bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA-04: Targeting the oncogenic state of RAS with tri-complex inhibitors
Authors: Singh Mallika 
Published: September 2024

Abstract
KRAS oncogenic driver mutations occur in approximately 30% of all human cancers, and in particular, in over 90% of patients with pancreatic ductal adenocarcinoma (PDAC). Small molecule inhibitors that selectively target the inactive, GDP-bound state of KRAS G12C mutant proteins have demonstrated clinical efficacy in non-small cell lung cancer (NSCLC) as monotherapies, and in the small subset of PDAC patients that harbor this mutation. However, there are no currently approved RAS-targeted therapy options for the majority of patients with non-G12C RAS mutant PDAC. We have designed a series of tri-complex inhibitors that specifically target the GTP-bound, active state of RAS (RAS(ON)). These small molecule inhibitors bind non-covalently to an abundant intracellular protein, cyclophilin A (CypA). The resulting binary complex selectively engages RAS(ON), forming a tri-complex that sterically inhibits RAS interaction with downstream effectors. We have generated mutant-selective inhibitors that covalently engage RAS(ON) G12C (RMC-6291) or RAS(ON) G12D (RMC-9805). In addition, RMC-6236 is a RAS(ON) multi-selective inhibitor that non-covalently inhibits the active, GTP-bound state of mutant and wild-type variants of the canonical RAS isoforms (KRAS, NRAS, and HRAS). Here we will describe the mechanism of action of these investigational agents and the preclinical profiles that support their clinical evaluation in patients with PDAC as monotherapies and in combination therapy regimens with standard-of-care agents or as novel RAS(ON) inhibitor doublets.
Citation Format: Mallika Singh. Targeting the oncogenic state of RAS with tri-complex inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr IA-04.
Abstract IA-05: Targeting KRAS for pancreatic cancer treatment
Authors: Der Channing J. 
Published: September 2024

Abstract
The approval of clinically effective inhibitors for KRAS G12C mutant non-small cell lung cancers in 2021 and 2022 marks a significant milestone in anti-KRAS oncogene drug discovery. This success has fueled intense efforts to develop inhibitors targeting additional KRAS mutations. However, primary and treatment-associated acquired resistance limit the depth and duration of efficacy of KRAS G12C selective and likely other KRAS inhibitors. Thus, a major challenge moving forward will be the elucidation of mechanisms of resistance to then guide development of effective combination anti-KRAS therapies. Recent studies have begun to identify mechanisms of acquired resistance, where most involve alterations in components in the RAS signaling network that then cause reactivation of KRAS effector signaling that bypass drug activity. Our studies have established the critical role of reactivation of the RAF-MEK-ERK mitogen activated protein kinase cascade, and the ERK target MYC, in driving resistance in KRAS-mutant pancreatic cancer. To fully understand how aberrant ERK and MYC activation overcomes KRAS inhibitor response, we have established a comprehensive molecular portrait of ERK- and MYC-dependent activities. We have also identified YAP/TAZ-TEAD activation as a mechanism of acquired resistance and have characterized KEAP1 loss as a mechanism of primary resistance. Together, these studies have identified drug combination strategies that enhance KRAS inhibitor activity. Progress in these and other studies will be presented.
Citation Format: Channing J. Der. Targeting KRAS for pancreatic cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr IA-05.
Abstract IA-07: RAS mutation tropism: insight into tumor initation
Authors: Counter Christopher M 
Published: September 2024

Abstract
How we get cancer, a process termed tumor initiation, remains an enigma, which has crucial clinical implications for early detection, prevention, and interception. Backtracking to catch the moment a specific mutagenic event in a single gene from an individual cell occurred decades before manifesting as cancer is challenging. However, the RAS family of small GTPases thate are commonly mutated in cancer provide some insight. Despite over 50 possible oncogenic RAS mutations, each cancer type exhibits a predilection or ‘tropism’ towards a distinct and often unique subset of these mutations. For example, most pancreatic ductal adenocarcinomas are driven by a G12D/V mutation in KRAS. As RAS mutations are often initiating, this tropism ostensibly reflects the fundamental biology underlying tumor initiation, which becomes embedded in the genome of the resulting tumors. Fortunately, the process of RAS mutation tropism can be studied in mice exposed to the environmental carcinogen urethane. Such carcinogenesis both captures the moment of tumor initiation (the point of carcinogen exposure) and displays RAS mutation tropism (lung lesions are induced by a specific RAS mutation). By using ultra-sensitive sequencing to detect mutations immediately after urethane exposure in different mouse genetic backgrounds, we find that the mutagenic bias of this carcinogen influences the type of RAS mutations generated. However, biological selection for an optimal or ‘sweet spot’ of oncogenic signaling ultimately appears to dictate which mutations go on to initiate tumorigenesis. Analysis of sequence datasets from human lung cancer suggests a similar dominant role for biological selection in the RAS mutation tropism of this cancer. In summary, RAS mutation tropism appears to be a combination of mutational bias, and even more so, biological selection, providing critical insights into the origins of cancers like pancreatic.
Citation Format: Christopher M Counter. RAS mutation tropism: insight into tumor initation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr IA-07.
Abstract IA-09: Spatiotemporal metabolic networks in pancreatic cancer and associated cachexia
Authors: Majem Blanca , Lee Min-Sik , Shin Kyung Cheul , Naqvi Insia , Dennis Courtney , Dailey Lucas , Jeanfavre Sarah , Mino-Kenudson Mari , Xavier Joao B , Clish Clary B , Mathur Deepti , Kalaany Nada Y 
Published: September 2024

Abstract
Cachexia or body wasting is a significant contributing factor to the morbidity and mortality of pancreatic cancer. Despite an unmet need, its metabolic underpinnings remain poorly understood. Here, we characterize an inducible mouse model of pancreatic cancer cachexia that recaptures human disease progression. We present longitudinal systemic metabolic profiling analyses through pre-, early and late cachexia stages in male and female pancreas, its interstitial fluid (IF), plasma, liver, adipose and skeletal muscle. We find that each tissue has a unique metabolome and trajectory across stages, and reveal metabolic signatures with marked lipid enrichment in the pancreatic IF. Using mathematical modeling, we identify metabolites participating in cross-tissue networks and in vivo validate a lactate-hexose connection. We find systemic metabolic changes prior to weight loss, and use feature selection algorithms to identify potential predictive markers of cachexia progression. Our study provides a resource for system-wide metabolic network evolution of pancreatic cancer cachexia, highlighting the potential for prevention and therapy.
Citation Format: Blanca Majem, Min-Sik Lee, Kyung Cheul Shin, Insia Naqvi, Courtney Dennis, Lucas Dailey, Sarah Jeanfavre, Mari Mino-Kenudson, Joao B Xavier, Clary B Clish, Deepti Mathur, Nada Y Kalaany. Spatiotemporal metabolic networks in pancreatic cancer and associated cachexia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr IA-09.
Abstract PR-03: Canonical Notch signaling in cancer-associated fibroblasts supports an immunosuppressive pancreatic tumor microenvironment
Authors: Bischoff Allison , Yan Wei , Bednar Filip , Pasca di Magliano Marina 
Published: September 2024

Abstract
Notch is a contact-dependent signaling pathway that plays critical roles in spatiotemporal patterning during embryogenesis. Beyond its role in development, Notch signaling can regulate tissue patterning in adult organs in response to tissue injury or cancer. In pancreatic cancer, Notch signaling drives pancreatic tumor epithelial growth and regulates myeloid function in the tumor microenvironment (TME). Its role in pancreatic cancer-associated fibroblasts (CAFs) is less clear. CAFs are a central component of the pancreatic TME and demonstrate significant phenotypic and functional differences depending on their spatial arrangement in pre-neoplastic and tumor tissue. Using Notch signaling reporter mice CBF: H2B-Venus bred into KC (Ptf1a cre/+;Kras LSL-G12D/+) and KPC (Ptf1a cre/+;Kras LSL-G12D/+;p53 flox/+) backgrounds, we demonstrate that canonical Notch signaling is activated in CAFs at different stages of neoplastic progression. Notably, Notch signaling appears to be most active in aSMA+ CAFs spatially located adjacent to pre-neoplastic/cancer cells, suggesting that Notch ligands expressed by pre-neoplastic/cancer cells are critical for this activation. To test the functional role of canonical Notch signaling in CAFs, we generated a fibroblast-specific, tamoxifen-inducible model of Notch inhibition that utilizes a dominant-negative form of the Notch transcriptional co-activator MAML1 (PDGFRa CreERT2/+ ,Rosa26 LSL-DNMAML). Using an orthotopic model of pancreatic cancer (50,000 cells; KPC) we demonstrate that inhibition of Notch signaling in CAFs results in smaller tumors. These CAFs expressed lower levels of the myofibroblastic marker aSMA+. Additionally, tumors from PDGFRa CreERT2/+, Rosa26 LSL-DNMAML mice had fewer Arg1+ macrophages and a dramatic influx of CD8+ T cells. Collectively, these results suggest that Notch signaling in CAFs regulates their phenotype and supports tumor progression by inducing an immunosuppressive tumor microenvironment.
Citation Format: Allison Bischoff, Wei Yan, Filip Bednar, Marina Pasca di Magliano. Canonical Notch signaling in cancer-associated fibroblasts supports an immunosuppressive pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-03.
Abstract PR-05: Endocrine beta-cell stress promotes pancreatic ductal adenocarcinoma through endocrine-exocrine cell crosstalk
Authors: Garcia Cathy , Venkat Aarthi , McQuaid Daniel , Agabiti Sherry , Tong Alex , Cardone Rebecca , Kibbey Richard , Krishnaswamy Smita , Muzumdar Mandar 
Published: September 2024

Abstract
For a long time, the pancreas was thought to have separate cellular compartments that functioned distinctly from one another. The endocrine pancreas (islets of Langerhans) regulates glucose homeostasis, while the exocrine pancreas (acini and ducts) produces and secretes digestive enzymes. However, it has recently become clear that the endocrine and exocrine compartments communicate with one another, and dysfunction in one leads to dysfunction in the other, resulting in diabetes or pancreatitis. However, whether and how the endocrine pancreas drives the development of pancreatic ductal adenocarcinoma (PDAC), an exocrine tumor, remains unresolved. Strikingly, we found that genetic ablation of insulin-producing islet beta (β) cells (Akita) in a faithful Kras/Trp53-driven PDAC model (KPC: Kras LSL-G12D /+; Trp 53172 /+; Pdx1-Cre) suppressed PDAC progression. Conversely, obesity-induced β cell hormone dysregulation promoted Kras-driven PDAC development. Single-cell RNA sequencing (scRNA-seq) analysis of wild-type and obese mice (high-fat diet-fed and leptin-deficient (Lep ob/ob )) revealed increased expression of the peptide hormone cholecystokinin (CCK) in a subset of β cells concordant with increasing obesity, and transgenic β cell overexpression of CCK was sufficient to promote exocrine tumorigenesis in KC mice. Combined in silico (pseudotime (TrajectoryNET) and archetypal (AANet) analysis) and experimental (CreER) lineage tracing demonstrated that CCK-expressing β cells originated from a pre-existing immature β cell population (virgin β cells). Grainger causality analysis of transcriptional networks uncovered a stress-induced JNK-cJun pathway that promotes CCK expression β cells, which we confirmed using JNK inhibitors in β cell models. Together, our findings identify cellular and molecular mechanisms of β cell adaptation to obesity that contribute to obesity-driven pancreatic cancer. Furthermore, we define a critical role for endocrine-exocrine signaling in PDAC progression and stress-induced β cell pathways which could be leveraged to target the endocrine pancreas to subvert exocrine tumorigenesis.
Citation Format: Cathy Garcia, Aarthi Venkat, Daniel McQuaid, Sherry Agabiti, Alex Tong, Rebecca Cardone, Richard Kibbey, Smita Krishnaswamy, Mandar Muzumdar. Endocrine beta-cell stress promotes pancreatic ductal adenocarcinoma through endocrine-exocrine cell crosstalk [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-05.
Abstract PR-06: Dietary fats dictate pancreatic cancer fate via phospholipid saturation
Authors: Ruiz Christian F , Ge Xiangyu , McDonnell Rylee , McQuaid Daniel , Kaplan Jennifer , Li Guangtao , Rudolph Michael C , Gorelick Fred F , Wysolmerski John , Canals Daniel , Haley John D , Rodeheffer Matthew , Muzumdar Mandar D 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the US and is anticipated to become the second within the next decade. Epidemiologic studies support a strong link between high fat diet (HFD) consumption and increased PDAC risk, however, the translational relevance of diet research has been limited by inconsistencies in fat source and consumption across human populations and mouse studies. Therefore, whether and how specific dietary fatty acids drive cancer development is poorly understood. To address this gap in knowledge, we performed a diet screen, comprised of 12 isocaloric HFDs differing solely in fat source and representing the diversity of modern human fat consumption, in an oncogenic Kras-driven mouse model (KC: Kras LSL-G12D /+;Pdx1-Cre) that closely mimics the genetic and histologic features of human PDAC progression. Unexpectedly, we discovered that diets rich in oleic acid – a monounsaturated fatty acid (MUFA) typically associated with good health – enhanced pancreatic tumorigenesis. Furthermore, we observed a strong positive correlation between increased tumor burden and diets exhibiting a high ratio of MUFAs to polyunsaturated fatty acids (PUFAs), concordant with high MUFA to PUFA levels in the plasma and in pancreatic phospholipids. Membrane phospholipid incorporation of MUFAs (relative to PUFAs) suppresses lipid peroxidation and cell death via ferroptosis. Consistent with this, pancreata from mice fed a MUFA-rich diet showed decreased expression of genes involved in lipid peroxidation and reduced histologic evidence of lipid peroxidation end products compared to a PUFA-rich diets. Furthermore, primary acinar cells from mice fed high MUFA diets were resistant to cell death upon treatment with ferroptosis inhibitors. Conversely, diets rich in PUFAs increased PUFA incorporation into pancreatic phospholipids, activated transcriptional programs of lipid peroxidation, and intercepted Kras-driven tumor progression in vivo. Collectively, these data support a role for dietary fatty acids in molding the pancreatic phospholipid landscape, altering lipid peroxidation and ferroptosis sensitivity to dictate tumor fate.
Citation Format: Christian F Ruiz, Xiangyu Ge, Rylee McDonnell, Daniel McQuaid, Jennifer Kaplan, Guangtao Li, Michael C Rudolph, Fred F Gorelick, John Wysolmerski, Daniel Canals, John D Haley, Matthew Rodeheffer, Mandar D Muzumdar. Dietary fats dictate pancreatic cancer fate via phospholipid saturation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-06.
Abstract PR-09: Temporally resolved proteomics identifies nidogen-2 as a co-target in pancreatic cancer that modulates fibrosis and therapy response
Authors: Timpson Paul , Pereira Brooke , Ritchie Shona , katie Gordon  , Cox Thomas 
Published: September 2024

Abstract
Pancreatic cancer (PC) is highly lethal, with a five-year survival rate of ∼13%. PC is characterised by progressive cancer-associated fibrosis. We and others have shown that targeting cancer fibrosis can improve chemotherapy efficacy and impair metastasis in pre-clinical models. As such, we aimed to use integrated temporal proteomics to dissect the matrix signatures of pancreatic tumours from the highly-metastatic KPC (Pdx1-Cre; LSL-K-rasG12D/+; LSL-p53R172H/+) and poorly-metastatic KPflC (Pdx1-Cre; LSL-K-rasG12D/+; LSL-p53fl/+) mouse models, with an aim to identify new metastatic drivers in this deadly disease. We collected pancreatic tissue from KPflC, KPC and wildtype (WT) controls at early (∼50 days), mid (∼90 days) and late-stage disease (∼200 days), enriched them for matrix proteins using ISDoT de-cellularisation and analysed them using data independent acquisition liquid chromatography-tandem mass spectrometry (DIA LC-MS/MS). DIA LC-MS/MS revealed an increased abundance of Nidogen-2 (NID2) in KPC tumours compared to KPflC. Organotypic matrices generated with NID2 CRISPR-interference (CRISPRi) CAFs had reduced fibrosis, shown via second harmonic generation (SHG) multiphoton imaging and Picrosirius Red/birefringence analysis. Organotypic invasion assays revealed that depletion of CAF NID2 significantly impeded the 3D invasion of cancer cells. Subcutaneous and orthotopic co-seeding experiments using NID2 CRISPRi CAFs with cancer cells showed that NID2 inhibition significantly impeded tumour growth and fibrosis. Intravital (in vivo) imaging with quantum dots revealed improved vascular patency in live NID2 targeted tumours, with improved response to chemotherapy. Strikingly, in orthotopic models, mice bearing NID2 targeting had significantly reduced liver metastasis and increased survival, revealing NID2 as a new stromal co-target in this aggressive disease.
Citation Format: Paul Timpson, Brooke Pereira, Shona Ritchie, katie Gordon, Thomas Cox. Temporally resolved proteomics identifies nidogen-2 as a co-target in pancreatic cancer that modulates fibrosis and therapy response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-09.
Abstract PR-12: The circadian rhythm gene Dec2 regulates multiple components of the antigen presentation pathway to promote pancreatic cancer dormancy by immune evasion
Authors: Harris Chris , Dudgeon Crissy , Wang Lan , Prela Orjola , Cazarin de Menezes Juliana , Altman Brian , Haab Brian , Gao Chongfeng , Klamer Zachary , Repesh Anna , De Subhajyoti , Carpizo Darren R 
Published: September 2024

Abstract
Metastatic recurrence following curative-intent pancreatic surgery is a major clinical problem as nearly all die of this at both early and latent periods following surgery. While latent recurrences are due to the reactivation of disseminated dormant tumor cells, the mechanisms that regulate dormancy remain unclear. Using a novel model of early-stage resectable pancreatic cancer that mimics early and latent outcomes in patients, we identified Dec2 (bhlh41) a transcriptional repressor and circadian regulator, as upregulated in dormant tumor cells harvested from the liver. Disseminated tumor cells harvest from the livers of latent recurrent mice were Dec2 hi/Ki67lo indicating that these cells are dormant. We confirmed the relationship of Dec2 and Ki67 in human pancreatic cancer using liver tissue specimens from patients with metastatic disease whereby small clusters of metastatic cells were Dec2hi/Ki67lo and larger metastatic tumors were Dec2lo/Ki67hi. To understand the mechanism of Dec2 in dormancy we deleted Dec2 from the tumor cells evaluated them in the resection model and observed a substantial increase in survival after resection due to an immune mediated mechanism as the survival benefit was abrogated in immunodeficient conditions indicating that Dec2 promotes tumor progression through immune mediated mechanism. Dec2 promotes immune evasion by downregulating multiple components of the antigen presentation pathway including proteosome and immunoproteosome genes, MHCI and MHCI chaperones. As Dec2 is a circadian regulator, we evaluated several components of the antigen presentation pathway including proteosome and surface MHCI and found these to display oscillation that was not only anti-phase with Dec2 but resulted in differential T-cell mediated tumor cell killing depending on the time of day. These studies elucidate a new mechanism by which Dec2 regulates cancer dormancy through immune evasion and identifies several novel therapeutic strategies to restore anti-tumor immunity. They also provide the first evidence that antigen presentation is under circadian regulation in pancreatic cancer.
Citation Format: Chris Harris, Crissy Dudgeon, Lan Wang, Orjola Prela, Juliana Cazarin de Menezes, Brian Altman, Brian Haab, Chongfeng Gao, Zachary Klamer, Anna Repesh, Subhajyoti De, Darren R Carpizo. The circadian rhythm gene Dec2 regulates multiple components of the antigen presentation pathway to promote pancreatic cancer dormancy by immune evasion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-12.