bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B103: Development and characterisation of KRASmulti inhibitors for the treatment of KRAS mutant pancreatic ductal adenocarcinoma
Authors: Tedeschi Antonio , Schaaf Otmar , Gmachl Michael , Herdeis Lorenz , Rocchetti Francesca , Popow Johannes , Schischlik Fiorella , Gerlach Daniel , Lipp Jesse , Bröker Joachim , Mantoulidis Andreas , Smethurst Chris , Kessler Dirk , Boettcher Jark , Wunberg Tobias , Santoro Valeria , Waterson Alex , Phan Jason , Little Andrew , Abbott Jason , Sun Qi , Fesik Stephen , Mcconnell Darryl , Pearson Mark A. , Kraut Norbert , Rudolph Dorothea 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second most common cause of cancer related death within the next decade. Late detection and limited therapeutic options drive the dismal prognosis for PDAC patients. Activating mutations within the KRAS gene occur within the vast majority (&gt;85%) of PDAC tumors. KRAS mutations occur at an early stage within PDAC development but remain necessary for continued tumor growth. Clinical responses observed in patients with KRASG12C mutant PDAC treated with selective KRASG12C inhibitors have driven drug development programmes that can address other, more frequently occurring KRAS alleles. Here we report the characterization of a KRASmulti inhibitor, BI-2493, that potently inhibits the proliferation of mutant KRAS PDAC cancer cell lines in vitro. The DMPK properties of the compound have been optimized so that oral administration resulted in regression of KRAS mutant PDAC xenograft models. These data support the continued development of compounds capable of addressing the most prevalent KRAS mutant alleles in PDAC with the potential to provide a therapeutic option to patients in an indication with a high unmet medical need.
Citation Format: Antonio Tedeschi, Otmar Schaaf, Michael Gmachl, Lorenz Herdeis, Francesca Rocchetti, Johannes Popow, Fiorella Schischlik, Daniel Gerlach, Jesse Lipp, Joachim Bröker, Andreas Mantoulidis, Chris Smethurst, Dirk Kessler, Jark Boettcher, Tobias Wunberg, Valeria Santoro, Alex Waterson, Jason Phan, Andrew Little, Jason Abbott, Qi Sun, Stephen Fesik, Darryl Mcconnell, Mark A. Pearson, Norbert Kraut, Dorothea Rudolph. Development and characterisation of KRASmulti inhibitors for the treatment of KRAS mutant 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 B103.
Abstract B108: Integrated in vivo dissection of metastatic phenotypes and molecular programs in pancreatic ductal adenocarcinoma
Authors: Karmakar Saswati , Lyulina Anastasia , Xiong Xiaochen , Tang Yuning J. , Lopez Steven , Hughes Nicolas William , Attardi Laura , Petrov Dmitri A. , Winslow Monte M. 
Published: January 2024

Abstract
The ability of pancreatic ductal adenocarcinoma (PDAC) cells to form tissue destructive metastases remains a critical impediment to therapy. Metastasis is a complex multistep process that is poorly understood and the molecular events and cellular states that enable cancer cells to overcome each step of the metastatic cascade remain elusive. To investigate the regulators of PDAC metastasis, we accrued and characterized a panel of 31 cell lines generated from mouse models of PDAC. Initial experiments indicated that these cell lines have an ~40-fold difference in their ability to form lung metastases after transplantation into immunocompetent recipient mice. To more accurately quantify the relationship between metastatic seeding, growth, organ tropism, and immune evasion across all cell lines in parallel, we tagged each cell line with a barcode that provides both cell line-level and subclonal-level resolution. We pooled all 31 barcoded cell lines, transplanted them to seed metastases in different organs, and performed barcode sequencing on DNA from the metastasis-bearing tissues after short (seeding) and long (expansion) time periods. Neither seeding nor metastatic outgrowth correlated with growth in culture. Metastatic seeding did not directly correlate with overall metastatic burden, indicating that these processes depend on distinct biological processes. Transplantation into syngeneic immune-competent and immune-deficient recipient mice quantified the impact of immune responses towards each cell line. Bulk and single cell RNA-sequencing uncovered unexpected intra- and inter-cell line heterogeneity. Future experiments will integrate the data on metastatic phenotypes with molecular information to uncover drivers and inhibitors of each step of the metastatic cascade. Broad-scale molecular profiling coupled with quantitative in vivo analysis of metastatic phenotypes will uncover the relationships between metastatic phenotypes, create a resource for the community, and reveal novel pathways that govern PDAC metastasis, which could have implications for developing novel therapeutic strategies.
Citation Format: Saswati Karmakar, Anastasia Lyulina, Xiaochen Xiong, Yuning J. Tang, Steven Lopez, Nicolas William Hughes, Laura Attardi, Dmitri A. Petrov, Monte M. Winslow. Integrated in vivo dissection of metastatic phenotypes and molecular programs 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 B108.
Abstract C020: Unconvering the hidden immunosuppressive landscape in pancreatic ductal adenocarcinoma
Authors: Qian Guhan , Zhang Hongrong , Knott Aine , Zettervall Jon , Stromnes Ingunn , Provenzano Paolo 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest forms of cancer with an extremely low survival rate. Despite the success of therapeutic T cells in hematologic cancers, many solid tumors, including PDA, remain unresponsive with such therapies, partly due to its mechanically complex, dense, and immunosuppressive stroma. Therefore, understanding the dynamic interplay between therapeutic T cells and the tumor microenvironment (TME) is crucial for revealing engineering targets for next-generation immunotherapies. We approach this problem with genetically engineered KPC (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx-1-Cre) mouse models that recapitulates PDA disease progression and stromal dynamics. Within live tumor slices from primary tumors, we are defining how stromal components such as dense collagen fiber networks and tumor-associated macrophages (TAMs) orchestrate an immunosuppressive landscape. We employ multiphoton laser scanning microscopy (MPLSM) to generate multiphoton excitation of fluorescence (cell dyes and immunofluorescence) and second harmonic generation (SHG) for collagen fibers to acquire multidimensional data (x, y, z, c, t) of T cell migration and interaction within the TME. We subsequently reveal T cell migration and interaction as a function of its physical and biological ECM components using advanced computer vision and machine learning algorithms based on the Clustered Random Convolutional Kernel Transform (cROCKET), revealing a hidden landscape in the feature space. Perturbations to the TME in KPC mice with CCR2 inhibitor CCX598 (in vivo) and clodronate liposomes (ex vivo) deplete CD11b+ myeloid cells, resulting in altered behaviors of the infiltrating T cells. Anti-PD-1 monoclonal antibody neutralizes the PD-1/PD-L1 axis in T cells, resulting in enhanced migration and infiltration in tumor slices.
Citation Format: Guhan Qian, Hongrong Zhang, Aine Knott, Jon Zettervall, Ingunn Stromnes, Paolo Provenzano. Unconvering the hidden immunosuppressive landscape 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 C020.
Abstract C023: PTEN/STAT3 pathway in cancer-associated fibroblasts in Pancreatic Cancer
Authors: Saberi Samaneh , Bumbleburg Cameron , Jordan Victoria , Lefler Julia E. , Sharma Sudarshana , Ostrowski Michael C. 
Published: January 2024

Abstract
Pancreatic cancer is a devastating disease with a high mortality rate with a five-year survival rate of 12%. Recent studies have shed light on the crucial role of cancer-associated fibroblasts (CAFs) in shaping the tumor microenvironment. Our group demonstrated PTEN loss occurs in CAFs in ~25% of PDAC patient samples, which leads to increased activation of signaling pathways in CAFs, including the STAT3 pathway. Conditional deletion of STAT3 in CAFs in a dual flpO/cre recombinase PDAC model correlated with increased survival, decreased M2-like macrophages and increased T-cell infiltration. In the present study we aimed to test the hypothesis that direct interactions between PTEN and STAT3 in cancer CAFs contributes to an immuno-suppressive tumor microenvironment in pancreatic ductal carcinoma (PDAC). To address this hypothesis, we utilized CAFS isolated from the dual recombinase PDAC model. Proximity ligation assays with these CAFS demonstrated that PTEN-STAT3 are in a complex in the cell cytosol that translocate to the nucleus upon IL6 treatment. This finding was validated by co-immunoprecipitation experiments. ChIP-seq analysis of CAFs with PTEN and pSTAT3/STAT3 antibodies revealed a significant overlap in PTEN and pSTAT3/STAT3 occupation of gene promoters. Integrative analysis of PTEN-STAT3 bound genes with corresponding RNA-seq data revealed that the PTEN/STAT3 complex targets cytokines and ligands that directly affect T-cell function, contributing to an immune suppressive microenvironment. Analysis of human PDAC samples support the relationship between STAT3 activation and T-cell activity. Identifying PTEN/STAT3 targets in CAFs may provide new avenues for overcoming the anti-tumor immune responses in PDAC.
Citation Format: Samaneh Saberi, Cameron Bumbleburg, Victoria Jordan, Julia E. Lefler, Sudarshana Sharma, Michael C. Ostrowski. PTEN/STAT3 pathway in cancer-associated fibroblasts 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 C023.
Abstract C024: Single-cell transcriptomics reveals unique stromal and metabolic heterogeneity in liver metastatic pancreatic cancer
Authors: Singh Rima , Yousefian Natalie , Steele Nina , Halbrook Christopher 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer related deaths in the US. This mortality is strongly linked to the complex PDA tumor microenvironment that drives resistance to chemotherapy and immune suppression. Most patients succumb to metastatic disease, with liver being the most frequently colonized organ. Despite this, most pre-clinical studies have focused on primary PDA models to study the disease. Accordingly, the extent that the liver metastatic niche promotes immune evasion and resistance to treatment remains unclear. To directly compare primary vs. metastatic tumors in PDA tumors, we have optimized a syngeneic experimental model to contrast primary vs. metastatic lesions. To define the similarities and differences between cell types present in these tumors, we employed a single-cell transcriptomics approach. Our analysis has identified shared populations of malignant epithelial, stromal, and immune cells between lesions, allowing for a direct comparison of programming. Here, we have observed that the dominant populations of PDA cells in pancreas vs. liver tumors engage in distinct metabolic programs that suggest different actionable vulnerabilities. Beyond these, we also observed fibroblasts and myeloid sub-populations that are exclusive to liver tumors. These data further support our hypothesis that alternative mechanisms of metabolic, immune, and stromal interactions take place in the metastatic tumor microenvironment. To define these crosstalk networks, we employed the interactome tool CellChat, which has uncovered unique signaling interactions between the CAF and cancer cell populations in pancreatic and liver tumors. Overall, these data have the potential to lead to new avenues to directly target cancer cells or engage an effective immune response that can be designed to treat metastatic pancreatic cancer- an urgent clinical need.
Citation Format: Rima Singh, Natalie Yousefian, Nina Steele, Christopher Halbrook. Single-cell transcriptomics reveals unique stromal and metabolic heterogeneity in liver metastatic 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 C024.
Abstract C032: The involvement of the splanchnic program at the cellular and molecular levels in pancreatic cancer associated fibroblasts
Authors: Walter Tom , Han Lu , Ostrowski Michael 
Published: January 2024

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by a dense stroma primarily composed of cancer associated fibroblasts (CAFs). Our group recently performed a lineage tracing study using genetically engineered mouse models. This study demonstrated that CAFs and pancreatic tissue resident fibroblasts (TRFs) are both derived from the fetal splanchnic mesenchyme, an area of mesoderm next to the foregut endoderm. To determine whether two major subtypes of CAFs are derived from the splanchnic mesenchyme, I analyzed co-expression of the lineage tracing marker Tomato and CAF subtype marker a smooth muscle actin (aSMA). This suggests that both myofibroblasts (aSMA high) and inflammatory fibroblasts (aSMA low) are derived from the splanchnic mesenchyme. Furthermore, we found that transcription factor Gata6 is expressed in the splanchnic mesenchyme and in some CAFs. We constructed mouse genetic models where Gata6 is specifically deleted in fibroblasts. These Gata6 conditional knock out mice had increased tumor burden, suggesting that stromally-expressed Gata6 has a tumor restraining role. We derived CAF and TRF cell lines from these genetic mouse models and their littermate normal mice. My preliminary data suggest that several important fibroblast factors, including type I collagen, aSMA, and Interleukin 6, are upregulated in the Gata6 KO CAFs and TRFs relative to normal CAFs and TRFs. In summary, our study showed that two major subtypes of pancreatic CAFs are derived from the splanchnic mesenchyme, and splanchnic factors may play a role in adult pancreatic fibroblasts to regulate the expression of critical fibroblast genes.
Citation Format: Tom Walter, Lu Han, Michael Ostrowski. The involvement of the splanchnic program at the cellular and molecular levels in pancreatic cancer associated fibroblasts [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 C032.
Abstract C036: Restoration of T effector cells function by targeting senescent cancer-associated fibroblast in tumor microenvironment of stroma-rich cancers
Authors: Wang Yao , Apostolopoulou Hara , Sanyal Arjun , Sun Hong , Sieland Cynthia , Gupta Kavya , Ye Jiayu , Gibbs David , Wong Paul , Vasilis Ntranos , Huang Sui , Gardner James , Maker Ajay , Tlsty Thea , Bhushan Anil , Alliston Tamara 
Published: January 2024

Abstract
The stroma that surrounds the tumor in many solid cancers exhibits potent immunosuppressive activity to promote tumor progression and confer resistance to immune-based therapies. Cancer associated fibroblasts (CAFs) encompassing functionally distinct populations are key components of the stroma that are emerging as a key cell type in regulating an immune response. However, the mechanisms by which CAFs can directly suppress the immune activity to promote tumor growth is not clear. Here, we identify that a subset of CAF in both rodent and human stromagenic cancers that displays characteristics of senescent fibroblasts and referred to as sCAFs. We show that sCAFs secrete a decoy protein that interferes with cytotoxic activity of activated T effector (Teff) cells. In mouse models for stroma-rich pancreatic cancer, administration of an antibody that blocked the decoy protein resulted in recalibration of the stromal fibroblast by promoted the formation of interferon-licensed-fibroblast cells at the expense of sCAFs. This switch not only enhanced infiltration of tumor-infiltrating T cells but also alleviated their direct suppression resulting in enhanced effector function and tumor regression. Collectively, these results point to the potent immunosuppressive activity of sCAFs mediated by decoy protein as a mechanism by which stroma can promote tumor progression. As stromagenic-cancers are resistance to current therapies, the development of treatments involving blocking of decoy protein may inhibit tumor growth and improve patient survival.
Citation Format: Yao Wang, Hara Apostolopoulou, Arjun Sanyal, Hong Sun, Cynthia Sieland, Kavya Gupta, Jiayu Ye, David Gibbs, Paul Wong, Ntranos Vasilis, Sui Huang, James Gardner, Ajay Maker, Thea Tlsty, Anil Bhushan, Tamara Alliston. Restoration of T effector cells function by targeting senescent cancer-associated fibroblast in tumor microenvironment of stroma-rich cancers [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 C036.
Abstract C038: Interim pharmacodynamic analyses of mitazalimab in combination with FOLFIRINOX in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) identify CD4 effector T cells as a correlate of treatment outcomes
Authors: Wattenberg Max M. , Smith Karin Enell , de Coana Yago Pico , Jimenez David Gomez , Carlsson Malin , Ambarkhane Sumeet Vijay , Ellmark Peter , Beatty Gregory L. 
Published: January 2024

Abstract
CD40 agonists are being investigated in combination with standard of care chemotherapy as an approach to trigger anti-tumor immunity and improve outcomes for patients with cancer. Preclinical models suggest the importance of appropriate sequencing of chemotherapy and a CD40 agonist. Herein, we report interim pharmacodynamic analyses and their association with outcomes from a Phase 2 study evaluating mitazalimab, a CD40 agonist, in combination with modified (m) FOLFIRINOX chemotherapy as first line therapy in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Patients with newly diagnosed mPDAC were treated with mitazalimab on day 1 prior to beginning an every 2-week regimen on day 8 of mFOLFIRINOX followed by mitazalimab 48 hours later. Tumor response was determined by RECIST v1.1 imaging. Peripheral blood was analyzed for selected cytokines and chemokines and by flow cytometry to assess changes in leukocyte subsets including B cells, monocytes, T cells, and NK cells. The neutrophil-to-lymphocyte ratio was determined from complete blood counts. The analysis included 23 patients with associated response data and indicated a mitazalimab-specific contribution to tumor response. Mitazalimab triggered an expected immune response characterized by transient cytokine (IL-8, IP-10, MCP-1, and MIP1b) release and B cell depletion. Chemotherapy provoked a reduction in classical monocytes and proliferating CD4+ T cells. Both mitazalimab and chemotherapy caused a transient reduction in circulating dendritic cells and NK cells. Tumor response was associated with an expansion in the frequency of effector CD4 T cells (p &lt; 0.0001) at day 8 after receiving mitazalimab but did not correlate with neutrophil-to-lymphocyte ratio (p = 0.851). In conclusion, mitazalimab and FOLFIRINOX modulate immune responses in patients with mPDAC in different ways. Interim results of pharmacological analyses identify CD4 effector T cells as a correlate of treatment outcomes suggesting the contribution of mitazalimab to tumor responses.
Citation Format: Max M. Wattenberg, Karin Enell Smith, Yago Pico de Coana, David Gomez Jimenez, Malin Carlsson, Sumeet Vijay Ambarkhane, Peter Ellmark, Gregory L. Beatty. Interim pharmacodynamic analyses of mitazalimab in combination with FOLFIRINOX in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) identify CD4 effector T cells as a correlate of treatment outcomes [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 C038.
Abstract C039: Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of pancreatic ductal adenocarcinoma
Authors: Wen Hui-Ju , Crawford Howard 
Published: January 2024

Abstract
Activation of cellular signaling pathways by crosstalk between tumor cells and their microenvironment is an essential mechanism supporting pancreatic carcinogenesis. In this study, we aim to disrupt cellular signaling pathways by targeting ADAM17 (a disintegrin and metalloprotease 17). ADAM17 is a membrane bound enzyme which cleaves cell surface proteins. Its function is closely linked with autocrine and paracrine signaling of immunomodulation as well as activation of EGFR, which is a central molecule for pancreatic tumorigenesis. To investigate whether EGFR is activated via a paracrine manner from macrophages, the most abundant immune-related stromal cells in pancreas cancers, we generated a pancreatic tumor mouse model with ADAM17 deletion in myeloid cells by using a dual recombinase strategy. We observed that lack of ADAM17 in the myeloid cells resulted in a delay of acinar cell transformation and an associated decrease in EGFR activation. To further examine the tumor supportive role of ADAM17, inhibition of ADAM17 using anti-ADAM17 antibody, MEDI3622, was tested in orthotopic tumor bearing mice. systemic inhibition of ADAM17 led to a reduction in tumor burden and a concomitant decrease in EGFR activation. These effects were observed exclusively in the immunocompetent animals, but not in the immunodeficient animals. It implicates that inhibition of tumor growth by MEDI3622 is highly dependent on the immune response. Furthermore, we found an elevated level of CCL21 in the MEDI3622-treated tumors resulting in increased tumor infiltration by dendritic cells and cytotoxic T cells for tumor killing. Altogether, ADAM17 blockade displays a pronounced anti-tumor effect, suggesting ADAM17 as a therapeutic target of pancreatic cancer.
Citation Format: Hui-Ju Wen, Howard Crawford. Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of 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 C039.