tbuckley/cabot-search huggingface dataset:
Abstract C116: Oncogenic Kras signaling shapes the tumor microenvironment in lung adenocarcinoma
Authors: Rachael Baliira, Emily Lasse Opsahl, Ivana Barravecchia, Marina Pasca di Magliano, Stefanie Galban
Journal: Cancer Research (2024)

Abstract Despite advancements in targeted therapy and immunotherapy, lung cancer remains the leading cause of cancer-related deaths in both men and women worldwide, with an estimated 2.2 million deaths each year. At 85%, non-small cell lung cancer (NSCLC) is by far the most common subtype, comprising adenocarcinomas and lung squamous cell carcinoma. Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR) and anaplastic lymphoma receptor tyrosine kinase (ALK) genes are common, with the worst overall survival in KRAS mutant adenocarcinoma patients. About 40% of lung tumors with KRAS mutations also harbor mutations in tumor protein p53 gene (TP53), a tumor suppressor gene. KrasG12C and KrasG12D are both prevalent mutations in lung cancer. Sotorasib, a KrasG12C inhibitor, was recently approved for treatment of NSCLC. However, only 37% of patients have an objective response to Sotorasib, with a median duration of just 11 months. The KrasG12D inhibitor MRTX1133 is entering clinical trials; elucidating the mechanism of action and potential resistance is imperative to design combination treatment approaches. While cell-intrinsic mechanisms of resistance in epithelial oncogenic KRASG12D (Kras*) are well studied, our group and others have shown that KRASG12D also extrinsically regulates the tumor microenvironment (TME) in pancreatic cancer. Whether and how this oncogene regulates the TME of lung cancer is less understood. To study the crosstalk between epithelial lung cells expressing oncogenic KRAS and the surrounding TME, we have established a triple transgenic murine model of Kras*-driven NSCLC, wherein both lung epithelial-specific expression of Kras* and expression of mutant TP53R172H (Tp53*) can be controlled in an inducible and reversible manner. Our preliminary data show that expression of Kras* drives tumor growth, while Kras* depletion results in regression, even in the presence of Tp53*. Here we interrogate how Kras* modulates the TME in lung adenocarcinomas. Harnessing scRNA sequencing, immunohistochemistry, and multiple biochemical approaches, we will provide insight into changes in stromal and immune contexture upon Kras* depletion in mice. Citation Format: Rachael Baliira, Emily Lasse Opsahl, Ivana Barravecchia, Marina Pasca di Magliano, Stefanie Galban. Oncogenic Kras signaling shapes the tumor microenvironment in lung 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 C116.
Abstract C043: Spatial proteomic immune profiling of pancreatic ductal adenocarcinoma and the tumor microenvironment
Authors: Jason Yeung, Yunhao Bai, Yao Yu Yeo, Huaying Qiu, Bokai Zhu, Lara R. Heij, Enas Abu Shah, Garry P. Nolan, Shivan Sivakumar, Sizun Jiang
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis and treatment options. Technological challenges in dissecting the immune constituents of the PDAC tumor microenvironment (TME) has limited our understanding of the complex disease mechanisms in vivo, which may in part explain the lack of novel therapeutics for this recalcitrant disease. Here, we performed spatial proteomics using the multiplexed ion beam imaging (MIBI) approach to quantify 36 spatial signatures in tissues from a cohort of twelve treatment naïve PDAC patients. We applied a deep learning segmentation algorithm to better resolve expression levels at the single cell resolution, and robustly stratify phenotypes through an iterative process of clustering and annotation, with expert visual validation. The combination of phenotypic quantification, functional marker evaluation within the cell types identified, as well as machine-learning based topic modeling to understand cellular neighborhoods, can better explain the cellular and functional components within the intricate PDAC TME. Our analysis revealed markedly lower B and effector T cell infiltration in the treatment-naive TME of patients who eventually relapsed to date following adjuvant chemotherapy. We additionally observed the enrichment of myeloid cell populations, including tumor-associated macrophages and neutrophils, associated with PDAC tumorigenesis and worse prognosis. A deeper analysis of our functional protein expression exhibited the enrichment of GATA3 in regulatory T cells in relapsed patients, a marker which has been associated with increased accumulation and infiltration of Tregs at inflammatory sites. Our study demonstrates the importance of a targeted dissection of the spatially orchestrated immune responses and dysregulation associated with PDAC, and exemplifies how a deeper understanding of the immune and tumor components and functional aspects in situ can help improve our understanding for patients with this disease. Citation Format: Jason Yeung, Yunhao Bai, Yao Yu Yeo, Huaying Qiu, Bokai Zhu, Lara R. Heij, Enas Abu Shah, Garry P. Nolan, Shivan Sivakumar, Sizun Jiang. Spatial proteomic immune profiling of pancreatic ductal adenocarcinoma and the 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 C043.
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: Max M. Wattenberg, Karin Enell Smith, Yago Pico de Coana, David Gomez Jimenez, Malin Carlsson, Sumeet Vijay Ambarkhane, Peter Ellmark, Gregory L. Beatty
Journal: Cancer Research (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 &amp;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 B078: A complex of NF1 and SPRED2 non-canonically behave as tumor promoters in pancreatic cancer
Authors: Sun Kim, Hsiu-Chi Ting, Astrid Deschenes, Jonathan Kastan, Youngkyu Park, David Tuveson
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with poor prognosis due to late detection and lack of effective therapeutic options. &amp;gt;90% of PDAC tumors are driven by activating mutations in the KRAS oncogene, making it an appealing subject for further investigation into understanding PDAC biology and offering a potential genetic vulnerability to target in patients. Our laboratory has previously reported a mutant-KRAS-proximal complex at the plasma membrane that consists of tumor-suppressor Neurofibromatosis type 1 (NF1), Sprouty Related EVH1 Domain Containing 2 (SPRED2), and Ribosomal S6 Kinase 1 (RSK1). This complex mechanistically suppresses WT KRAS signaling via RSK1, a suppression which is then relieved upon mutant KRAS inhibition, ultimately promoting adaptive resistance for PDAC cells under these conditions. We find that both knockout of either NF1 or SPRED2 in PDAC organoids induces a substantial growth defect in vivo. Our preliminary data suggests that NF1 and SPRED2 support KRAS activity in mouse pancreatic cancer in vivo. Moreover, both SPRED2 and NF1 KO show decreased proliferation, invasion, and attachment on collagen family members in vitro. Given NF1's well-established role as a tumor-suppressor, our observations of decreased tumorigenic properties upon NF1 deletion are unexpected. We hypothesize that NF1 and SPRED2 promote tumorigenesis via recruitment of RSK1 to the plasma membrane, inducing the phosphorylation of putative substrates to stimulate a pro-migratory cellular behavior. Our work suggests the existence of a unique RSK1 program localized at the plasma membrane by mutant KRAS, providing a new facet of oncogenesis to investigate for fundamental understanding and potential therapeutic opportunities. Citation Format: Sun Kim, Hsiu-Chi Ting, Astrid Deschenes, Jonathan Kastan, Youngkyu Park, David Tuveson. A complex of NF1 and SPRED2 non-canonically behave as tumor promoters 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 B078.
Abstract B035: Investigating the roles of GLI transcription factors in the pancreatic cancer microenvironment
Authors: Paola Isabel Medina-Cabrera, Michael Scales, Nina Steele, Benjamin Allen, Marina Pasca di Magliano
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDA) remains a difficult cancer to treat due to an extensive and complex tumor microenvironment. In particular, intercellular signaling between tumor cells, fibroblasts and immune cells is a key contributor to pancreatic tumor growth. One of these signals, the Hedgehog (HH) pathway, is a known feature of PDA. Pancreatic tumor cells secrete HH ligands, which signal in a paracrine fashion to fibroblasts in the tumor microenvironment. Notably, the role of HH signaling is complicated, with reports suggesting both tumor-promoting and tumor-restraining functions in pancreatic cancer. GLI proteins (GLI1-3) are the transcriptional effectors of the HH pathway; their contribution to pancreatic tumor growth is equally complex. This study seeks to investigate the contribution of GLI1-3 in PDA progression. Our lab has demonstrated that Gli1-3 are expressed in pancreatic fibroblasts and that all three Glis functionally contribute to pancreatic cancer progression through effects on immune cell infiltration. To further explore the mechanisms of GLI function, we have generated a novel mouse model carrying endogenous, epitope-tagged Gli alleles (Gli1FLAG/FLAG;Gli2HA/HA;Gli3V5/V5). This model will allow us to define GLI protein processing and localization as well as the identification of target genes to elucidate the contribution of GLI-driven transcriptional programs that regulate tumor immune infiltration in PDA. Citation Format: Paola Isabel Medina-Cabrera, Michael Scales, Nina Steele, Benjamin Allen, Marina Pasca di Magliano. Investigating the roles of GLI transcription factors in the pancreatic cancer 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 B035.
Abstract A081: The pan-quadruplex experimental drug QN-302 in pancreatic ductal adenocarcinoma (PDAC): Potential biomarkers for clinical studies
Authors: Ahmed Ahmed, Tariq Arshad, Stephen Neidle
Journal: Cancer Research (2024)

Abstract Quadruplexes (G4s) are formed from G-rich elements widely prevalent in the human and other genomes. They comprise repetitive G-tracts of varying length, interspersed with short general sequences, which can fold into higher-order four-stranded G4 structures under appropriate circumstances. Their prevalence is non-random, and they are over-represented in the promoter and untranslated regions of genes involved in replication and replication pathways, especially in cancer-related events and pathways. Promoter G4s have been characterised in, for example, the RAS, MYC, KIT, B-RAF, HIF, VEGF genes. The existence of stable G4 structures within duplex DNA is likely to be transient since they can be effectively unwound by helicases. However, it is now well-established that they can be stabilised by appropriate small molecules, leading to impairment of polymerase precession and transcription factor binding, and then to down-regulation of the expression of the affected gene. This therapeutic strategy has been exploited in the design of a series of potent G4-binding compounds based on the naphthalene diimide framework, culminating in the development of the compound QN-302, which has selectivity to PDAC cell lines with low nM potency. It is also active in several in vivo models of PDAC. Its transcriptional profile shows that it affects multiple G4 promoter genes and thus acts as a pan-G4 agent. QN-302 has been undergoing pre-clinical development by Qualigen Inc and in 2022 was granted Orphan Drug designation for PDAC by the FDA. It is currently being evaluated for clinical development in solid tumors including PDAC. As part of this program, several potential biomarkers are currently being considered. These in large part are suggested by the transcriptome analyses of QN-302 in cells and in vivo. They are established markers of progressive PDAC and thus may be useful for indicating the success of QN-302 therapy in humans. In addition, our orthotopic study of the effects of QN-302 on orthotopically implanted BX-PC3 tumors has indicated that circulating tumor DNA may be a useful indicator of tumor regression by QN-302. Citation Format: Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The pan-quadruplex experimental drug QN-302 in pancreatic ductal adenocarcinoma (PDAC): Potential biomarkers for clinical studies [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 A081.
Abstract A067: A single sample classifier of Bailey's molecular subtype of PDAC
Authors: Taisuke Baba, Masaki Sunagawa, Junpei Yamaguchi, Toshio Kokuryo, Tomoki Ebata
Journal: Cancer Research (2024)

Abstract &amp;lt;Background&amp;gt; Transcriptomic molecular subtype of pancreatic cancer (PDAC) is expected to be an important part of future personalized medicine. However, most classifier methods are based on the relative expression patterns in the dataset. Batch correction methods are still under development, thus no one can know if the subtyping of their own dataset is accurate, which has made many researchers hesitant to perform studies involving molecular subtyping. PurIST is a robust classifier of Moffitt tumor subtype invented by Rashid et al. It calculates a score based on the expression pattern within a sample and predicts a specific subtype. Unlike traditional cluster-based subtyping, the predicted subtype never changes. Because these types of methods are independent of the cohort composition and the prediction can be made for even a single sample, these methods are called single sample classifiers (SSCs). The approaches of most SSCs to absorb the batch differences are to make the information fuzzy, thus sacrificing the predictive ability. In this study, we invented a single sample classifier called inverse pair boosting (IPB). Our approach does not lose information, instead, magnifies the differences between subtypes and relatively reduces the differences between batches to a negligible level. &amp;lt;Methods and Results&amp;gt; Considering Moffitt's tumor classification, classical tumors have high classical gene expressions and low basal-like gene expressions, whereas, the gene expression patterns of basal-like tumors are the other way around. This kind of one side up and the other side down relationship is widely observed in the gene expression pattern. We used this to enhance the subtyping difference and overcome the batch differences. We developed a machine learning model with IPB method based on the Bailey's original RNA-seq data (PACA-AU RNA-seq), and tested its robustness with PACA-AU microarray data. Although there is a huge gap between RNA-seq data and microarray data due to their different modalities, the accuracy of the Bailey's subtype prediction on microarray data was 0.86, which was much higher than other SSCs (accuracy = 0.60 - 0.67). &amp;lt;Conclusion&amp;gt; We developed a single sample classifier of Bailey's molecular subtype of PDAC using novel approach called IPB. Our AI model can make a significant contribution to the development of research on molecular subtypes of PDAC. Citation Format: Taisuke Baba, Masaki Sunagawa, Junpei Yamaguchi, Toshio Kokuryo, Tomoki Ebata. A single sample classifier of Bailey's molecular subtype of 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 A067.
Abstract A019: Neoplastic co-option of epithelial-immune interactions in pancreatic cancer
Authors: Direna Alonso-Curbelo
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is initiated by a complex interplay between genetic and environmental insults that induce a marked remodeling of the pancreatic epithelium and its immune cell landscape. These tissue changes are highly reminiscent of wound healing responses, yet they critically contribute to disease pathogenesis. How regenerative tissue plasticity is co-opted to drive PDAC pathogenesis remains poorly understood. Our recent work identified cancer-associated chromatin alterations in the pre-malignant pancreatic epithelium that are induced by cooperative effects of mutant KRAS and tissue damage (inflammation). These synergistic processes aberrantly activate several cell communication factors, such as IL-33, that establish an expansive communication network among selective KRAS-mutant subpopulations and their immune environment that contributes to tumor development (Alonso-Curbelo et al., Nature 2021; Burdziak*, Alonso-Curbelo* et al., Science 2023). These epigenetically-activated communication networks are not shared with physiological regenerative processes, and represent a molecular groundwork to understand (onco)gene-environment cooperation and identify early, tumor-specific cancer mechanisms. They also provide new opportunities at the intersection of cancer biology, epigenetics and immuno-oncology for exploiting cell-cell communication traits of early KRAS-mutant cells and their niches to block the emergence and progression of neoplastic lineages. To address these questions, we are integrating single-cell genomics profiling, functional perturbations, and multiplexed tissue analyses to identify early molecular programs responsible for co-opting immune responses in PDAC, define how these shape influence tumor evolution, and identify crosstalk networks sustaining disease maintenance. Ultimately, a deeper mechanistic understanding of how early epigenetic dysregulation directs regenerative immune responses towards cancer will expose new therapeutic concepts to selectively target pro-tumor inflammation without impairing homeostatic tissue responses. Citation Format: Direna Alonso-Curbelo. Neoplastic co-option of epithelial-immune interactions 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 A019.