spatially throughout tumors raising the likelihood that multiple, distinct mechanisms of immune evasion will need to be circumvented for immunotherapy to produce benefit for most patients.
Citation Format: Gregory Beatty. Immune health and intratumoral immune heterogeneity: Barriers to the efficacy of immunotherapy in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-05.
Abstract IA-11: An exception to the rule: A coding functional variant at a pancreatic cancer GWAS locus
Authors: Jermusyk Ashley , Zhong Jun , Gordon Naomi , Connelly Katelyn , Perera Sumeth , Abdolalizadeh Ehssan , Zhang Tongwu , O'Brien Aidan , Hoskins Jason , Collins Irene , Eiser Daina , Yuan Chen , Risch Harvey , Jacobs Eric J. , Li Donghui , Du Mengmeng , Stolzenberg-Solomon Rachael , Klein Alison P. , Smith Jill P. , Wolpin Brian M. , Chanock Stephen J. , Shi Jianxin , Petersen Gloria M. , Westlake Christopher , Amundadottir Laufey T. 
Published: November 2020

Abstract
Genome wide association studies (GWAS) in 9,013 pancreatic cancer patients and 12,452 controls of European ancestry have discovered over 20 risk loci in the human genome. Here, we fine mapped one such locus on chromosome 16q23.1 in the vicinity of two Chymotrypsinogen precursor genes, CTRB1 and CTRB2. We fine-mapped this locus to rs72802365 (P=2.51x10-17, OR=1.36, 95% CI=1.31-1.40) and identified colocalization (PP=87%) with aberrant exon 5→7 CTRB2 splicing in pancreatic tissues. Imputation of a 584 bp insertion/deletion variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (P=2.83x10-16, OR=1.36, 95% CI=1.31-1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsin B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). The intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein may lead to ER stress and pancreatic inflammation, which in turn, may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles.
Citation Format: Ashley Jermusyk, Jun Zhong, Naomi Gordon, Katelyn Connelly, Sumeth Perera, Ehssan Abdolalizadeh, Tongwu Zhang, Aidan O'Brien, Jason Hoskins, Irene Collins, Daina Eiser, Chen Yuan, Harvey Risch, Eric J. Jacobs, Donghui Li, Mengmeng Du, Rachael Stolzenberg-Solomon, Alison P. Klein, Jill P. Smith, Brian M. Wolpin, Stephen J. Chanock, Jianxin Shi, Gloria M. Petersen, Christopher Westlake, Laufey T. Amundadottir. An exception to the rule: A coding functional variant at a pancreatic cancer GWAS locus [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-11.
Abstract PO-010: Elucidating intratumoral heterogeneity and predicting effective combination regimens in PDAC PDOs using scRNA-seq and snATAC-seq
Authors: Guerrero Paola A. , Maitra Anirban , Monberg Maria E. , Lee Jaewon J , Bernard-Pagan Vincent , Muthuswamy Senthil 
Published: November 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. The overwhelming majority of patients (up to 85%) present with unresectable disease, and the 5-year survival rate stands at a dire 9%. Current chemotherapeutic regimens extend survival by only a few months, and the molecular underpinnings of treatment failure in advanced disease remain largely unknown. Recently, single-cell sequencing techniques have emerged as highly effective methods to uncover intratumoral heterogeneity across many cancer types, including PDAC. These studies, and our own unpublished data, have reiterated profound transcriptomic subclonal diversity in PDAC, which likely underlies the divergent therapeutic responses and eventual treatment failure. Using a patient-derived organoid (PDO) platform, we have characterized, on the single cell level, gene expression and regulation profiles to understand the heterogeneity and clinical utility of this model. We applied predictive RNA-seq-based algorithms (CMap) to our initial PDO profiling data to design “custom” PDO combinatorial regimens as a true precision medicine-based approach. We are in the process of validating these predictions in vitro; however, preliminary single-cell RNA (scRNA-seq) data shows treatment PDOs with CMap-predicted compounds induced dramatic transcriptomic shifts in subclones reflective of an efficacious treatment strategy. Additionally, we conducted single-nuclei ATAC sequencing (snATAC-seq) of PDOs pre- and post-treatment with CMap-predicted compounds. This data, coupled to our scRNA-seq, allowed for construction of chromatin regulatory maps, and determined alterations in chromatin accessibility and gene regulation induced by targeted combinatorial therapeutics. These findings provide meaningful insight to biological processes driven by treatment-induced chromatin accessibility, and its relationship to heterogeneous transcriptional architecture. Our data suggests that differential regulation across PDO subclones may drive responses to therapy and acquired resistance mechanisms observed in the clinic, which could be predicted and therapeutically targeted with scRNA sequencing. Thus, this work represents the importance of leveraging subclonal architecture in the preclinical space to ensure both treatment efficacy and the consideration of novel therapeutic combinations in PDAC patients.
Citation Format: Paola A. Guerrero, Anirban Maitra, Maria E. Monberg, Jaewon J Lee, Vincent Bernard-Pagan, Senthil Muthuswamy. Elucidating intratumoral heterogeneity and predicting effective combination regimens in PDAC PDOs using scRNA-seq and snATAC-seq [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-010.
Abstract PO-016: STAT3 in cancer-associated fibroblasts promotes an immunosuppressive tumor microenvironment in PDAC
Authors: Lefler Julia E. , MarElia Katie , Hildreth Blake E. , Thies Katie A. , Cuitino Maria C. , Ostrowski Michael C. 
Published: November 2020

Abstract
One of the defining characteristics of pancreatic ductal adenocarcinoma (PDAC) is the formation of a dense stroma comprised of cancer associated fibroblasts (CAFs) and immune cell populations. This stroma is immunosuppressive and can act as a physical barrier against common therapeutic treatments. Attempts to therapeutically target the PDAC stroma have yielded contradictory results, suggesting both tumor promoting and tumor limiting roles for CAFs. These studies emphasize the need to understand important transsignaling pathways between CAFs, tumor cells, and the immune microenvironment. IL-6 is a pleiotropic cytokine involved in several physiological functions and its increased expression is strongly associated with poor survival rates in PDAC patients. STAT3 is a major downstream target of IL-6, and its aberrant activation has been implicated in PDAC tumor progression and immune evasion. IL-6 expression and the IL-6/STAT3 signaling axis in PDAC has been characterized in epithelial tumor cells, however its stromal-specific function on PDAC has yet to be elucidated. We hypothesized that the STAT3 signaling axis in pancreatic CAFs contributes to the immunosuppressive and fibrotic phenotype seen with disease progression. Employing CreLoxP technology, the fibroblast specific protein-1 (Fsp-Cre) transgene was used to conditionally delete STAT3 in fibroblasts in the PdxFlp; KrasG12D; p53 frt/frt (KPF) PDAC mouse model developed by our lab. Deletion of STAT3 in fibroblasts significantly increased the survival in a cohort of KPF mice compared to those with intact STAT3. Loss of fibroblast STAT3 also resulted in a significant decrease in ECM deposition in the pancreas. In preliminary investigations into the immune microenvironment, we found an increase in overall T cell infiltration and decrease in regulatory T cell populations in the STAT3 deleted cohort. Further, STAT3 deletion resulted in an increase in the ratio of M1 to M2 macrophages within the PDAC stroma, suggesting CAF STAT3 signaling is important to maintaining an immune microenvironment conducive to tumor progression. Ultimately, these preliminary results suggest STAT3 signaling in PDAC CAFs contributes to an overall survival disadvantage, an immunosuppressive tumor microenvironment, and an increase in ECM deposition.
Citation Format: Julia E. Lefler, Katie MarElia, Blake E. Hildreth, Katie A. Thies, Maria C. Cuitino, Michael C. Ostrowski. STAT3 in cancer-associated fibroblasts promotes an immunosuppressive tumor microenvironment in PDAC [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-016.
Abstract PO-031: Repurposing of alexidine dihydrochloride as an apoptosis-initiator and cell cycle inhibitor in human pancreatic cancer
Authors: Kasikci Ezgi , Aydemir Esra , Yogurtcu Bekir Mustafa , Sahin Fikrettin , Bayrak Omer Faruk 
Published: November 2020

Abstract
Purpose: Highly aggressive and resistant to chemotherapy, pancreatic cancers are the fourth leading cause of cancer-related deaths in the western world. The absence of effective chemotherapeutics is leading researchers to develop novel drugs or repurpose existing chemicals. Alexidine dihydrochloride (AD), an orally bioavailable bis-biguanide compound, is an apoptosis stimulating reagent. It induces mitochondrial damage by inhibiting a mitochondrial-specific protein tyrosine phosphatase, PTPMT1. The aim of this study was to test AD as a novel compound to induce apoptosis in a human pancreatic adenocarcinoma cell lines, Panc-1, MIA PaCa-2, AsPC-1, and Psn-1. Methods: After IC50 value of the AD was determined by cytotoxicity assay, apoptosis was observed by a variety of methods including the detection of early apoptosis marker Annexin V and the proteomic profile screening by apoptosis array. Multicaspase and mitochondrial depolarization were measured and changes in cell cycle were analyzed. Results: AD is found to initiate apoptosis by activating the intrinsic pathway and inhibit cell cycle in pancreatic cancer cell lines. Conclusions: As a conclusion, considering its anti-cancer properties and bioavailability, Alexidine dihydrochloride can be considered as a potential candidate against pancreatic adenocarcinomas.
Citation Format: Ezgi Kasikci, Esra Aydemir, Bekir Mustafa Yogurtcu, Fikrettin Sahin, Omer Faruk Bayrak. Repurposing of alexidine dihydrochloride as an apoptosis-initiator and cell cycle inhibitor in human pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-031.
Abstract PO-035: Overcoming adaptive resistance to mutant KRAS and MEK inhibitors by co-targeting mTORC1/2 in pancreatic cancer
Authors: Brown Wells , McDonald Paul , Dedhar Shoukat 
Published: November 2020

Abstract
Activating KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDAC), yet KRAS has remained a difficult target to inhibit pharmacologically. While mutant KRAS-specific inhibitors have recently been developed, there is increasing awareness that adaptive resistance to these inhibitors limits their efficacy as single agents. Here, we demonstrate, using several human and mouse models of PDAC, rapid acquisition of tumor resistance in response to genetic or pharmacologic targeting of KRAS or MEK, associated with increased phosphorylation of Akt and Rictor, in an ILK-dependent manner. While pharmacologic inhibition ofmTORC1/2 results in a compensatory increase in ERK phosphorylation, combinatorial treatment of PDAC cells with either KRAS or MEK inhibitors together with mTORC1/2 inhibitors results in synergistic cytotoxicity and cell death reflected by sustained inhibition of p-ERK and p-Rictor/p-Akt, and of downstream regulators of protein synthesis and cell survival. Importantly, relative to single agents alone, this combination leads to significant inhibition of tumor growth in vivo, including durable tumor regressions and increased survival. We have identified a highly effective combinatorial treatment strategy, using clinically viable inhibitors, which can be applied to PDAC tumors with different KRAS mutations.
Citation Format: Wells Brown, Paul McDonald, Shoukat Dedhar. Overcoming adaptive resistance to mutant KRAS and MEK inhibitors by co-targeting mTORC1/2 in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-035.
Abstract PO-045: Interleukin 1 receptor accessory protein (IL1RAP) in novel targetable pathway in pancreatic cancer
Authors: Zhang Yang , Chen Xiaoyi , Gordon-Mitchell Shanisha , Pradhan Kith , Choudhary Gaurav , Bhagat Tushar D. , Agarwal Beamon , Steidl Ulrich , Maitra Anirban , Verma Amit 
Published: November 2020

Abstract
Interleukin-1 Receptor Accessory Protein (IL1RAP) is a surface molecule that mediates activation of pro-inflammatory IL-1 associated signaling pathways. It is overexpressed in myeloid leukemias and is associated with worse prognosis. We aimed to evaluate IL1RAP as a target for therapy in pancreatic adenocarcinoma (PDAC). Immunohistochemistry demonstrated overexpression of IL1RAP in PDAC specimens from K-Ras/p53/Cre (KPC) mice when compared to controls. Evaluation of human PDAC tissue microarrays containing 262 samples also revealed overexpression of IL1RAP in 81% of the samples. Single cell RNA-Seq analysis of human primary pre-neoplastic lesions and frank adenocarcinoma specimens indicated that overexpression occurs on malignant EPCAM positive cells during carcinogenesis. IL1RAP knockdown via siRNA on the A6L PDAC cell line significantly reduced cell viability, invasiveness, and ability to form colonies. IL1RAP knockdown cells showed significant arrest in the G1/G0 phase of the cell cycle on flow cytometry and showed reduced phospho-ERK proliferative signaling on Western blot. RNA sequencing of IL1RAP knockdown cells indicated downregulation of several groups of genes involved in cell cycle progression, including CDK1 and TOP2A, whose reduced expression was confirmed on Western blot. Inhibition of the downstream signaling molecule IRAK4 (interleukin-1 receptor-associated kinase 4) using two pharmacologic inhibitors, CA-4948 and PF06650833, resulted in significantly reduced growth in pancreatic cancer cell lines and reduced proliferative phospho-ERK signaling on Western blot. Preliminary in vivo data in NSG mice showed a reduction in tumor size with oral treatments of these two IRAK4 inhibitors. Overall, our studies indicate IL1RAP is overexpressed in PDAC, and reducing IL1RAP and inhibiting downstream IRAK4 result in lowered tumor proliferation in vitro and in vivo, potentially via cell cycle arrest and reduced proliferative signaling.
Citation Format: Yang Zhang, Xiaoyi Chen, Shanisha Gordon-Mitchell, Kith Pradhan, Gaurav Choudhary, Tushar D. Bhagat, Beamon Agarwal, Ulrich Steidl, Anirban Maitra, Amit Verma. Interleukin 1 receptor accessory protein (IL1RAP) in novel targetable pathway in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-045.
Abstract PO-060: Gna13 delays disease progression in mouse models of pancreatitis and pancreatic cancer
Authors: Shields Mario A. , Spaulding Christina , Khalafalla Mahmoud G. , Pham Thao D.N. , Munshi Hidayatullah G. 
Published: November 2020

Abstract
We previously reported that Gα13 (Gna13), a member of the G12 heterotrimeric G proteins, is upregulated in pancreatic cancer patients and contributes to invasion in cancer cells in vitro. While other reports have demonstrated a tumor promoting function of Gα13 in solid tumors, Gα13 functions as a tumor suppressor in mouse models of B cell lymphoma. In this study, we evaluated the role of Gα13 in mouse models of pancreatitis and pancreatic cancer. To examine the role of Gα13 in pancreatic cancer development and progression, we crossed mice with a floxed allele of Gna13 to mice expressing oncogenic KrasG12D (KrasG12D;Pdx1-Cre). In parallel, we measured transplanted tumors established from pancreatic cell lines, where Gna13 is silenced or deleted. Further, we determined how loss of Gα13 influences cerulein-induced pancreatitis and inflammation-driven tumor progression in mice. Tumors derived from Gα13-deficient cells grew significantly slower than control cells when transplanted in either the orthotopic or subcutaneous site. However, cancer development and overall survival were unaffected in mice with heterozygous loss of Gα13, when compared to mice with intact expression of Gα13. Interestingly, in an aggressive cancer model (KrasG12D;P53R172H;Pdx1-Cre) loss of Gα13 led to faster tumor development and decreased overall survival. Furthermore, we found that Gα13 loss leads to enhanced inflammation and more progressive acinar-ductal metaplasia in pancreatitis. Overall, our results demonstrate a context-dependent role of Gα13 in the pancreas. Similar to previous reports, we show that inhibiting Gα13 in cancer cell lines limits tumor growth in vivo. However, in a genetic mouse model, loss of Gα13 promotes pancreatitis-induced inflammation and promotes tumor development and progression.
Citation Format: Mario A. Shields, Christina Spaulding, Mahmoud G. Khalafalla, Thao D.N. Pham, Hidayatullah G. Munshi. Gna13 delays disease progression in mouse models of pancreatitis and pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-060.