tbuckley/cabot-search huggingface dataset:
Abstract C063: Keratin 17 as a predictor of chemotherapy response in pancreatic ductal adenocarcinoma
Authors: Lyanne Oblein, Lucia Roa, Sruthi Babu, Michael Horowitz, Emanuel Petricoin, Lynn M. Matrisian, Edik Blais, Natalia Marchenko, Felicia Allard, Ali Alkalin, Wei Jiang, Brent Larson, Andrew Hendifar, Vincent Picozzi, Minsig Choi, Luisa Escobar-Hoyos, Kenneth Shroyer
Journal: Cancer Research (2024)

Abstract Background: Two chemotherapies based on either gemcitabine- or 5-fluorouracil (5-FU) remain standard-of-care for pancreatic ductal adenocarcinomas (PDACs). Patients, however, differ in response and thus many clinical trials for experimental drugs have failed. Therefore, there is an urgent need to establish clinically deployable and rapid biomarkers to decide the best chemotherapeutic regimen for subgroups of patients and prevent toxic side effects. We previously reported that keratin 17 (K17) expression, detected at either the level of messenger RNA or protein by immunohistochemistry (IHC), is as accurate as molecular subtyping to identify subgroups of PDAC patients with shortest survival. In this work, we determined the predictive value of K17 testing for both chemotherapeutic approaches to treat PDAC. Methods: We profiled keratin 17 (K17) expression, a hallmark biomarker of the basal molecular subtype of PDAC, using immunohistochemistry in two cohorts of formalin-fixed paraffin-embedded PDACs (total n=305). These cases were collected through the Know Your Tumor® initiative and three high-volume treating institutions in the U.S. We performed multivariate predictive analyses and determined the threshold to define positive vs negative test. Results: Patients with advance stage disease, low K17, and treated with 5-FU- chemotherapy had three-times longer survival rates compared to counterparts treated with gemcitabine-based chemotherapy. These results contrast to those found in cases with high K17, where no differences were seen with either regimen. Based on RECIST, 72% of low K17 cases responded to treatment compared to 24% of high K17 cases. Predictive value of K17 was independent of mutation status and clinical variables. Conclusions: Our findings indicate that 5-FU-, rather than gemcitabine- based therapies are more likely to extend survival for patient's tumors expressing low rather than high K17. A K17 IHC test rapid test in PDACs has been patented (US11,092,603) and it is currently being tested in prospective phase II clinical trials (NCT04469556, NCT02047474 and NCT03991962). Results from these trials will test the presented findings. Citation Format: Lyanne Oblein, Lucia Roa, Sruthi Babu, Michael Horowitz, Emanuel Petricoin, Lynn M. Matrisian, Edik Blais, Natalia Marchenko, Felicia Allard, Ali Alkalin, Wei Jiang, Brent Larson, Andrew Hendifar, Vincent Picozzi, Minsig Choi, Luisa Escobar-Hoyos, Kenneth Shroyer. Keratin 17 as a predictor of chemotherapy response 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 C063.
Abstract B048: Targeting PPARG to block obesity-associated pancreatic cancer progression
Authors: L. Paige Ferguson
Journal: Cancer Research (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 B104: Epigenetic small molecule library screen to discover compounds that inhibit and reverse pancreatic acinar to ductal metaplasia
Authors: Corey M. Perkins, Kalina R. Atanasova, Ranjala Ratnayake, Jinmai Jiang, Qi-Yin Chen, Thomas D. Schmittgen, Hendrik Luesch
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) development is believed to be preluded by the event of acinar to ductal metaplasia (ADM), the transdifferentiation of acinar cells into a duct-like state. It is widely accepted that either acinar or ductal cells bearing mutant Kras drive the development of PDAC. We have previously shown that we can inhibit and reverse ADM in a 3D organoid assay using primary pancreatic tissue from p48Cre/+LSL-KRASG12D/+ mice using the histone deacetylase inhibitor (HDACi), Trichostatin A (Da Silva, 2022). We further employed our 3D organoid model to perform a phenotypic and molecular screening of 144 epigenetic compounds. We identified class I HDACi, FK228, and the histone methyltransferase inhibitor, Chaetocin, as the top hits of reversing ADM without inducing cytotoxicity as assessed by calcein AM staining. Largazole homodomer, a novel HDACi derived from marine cyanobacteria, was also identified as both an inhibitor and reversal agent of ADM. These three compounds demonstrated phenotypic and molecular reversal of duct-like structures back into their acinar state, in addition to relative mRNA upregulation of acinar markers (Amy2a, Cela1, Cpa2) and downregulation of ductal markers (Krt19, Krt7, Sox9). Bulk-RNA sequencing combined with pathway analysis demonstrated pronounced inhibition of cancer signaling pathways during ADM reversal, such as TGFβ1, Vegf, TNF, IL-6, and STAT3. Moreover, RNA sequencing showed significant upregulation and downregulation of acinar and ductal/PDAC markers, respectively. Thus, a novel phenotypic small molecular screen based on organoid morphology was developed to discover compounds that inhibit and reverse pancreatic ADM in a mouse model with mutant Kras. Citation Format: Corey M. Perkins, Kalina R. Atanasova, Ranjala Ratnayake, Jinmai Jiang, Qi-Yin Chen, Thomas D. Schmittgen, Hendrik Luesch. Epigenetic small molecule library screen to discover compounds that inhibit and reverse pancreatic acinar to ductal metaplasia [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 B104.
Abstract B103: Development and characterisation of KRASmulti inhibitors for the treatment of KRAS mutant pancreatic ductal adenocarcinoma
Authors: 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
Journal: Cancer Research (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 (&amp;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 B051: Investigating lipid homeostasis in pancreatic ductal adenocarcinoma under tumor-like stress
Authors: Xu Han, Michelle Burrows, Laura Kim, Clementina Mesaros, John Tobias, Brian Keith, Celeste Simon
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a 5-year survival rate of only 10%. One hallmark of PDAC’s tumor microenvironment is dense desmoplasia, due to abnormal accumulation of extracellular matrix and proliferative fibroblasts. During tumorigenesis, pancreatic stellate cells (PSCs) obtain myofibroblast-like signatures and contribute to the fibrotic environment of PDAC. Desmoplasia-induced hypovascularity severely limits oxygen and nutrient delivery. Our laboratory revealed that hypoxia is prominent even at the pancreatic intraepithelial neoplasia (PanIN) stage, a dominant precursor lesion of PDAC. Hypoxia inhibits oxygen-dependent metabolic processes. For example, unsaturated lipid biosynthesis relies on oxygen to maintain desaturase enzymatic activities. Hypoxia also stimulates lipid uptake. Previous studies demonstrated that RAS-transformed cells preferentially import unsaturated lysophosphatidylcholines (LPCs) from culture media. However, in a nutrient-limited fibrotic environment, the potential source of lipids is unclear. Interestingly, a lipidomic study of a PSC secretome displayed a significant amount of LPCs, suggesting that PSCs are the potential lipid source in the PDAC microenvironment. Our data indicate that exogenous unsaturated lipids sustain PDAC cell viability under hypoxia and nutrient deficiency. Moreover, we find PDAC cell survival under tumor-like stress is enhanced in PSC conditioned medium, but not in delipidated conditioned medium. Strikingly, we show that cancer-associated fibroblasts do not experience hypoxic stress as much as adjacent malignant epithelium cells in vivo, suggesting cancer-associated fibroblasts provide unsaturated (and other) lipids to PDAC cells. Based on our lipidomic mass spectra of PSC conditioned medium, we determined that LPCs are actively utilized by PDAC cells for phosphatidylcholine and triglyceride regeneration. By inhibiting LPC to PC conversion with the drug TSI-01, which targets LPCAT (acyltransferase), unsaturated LPC no longer sustains cancer cell survival and ER stress is reactivated. In this study, we demonstrated metabolic crosstalk between fibroblasts and PDAC cells under stress conditions. Our findings revealed a novel metabolic inhibitor to disrupt the metabolic crosstalk between PSC and pancreatic cancer cells which might benefit developing combinatorial therapy of PDAC. Citation Format: Xu Han, Michelle Burrows, Laura Kim, Clementina Mesaros, John Tobias, Brian Keith, Celeste Simon. Investigating lipid homeostasis in pancreatic ductal adenocarcinoma under tumor-like stress [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 B051.
Abstract PR14: E<i>x vivo</i> models of pancreatic cancer that recapitulate the metabolic tumor microenvironment identify glycine as a chemoresistance-inducing oncometabolite
Authors: Guillaume Cognet, Colin Sheehan, Grace Croley, Lyndon Hu, Alexander Muir
Journal: Cancer Research (2024)

Abstract Pancreatic adenocarcinoma (PDAC) tumors are poorly perfused due to intense desmoplasia and dysfunctional vasculature. This limited perfusion leads to abnormal availability of nutrients and metabolic substrates in the tumor microenvironment. To understand how microenvironmetnal nutrient availability impacts PDAC biology, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of PDAC tumors to comprehensively characterize nutrient availability in the PDAC microenvironment. We have used this information to develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling the study of PDAC biology under physiological nutrition. By transcriptomic analysis, we show that PDAC cells cultured in TIFM, compared to standard ex vivo models, adopt a cellular state more similar to PDAC cells in tumors, identifying TME nutrient availability as a key microenvironmental factor regulating PDAC biology in vivo. Given that PDAC cells in TIFM adopt an in vivo-like cell state, we next asked if PDAC cells in TIFM would exhibit phenotypes that PDAC cells primarily exhibit in vivo, such as resistance to chemotherapeutic treatment. We found that TIFM culture dramatically increases the resistance of PDAC cells to chemotherapeutic challenge. As TIFM is chemically defined, we systemically screened microenvironmental nutrient cues to identify those triggering therapy resistance. We found that glycine, an amino acid that accumulates to high levels in the PDAC microenvironment, was necessary and sufficient to cause PDAC therapy resistance. Glycine, at the concentrations found in the PDAC microenvironment, has been found to broadly cytoprotective by inhibiting cell death elicited by diverse cellular stresses. In mechanistic experiments, we similarly find that microenvironmental glycine does not prevent chemotherapeutic damage of PDAC cells but blocks cell death in response to this damage. Thus, we propose glycine is a novel oncometabolite that PDAC tumors accumulate, enabling them to cope with diverse stresses, including chemotherapeutic challenge. Altogether, these data show that nutrient availability in the microenvironment is an important determinant of PDAC biology, and models incorporating tumor nutrition can enable mechanistic study of microenvironmentally-programmed PDAC phenotypes. Citation Format: Guillaume Cognet, Colin Sheehan, Grace Croley, Lyndon Hu, Alexander Muir. Ex vivo models of pancreatic cancer that recapitulate the metabolic tumor microenvironment identify glycine as a chemoresistance-inducing oncometabolite [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 PR14.
Abstract PR13: Single-cell mapping reveals a common origin for diverse subtypes of pancreatic cancer
Authors: Nirakar Rajbhandari, Michael Hamilton, Tannishtha Reya
Journal: Cancer Research (2024)

Abstract The detailed understanding of the molecular basis of tumor initiation and progression is essential for the effective management and treatment of any cancer, including pancreatic cancer. To determine if the stem and progenitor cells can serve as cells of origin for pancreatic cancer, we have created a new mouse strain in which tamoxifen inducible Cre (CreERT2) is knocked into the endogenous locus encoding the stem cell regulator Musashi2 (Msi2). When crossed to a Cre-regulatable Myc transgenic (CAG-LSL-MycT58A) strain, Msi2-CreERT2 mice develop multiple pancreatic cancer subtypes: pancreatic ductal adenocarcinoma (PDAC), adenosquamous carcinoma of the pancreas (ASCP), and acinar cell carcinoma (ACC) following Myc activation in Msi2+ cells in the adult stage. A combination of single-cell genomics with computational analysis of developmental states and lineage trajectories of tumors in our model suggests that oncogenic Myc preferentially triggers the transformation of the most immature subset of Msi2+ cells, leading to the rise of a common pool of pre-cancer cells with multi-lineage potential. These pre-cancer cells subsequently take distinct fates within the same mice by activation of distinct transcriptional programs and large-scale genomic changes. Additionally, combining transcriptomic and functional genomic approaches, we have identified hyaluronan-mediated motility receptor (HMMR) as a potential novel dependency in mouse and human ASCP cells, providing a framework to develop interception strategies for this lethal disease. In summary, our study shows that multiple pancreatic cancer subtypes can arise from a common pool of Msi2+ cells and provides a powerful framework to understand and control the programs that shape divergent fates in pancreatic cancer. Citation Format: Nirakar Rajbhandari, Michael Hamilton, Tannishtha Reya. Single-cell mapping reveals a common origin for diverse subtypes 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 PR13.
Abstract B102: Development of covalent inhibitors targeting Ras Q61 hotspot mutants
Authors: Julius Pampel, Johannes Morstein, Qinheng Zheng, David M. Peacock, Kevan M. Shokat
Journal: Cancer Research (2024)

Abstract Mutations in the proto-oncogenes RAS are a key driver of various cancers, including pancreatic, colorectal, non–small cell lung cancer (NSCLC), melanoma, and thyroid cancer. Despite being considered undruggable for many years, recent efforts have led to the FDA approval of two drugs, Sotorasib and Adagrasib. They covalently target the K-Ras mutant isoform K-Ras(G12C), thereby inhibiting its oncogenic effect. However, the use of these drugs is inherently limited to cancers driven by the K-Ras(G12C) mutant, which is very common only in NSCLC. Although other covalent inhibitors targeting the K-Ras mutants K-Ras(G12S) and K-Ras(G12R) have been developed, it has so far not been possible to target the other frequently mutated amino acid Q61. Here we present our approach for the development of novel covalent inhibitors specifically targeting Q61 mutations in Ras proteins, which are prevalent in melanoma, multiple myeloma, and thyroid cancer. We demonstrate how covalent inhibitors specifically react with the mutant Q61C in both K and H-Ras proteins as proof-of-concept and show our efforts to extend this to the other Q61 mutant isoforms. We base our strategy on the modification of well-established switch-II pocket K-Ras inhibitors and explore multiple novel scaffolds specifically designed to target mutations of Q61. In addition to its occurrence in various cancers, Ras(Q61X) is also a common resistance mutation in patients treated with MAPK inhibitors. This work could further increase the number of patients potentially benefiting from Ras(Q61X) targeting drugs. Citation Format: Julius Pampel, Johannes Morstein, Qinheng Zheng, David M. Peacock, Kevan M. Shokat. Development of covalent inhibitors targeting Ras Q61 hotspot mutants [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 B102.