bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B037: Anti-fibrotic FAK ‘priming’ to improve contemporary chemotherapy in pancreatic cancer
Authors: Murphy Kendelle J. , Reed Daniel A. , Chambers Cecilia R. , Channon Lily M. , Pajic Marina , Herrmann David , Timpson Paul 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemo-resistant malignancy and is characterized by a dense, desmoplastic stroma that increases the biomechanical force load on cancer cells and is thought to both promote and restrict disease advancement. Using the p53 mutant KPC mouse model of PDAC, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signalling. The fluorescent ubiquitination-based cell cycle indicator (FUCCI) cell cycle reporter was used during intravital (in vivo) imaging to monitor dynamic changes in FAK activity, stromal biomechanics and gemcitabine/Abraxane-induced effects. Critically, micropatterned pillar plates and stiffness-tuneable matrices were used to pinpoint the contribution of mechanical environmental cues to chemo-sensitization, while fluid flow– induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how FAK inhibition can reduce PDAC spread. In a precision medicine approach, stratification of PDAC patient samples via Merlin status revealed a subset of patients that are likely to respond to FAK priming before chemotherapy. This dataset has led to the establishment of a Phase II clinical trial of first- line FAK inhibition in combination with Gemcitabine/Abraxane in PDAC Patients (NCT05355298).
Citation Format: Kendelle J. Murphy, Daniel A. Reed, Cecilia R. Chambers, Lily M. Channon, Marina Pajic, David Herrmann, Paul Timpson. Anti-fibrotic FAK ‘priming’ to improve contemporary chemotherapy 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 B037.
Abstract B048: Targeting PPARG to block obesity-associated pancreatic cancer progression
Authors: Ferguson L. Paige 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-related death in the United States and one of the few cancers for which incidence is increasing. This trend in increased incidence has been attributed in part to obesity. Obesity is associated with increased risk of pancreatic cancer and advanced disease stage in patients, concordant with rodent studies showing that obesity accelerates tumorigenesis and metastasis. Although studies have largely focused on the role of inflammation in obesity-associated pancreatic cancer, the cancer cell-autonomous mechanisms by which lipid availability in obesity impacts tumorigenesis remain quite poorly understood. Given the abundant evidence for dysregulated lipid metabolism in tumors, I hypothesized that cancer cells are primed to exploit exogenous lipids in obesity, accelerating disease progression. By mapping lipid-protein interactions in tumor and metastasis-enriched RNA-seq networks, I identified the nuclear hormone receptor PPARG as a potential mediator of obesity-associated lipid signaling in pancreatic cancer. PPARG is an attractive prospective mediator of obesity-associated PDA progression because it is a metabolic regulator activated by a broad set of lipid ligands, suggesting a dual role in lipid sensing and metabolic control. PPARG is also positioned at an interesting junction in PDA etiology; PPARG agonists are used to treat diabetes (a PDA risk factor) and have previously been studied for anti-cancer effects. However, PPARG agonists have seen little clinical success in and recent work has suggested that their use may even increase bladder cancer risk. PPARG is overexpressed in pancreatic tumors where it is associated with poor prognosis, further casting doubt on its anti-tumorigenic function. In my own studies, I found that PPARG agonists had no effect on tumor viability, while the PPARG antagonist T0070907 reduced organoid viability in vitro. Modeling the convergent effects of PPARG and obesity, I supplemented organoids with a mixture of lipids in the presence of PPARG antagonist and found that lipids boosted the viability of both tumor and metastatic organoids dependent on PPARG activity in vitro. These results suggest that PPARG can mediate the pro-tumorigenic function of exogenous lipids. As the incidence of both obesity and pancreatic cancer continue to rise, defining the role of PPARG in PDA could have significant implications for the development of new strategies to treat or prevent obesity-associated cancer.
Citation Format: L. Paige Ferguson. Targeting PPARG to block obesity-associated pancreatic cancer progression [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 B048.
Abstract B063: Tertiary lymphoid organogenesis and lymphocyte activation in human organ chips
Authors: Zhai Yunhao , Prabhala Pranav , Barck Lucas , Ku Min Wen , Patil Aditya , Horvath Viktor , Gould Russell A. , Ingber Donald E. , Goyal Girija 
Published: January 2024

Abstract
The rates of tertiary lymphoid organ (TLO) formation in pancreatic cancer are very low but patients with TLO have dramatically better survival rates. Our goal is to understand how pancreatic cancer suppresses TLO so that we can improve patient survival and reduce recurrence. We integrated human cell lines from pancreatic and lung cancer with either high or low PDL1/L2 expression into our previously described lymphoid follicle (LF) chip (Goyal et al., Adv. Sci, 2022), where peripheral blood mononuclear cells are induced to form 3D TLO-like structures. The hot lung cancer cell line, which expressed high levels of PDL1/L2 and a “hot” phenotype in published murine studies, produced a high levels of cytokines and stimulated increased TLO formation in the LF chip. In contrast, the cold lung and pancreatic cell lines did not induce the cytokine signature or TLOs. Importantly, TLO formation correlated with increased B cell activation, anti-tumor CD8 activity and tumor cell death. We have coupled this in vitro study with analysis of the pancreatic cancer transcriptome from the Cancer Genome Atlas to identify therapeutic targets to promote TLO formation in pancreatic cancer. In ongoing studies, we are assessing the functionality of the lung cancer TLO in vitro and in vivo and identifying therapeutics that may improve TLO formation in pancreatic cancer.
Citation Format: Yunhao Zhai, Pranav Prabhala, Lucas Barck, Min Wen Ku, Aditya Patil, Viktor Horvath, Russell A. Gould, Donald E. Ingber, Girija Goyal. Tertiary lymphoid organogenesis and lymphocyte activation in human organ chips [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 B063.
Abstract B081: SOAT1 as a targetable KRAS dependency in PDAC
Authors: Lan Wenjun , Sun Shoujun , Nigri Jeremy , Homer Josh , Park Young , Deschenes Astrid , Cifani Paolo , Cross Justin , Gaeth Victoria , Kim Sunny , Ting Shawn , Rubino Rachel , Moses John , Tuveson David 
Published: January 2024

Abstract
Metabolic rewiring is an emerging hallmark of neoplasia. In pancreatic ductal adenocarcinoma (PDAC), KRAS alters myriad metabolic programs to promote cellular transformation. Among them, the cholesterol synthesis pathway has emerged as a vulnerability of cancer cells due to the importance of cholesterol in membrane fluidity and the production of isoprenoid intermediates that enable KRAS membrane localization and activation in pancreatic cancer. We recently reported that the non-essential gene SOAT1 (Sterol-O-Acyl transferase 1), encoding an enzyme that esterifies free cholesterol into an insoluble form for storage and transport, is markedly upregulated in metastatic PDAC cells. SOAT1 promotes the hyperactivation of the mevalonate synthesis pathway due to loss of negative feedback by free cholesterol, thereby leading to increased production of isoprenoids such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are required for RAS and RHO membrane localization and activity, respectively. Genetic ablation of Soat1 reduced RAS and RHO membrane localization and inhibited cellular proliferation and mitochondrial function in vitro, and these effects were largely rescued by exogenous FPP and GGPP. Therefore, our study nominated SOAT1 as a new candidate gene for therapeutic targeting. Based on SuFEx Click Chemistry (ASCC) technology, we have designed and synthesized a panel of drug-like candidates. The first series of Soat1 probes selectively impair the proliferation of PDAC cells that express SOAT1, reduce SOAT1 protein content in cells, and covalently bind to SOAT1. In mice, the most active SOAT1 probes were tolerated in a 28-day daily dosing study up to 120 mg/kg. Marked tumor growth inhibition was noted in mice bearing PDAC xenografts and GEMM mice treated as monotherapy with 15 mg/kg/d of the most active SOAT1 probe, and tissue analysis demonstrated tumor necrosis, decreased proliferation, and increased apoptosis. Mechanistically, SOAT1 loss or inhibition targets multiple important components of cellular transformation in PDAC including KRAS, RHO, and mitochondrial biology, and our work suggests that it is an attractive target to pursue for further drug development in this cancer.
Citation Format: Wenjun Lan, Shoujun Sun, Jeremy Nigri, Josh Homer, Young Park, Astrid Deschenes, Paolo Cifani, Justin Cross, Victoria Gaeth, Sunny Kim, Shawn Ting, Rachel Rubino, John Moses, David Tuveson. SOAT1 as a targetable KRAS dependency in PDAC [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 B081.
Abstract B084: Overcoming drug resistance of ‘tri-complex’ pan-RAS inhibitors: Inhibition of mTOR signaling
Authors: Lin Qingxiang (Nick) 
Published: January 2024

Abstract
Background: RAS mutations occur in ~20% of all cancers that drive tumor progression, and therapy targeting most predominant RAS mutations remains unavailable. Mutant-selective RAS inhibitors (RASi), such as FDA-approved KRAS G12C inhibitors, have demonstrated initial clinical responses but drug resistance frequently emerges that minimize the drug efficacy, mechanistically mediated by RAS signaling reactivation. Methods and Results: To address this challenge, we characterized a class of novel pan-RASi that universally inhibit all RAS mutations, which forms a ‘tri-complex’ with the chaperone protein (cyclophilin A) that specifically binds to RAS, including wild-type RAS (KRAS, NRAS, HRAS). Mutant-selective RASi induced RAS signaling rebound intensively, whereas pan-RASi enabling to inhibit wild-type RAS minimized this rebound, which was surmountable in a concentration-dependent manner. Importantly, pan-RASi abrogated cell viability in patient-derived KRAS-mutant cancer organoids rather than in normal patient-derived wild-type RAS organoids, implicating drug selectivity and manageable toxicity. Interestingly, intrinsic resistance to pan-RASi was rare in RAS-mutant cancer cell screening but was observed only in a handful of pancreatic and lung cancer cell lines. Our time-resolved signaling analyses of pan-RASi treatment showed the re-activation of mTOR signaling and a contrast correlation that mTOR signaling decreased in sensitive lines but remained in resistant lines, underscoring the critical contribution of mTOR pathways to RASi resistance. Mechanistically, we further identified mTOR signaling that drives intrinsic resistance to pan-RASi, and combined pan-RASi with mTOR inhibitors (mTORi) suppressed mTOR signaling in resistant lines, thereby improving efficacy. Conclusion: Pan-RASi hold promise in treating RAS-mutant cancer clinically and a combination of pan-RASi with mTORi can improve drug efficacy.
Citation Format: Qingxiang (Nick) Lin. Overcoming drug resistance of ‘tri-complex’ pan-RAS inhibitors: Inhibition of mTOR signaling [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 B084.
Abstract B092: CDK8 and CXCL2 remodel the tumor microenvironment to contribute to KRASG12D small molecule inhibition resistance in pancreatic ductal adenocarcinoma
Authors: McAndrews Kathleen M. , Mahadevan Krishnan K. , Li Bingrui , Sockwell Amari M. , Morse Sami J. , Kelly Patience J. , Kirtley Michelle L. , Conner Meagan R. , Patel Sarah I. , Khumbar Shreyasee V. , Arian Kent A. , Barekatain Yasaman , Moreno Diaz Barbara A. , Lyu Hengyu , Sugimoto Hikaru , Sthanam Lakshmi Kavitha , Sobhani Navid , Paradiso Francesca , Bernard Vincent , Guerrero Paola , Ying Haoqiang , Maitra Anirban , Heffernan Timothy P. , Kalluri Raghu 
Published: January 2024

Abstract
Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with over 50% of PDAC patients presenting with KRASG12D mutations. The recent development of small molecule inhibitors targeting KRASG12D has enabled effective targeting of mutant KRAS signaling and suppression of tumor growth; however, the contribution of the tumor microenvironment to the therapeutic efficacy of KRASG12D inhibition and mechanisms of resistance to KRASG12D suppression remain to be fully elucidated. Here, we employed spatial transcriptomics and proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRASG12D inhibition with MRTX1133. MRTX1133 treatment was associated with increased antigen presenting cells (APCs), T cells, and putative tumor-restraining fibroblasts within proximity to cancer cells, suggesting that antigen presentation and remodeling of the local microenvironment facilitates an effective response to KRASG12D inhibition. In the context of relapsed MRTX1133 treated tumors, single cell RNA sequencing and validation identified CDK8 as an intrinsic mediator of resistance and CXCL2 as an extrinsic mediator of resistance. Together, these studies identify APCs and CDK8 as therapeutic targets for enabling long term responses to small molecule KRASG12D inhibition with MRTX1133.
Citation Format: Kathleen M. McAndrews, Krishnan K. Mahadevan, Bingrui Li, Amari M. Sockwell, Sami J. Morse, Patience J. Kelly, Michelle L. Kirtley, Meagan R. Conner, Sarah I. Patel, Shreyasee V. Khumbar, Kent A. Arian, Yasaman Barekatain, Barbara A. Moreno Diaz, Hengyu Lyu, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Navid Sobhani, Francesca Paradiso, Vincent Bernard, Paola Guerrero, Haoqiang Ying, Anirban Maitra, Timothy P. Heffernan, Raghu Kalluri. CDK8 and CXCL2 remodel the tumor microenvironment to contribute to KRASG12D small molecule inhibition resistance 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 B092.
Abstract B096: Acquired resistance to KRAS inhibition modulates the pancreatic cancer tumor microenvironment
Authors: Gulay Kevin Christian Montecillo , Patel Jay , Ng Isabella , de Mendoza Tatiana Hurtado , Tiriac Herve , Lowy Andrew 
Published: January 2024

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with dismal patient outcomes. Acquired resistance to chemotherapeutics is a major barrier to successful pancreatic cancer treatment. MRTX-1133 is a potent, selective KRAS G12D inhibitor that is in early-phase clinical trials. While initially effective, clinical experience with KRAS G12C inhibitors has shown tumors rapidly acquire therapeutic resistance. The tumor microenvironment (TME) plays a pivotal role in resistance development by activating prosurvival pathways, promoting epithelial-mesenchymal transition (EMT) and stemness, and inhibiting apoptosis. In this study, we sought to understand changes in the PDAC TME associated with acquired resistance to KRAS G12D inhibition. Methods: In order to investigate resistance to KRAS G12D inhibition in PDAC, we developed various mouse and human MRTX-1133 resistant (MRTXR) cell models (FC1199, FC1242, FC1245, and SUIT2). Intriguingly, these models also displayed resistance to several pan-RAS(ON) inhibitors. We utilized flow cytometry analysis to investigate the dynamic changes occurring in the TME following resistance to MRTX-1133, and we employed cytokine array and RNA-seq analyses to elucidate the impact of cancer cells on gene and protein expression of TME cells. Results: A comparative analysis between parental PDAC cells and MRTXR tumors revealed significant alterations within the TME. We found a significant decrease (p=0.013, p=0.045, respectively) in the number of inactivated and naïve CD8 T cells (CD8+/CD69+ and CD44-/CD62L+ cells) in MRTXR tumors. We also observed an upregulation of CXCL1, CCL20, and CXCL2 secretion in MRTXR cells compared to parental cells. Conclusions: Pancreatic cancer cells with acquired resistance to KRAS inhibitors modulate their tumor microenvironment uniquely. Ongoing studies aim to identify the critical pathways responsible for these alterations and to develop alternative treatment strategies for KRAS therapy-resistant tumors.
Citation Format: Kevin Christian Montecillo Gulay, Jay Patel, Isabella Ng, Tatiana Hurtado de Mendoza, Herve Tiriac, Andrew Lowy. Acquired resistance to KRAS inhibition modulates the pancreatic cancer tumor microenvironment [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 B096.
Abstract C011: Detection of circulating tumor cells for the early detection of pancreatic cancer
Authors: Yeo Dannel , Klemm Vera , Saxena Payal , Bastian Althea , Strauss Heidi , Sandroussi Charbel , Wahlroos Sara , Grimison Peter , Rasko John E.J. 
Published: January 2024

Abstract
Introduction The majority of pancreatic cancer patients are diagnosed with advanced, metastatic disease. Biomarkers to detect pancreatic cancer at earlier stages could drastically improve the poor survival rates. Circulating tumor cells (CTCs) are tumor cells that disseminate or are shed into the vascular system and have been detected in patients at pre-malignant stages. However, detecting these rare cells accurately and reliably remains a challenge. The AccuCyte-CyteFinder system uses density-based enrichment of blood nucleated cells followed by detection of CTCs using fluorescence staining, whole slide scanning and automated image analysis. This study aimed to examine whether CTCs could be used to identify patients with pancreatic lesions likely to malignant. Methods 50 patients undergoing an endoscopic ultrasound procedure for a pancreatic mass were recruited at the Royal Prince Alfred Hospital, Sydney, Australia or Chris O’Brien Lifehouse, Sydney, Australia. Peripheral blood was collected prior to the procedure and processed for CTCs on the AccuCyte-CyteFinder platform using a CK+ EpCAM+ CD45- staining panel. Results 28% (14/50) were found to have an intraductal papillary mucinous neoplasm (IPMN), 10% (5/50) pancreatic ductal adenocarcinoma (PDAC), 6% (3/50) pancreatic neuroendocrine tumor (PNET), 42% (21/50) non-neoplastic pancreatic cyst, and 14% (7/50) normal (no mass found). CTCs were highest in the PDAC group with an average of 5 cells/ml, followed by the IPMN (3 cells/ml), pancreatic cyst (2.5 cells/ml), and PNET (0 cells/ml). 86% (12/14) of IPMN patients had detectable CTCs. 2 IPMN patients with CTC counts of more than 5 cells/ml resulted in a resected sample having high-grade dysplasia while 3 IPMN patients with no/low CTC counts resulted in a resected sample having low-grade dysplasia. There was no correlation with the size of the pancreatic mass and CTC number. Conclusions CTCs could be detected in patients with pre-malignant pancreatic cancer and could determine malignancy. CTCs could potentially be used to detect pancreatic cancer early however, larger patient numbers and longer follow-up are required to validate these findings.
Citation Format: Dannel Yeo, Vera Klemm, Payal Saxena, Althea Bastian, Heidi Strauss, Charbel Sandroussi, Sara Wahlroos, Peter Grimison, John E.J. Rasko. Detection of circulating tumor cells for the early detection 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 C011.
Abstract C017: The anti-fungal itraconazole improves immunotherapy efficacy in pancreatic ductal adenocarcinoma by reversing the immune-suppressive tumor microenvironment
Authors: Porazinski Sean , Man Jennifer , Chacon-Fajardo Diego , Yim Howard , El-Omar Emad , Joshua Anthony , Pajic Marina 
Published: January 2024

Abstract
Pancreatic cancer (PC) has 5-year survival rates of 11% and is projected to become the second leading cause of cancer-related deaths by 2030. Poor outcomes result from early metastasis and a lack of effectual therapies for advanced disease. Our previous large-scale genomics studies revealed PC is molecularly highly varied (1). This heterogeneity, lack of effective therapies and high mortality rate make PC a prime arena to advance personalised medicine strategies, where individual cancers are selected for optimal therapy depending on molecular subtype. Utilising our significant experience of molecular-guided anti-cancer therapies (2-6) and stromal biology expertise (2,6,7), we are taking drug-repurposing approaches to test agents with effects on stromal biology in combination with standard-of-care chemotherapies and immunotherapy, to improve clinical outcomes. Itraconazole is an FDA-approved anti-fungal with potential anti-cancer effects, although its efficacy in PC remains relatively unexplored. Preliminary in vivo findings indicate that itraconazole, in combination with standard-of-care chemotherapy gemcitabine/nab-paclitaxel, significantly delays disease progression in both mouse and patient-derived xenograft models of PC. Single cell RNA-seq analyses of tumors from the KPC orthotopic model of PC suggest itraconazole treatment can inhibit immunosuppressive aspects of the stroma and pro-tumorigenic, pro-metastatic signalling. Excitingly, combining itraconazole with anti-PD1/-CTLA4 immunotherapy provides significant survival advantages in the KPC orthotopic model of PC. Finally, using a model of metastatic PC, we show that itraconazole hinders metastatic colonisation in the liver. This work aims to identify subtypes of PC responsive to itraconazole allowing optimisation and translation of tailored therapies combining itraconazole and the latest clinically-utilised chemotherapies and immunotherapies. References1. Waddell, N. et al. Nature (2015). 2. Chou, A. et al. Gut (2018). 3. Li, L. et al. Br. J. Cancer (2020). 4. Belali, T. et al. BBA - GRM (2020). 5. Uzor, S. et al. Sci. Rep. (2021). 6. Porazinski, S. et al. Nature (2015). 7. Vennin, C. et al. Science Translational Medicine (2017).
Citation Format: Sean Porazinski, Jennifer Man, Diego Chacon-Fajardo, Howard Yim, Emad El-Omar, Anthony Joshua, Marina Pajic. The anti-fungal itraconazole improves immunotherapy efficacy in pancreatic ductal adenocarcinoma by reversing the immune-suppressive tumor microenvironment [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 C017.