Concurrent ischemic stroke, pulmonary embolism, and hemorrhagic brain metastasis in pancreatic ductal adenocarcinoma: A case report.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. At present, surgical resection is the only curative treatment for PDAC, but the majority of PDAC patients show early recurrence even after curative resection. There is a possibility of having been distant micrometastasis at early stage of carcinogenesis in PDAC. The control of PDAC metastatic progression leads to improve the prognosis of PDAC patients. Recently, it is reported that a verified mediator of distant metastasis, Metadherin (MTDH), promotes metastasis in experimental models of breast cancer, and its high expression is associated with poor prognosis in a large spectrum of cancer types. Recent evidences imply that the epithelial-mesenchymal transition (EMT) and putative cancer stem cell (CSC) functions orchestrates to play crucial roles in cancer progression. In this study, we aim to investigate the function of MTDH in PDAC progression concomitant with undergoing EMT/MET plasticity or involving putative CSC functions. Experimental methods: We investigated MTDH expression in 7 human and 6 mouse PDAC cell lines and elucidated the roles of MTDH in PDAC progression by in vitro experiments for the loss of function using siMTDH and shMTDH. In immunohistochemical (IHC) staining of MTDH in resected PDAC tissues, we analyzed the correlation between MTDH expression and the clinico-pathological parameters as well as clinical outcome of the 82 PDAC patients. Results: Western blot analyses showed higher MTDH protein expression in metastatic PDAC compared to primary PDAC cell lines. In metastatic cell lines, MTDH expression has a positive correlation with E-cadherin expression. These data suggest that MTDH might be related to mesenchymal-epithelial transition (MET) and play a crucial role in metastatic cascade of PDAC. Conversely, MTDH has a negative correlation with E-cadherin in primary PDAC cell lines. It is implicated that MTDH might play inverse functions in primary site and metastatic site. Next, to examine what is the role of MTDH in the EMT/MET process, we evaluated the expression pattern of EMT markers and MTDH in response to transient TGF-β1 treatment. We found that E-cadherin expression decreases at 8 to 24 hours after treatment (EMT initiation), and then comes back to increase of the expression at 4 days after treatment (MET induction). While MTDH and E-cadherin expression shows an inverse relation during EMT initiation, these two expressions have a positive correlation during MET period (from 7 days after treatment). Additionally, we found EMT induction by TGF-β1 is attenuated by knockdown of MTDH, These results suggest MTDH might contribute to the phenotypic switch of PDAC cells via the EMT/MET process. MTDH knockdown significantly impaired the ability of pancreatosphere formation in PDAC cells and sensitized PDAC cells to gemcitabine. In FACS analyses, we also found that the percentage of CD133-positive cancer stem cell subpopulation was significantly reduced in MTDH knockdown metastatic PDAC cells. In anoikis assay, (this assay evaluate the resistance for apoptosis after losing contact from extracelluar matrix), MTDH knockdown reduced anoikis resistance in PDAC cells. These data indicate that MTDH might foster putative CSC functions in PDAC cells. In IHC staining, high MTDH expression indicated significantly higher incidence of hematogenous metastasis (p=0.02). Furthermore, High expression group showed poorer prognosis of PDAC patients compared to Low expression group in Kaplan Meier analysis (p=0.029). Conclusions: MTDH might promote PDAC metastasis to undergo EMT in primary PDAC and MET in metastatic PDAC along with.putative CSC functions. The regulation of MTDH might develop the new strategy for PDAC treatment, and lead to improve the outcome of patients. Citation Format: Kensuke Suzuki, Shigetsugu Takano, Hideyuki Yoshitomi, Shingo Kagawa, Hiroaki Shimizu, Masayuki Otsuka, Katunori Furukawa, Tukasa Takayashiki, Satoshi Kuboki, Daisuke Suzuki, Nozomu Sakai, Hiroyuki Nojima, Masaru Miyazaki.{Authors}. The elucidation for functional roles of Metadherin in metastatic cascade of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B29.

We previously identified an oncogenic role for the transcription factor HNF1A in pancreatic ductal adenocarcinoma (PDAC). However, the role of HNF1A in the metastatic progression of PDAC remains unknown and targeting modalities for HNF1A -dependent phenotypes have yet to be identified. Transwell chambers were used to assess the effects of HNF1A and FGFR4 modulation on the migration and invasion of ATCC and patient-derived PDAC cells in vitro . An intrasplenic injection xenograft model was used to evaluate the impact of HNF1A knockdown and overexpression on metastatic tumor burden. Single-cell RNA sequencing, tissue microarray (TMA) data, and UMAP spatial profiling were used to identify FGFR4 as an HNF1A target gene upregulated in metastatic cells. RNAi and two FGFR4 inhibiting modalities (H3B-6527 and U3- 1784) were utilized to demonstrate the efficacy of FGFR4 inhibiting agents at reducing HNF1A- driven metastasis. Knockdown of HNF1A significantly decreases and HNF1A overexpression significantly increases PDAC cell migration and invasion. In vivo studies show that HNF1A knockdown significantly abrogates metastasis, while overexpression significantly promotes metastasis. Single-cell RNAseq shows that FGFR4 is upregulated in metastatic PDAC cells and staining for HNF1A and FGFR4 in a PDAC TMA reveals significant correlation between HNF1A and FGFR4 in PDAC patients. Further, knockdown and inhibition of FGFR4 significantly decreases HNF1A- mediated cell migration and invasion, and blocks HNF1A-driven metastasis in vivo . These findings demonstrate that HNF1A drives PDAC metastasis via upregulation of FGFR4, and FGFR4 inhibition is a potential mechanism to target metastasis in PDAC patients. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, made even more devastating when metastases overwhelm major organs. The vast majority of PDAC patients either present with metastases or will relapse with recurrent metastatic PDAC after primary tumor resection. Unfortunately, toxic and largely ineffective chemotherapies are currently the only approved treatment options for these patients and therefore there exists a critical and unmet clinical need for targeted therapies against pro-metastatic pathways in PDAC. In the current study, we identify HNF1A as an oncogenic transcription factor that drives metastasis in PDAC, and it does so through upregulation of the receptor tyrosine kinase FGFR4. Importantly, FGFR4 is a targetable vulnerability and treatment with an FGFR4 blocking antibody reduces HNF1A-driven metastasis. These findings suggest that FGFR4 inhibitors could be an efficacious treatment for PDAC patients for the prevention or delay of metastatic tumor development.

Background: Pancreatic ductal adenocarcinoma (PDAC) is projected to become a leading cause of cancer-related mortality, driven by its late-stage diagnosis, aggressive progression, and propensity for metastasis. Currently, no approved therapeutic effectively targets PDAC metastasis. Emerging evidence implicates extracellular matrix (ECM), and cytoskeletal dynamics are key to invasion, a pertinent contributor to PDAC metastasis. Our previous studies identified cAMP-response element binding protein 1 (CREB) as a key regulator of ECM alterations in PDAC. This study investigates the role of CREB-ROCK in regulating tumor cell invasion and metastasis at the molecular level. Methods: Expression profiles of CREB and invasion-related genes were analyzed using The Cancer Genome Atlas (TCGA) PDAC patient’s dataset. CREB expression and localization were examined in PDAC patient’s tissue microarrays (TMAs) and patient-derived xenograft (PDX) models. A novel conditional Creb knockout (Crebfl/fl) model, in an LSL-KrasG12D/+; Trp53 R172H/+; Pdx1Cre/+ (KPC) background (KPCC-/-), was generated to delineate CREB’s role in PDAC progression and metastasis. Functional studies included lentiviral creb overexpression, CRISPR/Cas9-based Creb knockout, RNA sequencing (RNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq). Metastatic lesions were assessed in genetically engineered mouse and orthotopic models (GEMMs). Matrigel invasion assays, immunohistochemistry, immunoblotting, and qPCR were used to validate the findings in vitro and in vivo. Results: TCGA analysis revealed elevated CREB and invasive gene expression in PDAC compared to normal pancreatic tissues. Immunostaining of TMAs showed increased CREB expression localized to ductal tumor cells. Creb knockout in KPCC-/- mice reduced metastatic burden, while Creb overexpression induced liver metastasis in orthotopic models. Invasion assays confirmed decreased invasiveness of tumor cells with CREB inhibition or deletion. CREB inhibition showed reduced expression of ROCK1/2, a key mediator of cytoskeletal dynamics and ECM remodeling. RNA-seq, qPCR, and ChIP-Seq analysis identified CREB as a transcriptional regulator of genes essential for invasion and ECM remodeling. CREB deletion or inhibition attenuated the expression of these targets, decreasing tumor cell invasion and metastatic potential. Conclusion: These findings establish CREB-ROCK as a central mediator of PDAC metastasis and targeting CREB-ROCK represents a promising therapeutic strategy for inhibiting invasive PDAC progression and metastasis. Citation Format: Sudhakar Jinka, Siddharth Mehra, Varunkumar Krishnamoorthy, Andrew M. Adams, Anna Bianchi, Luis N. Alberto, Yuguang Ban, Jashodeep Datta, Nipun Merchant, Nagaraj Nagathihalli. CREB-driven tumor cell invasion and ECM remodeling promote metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1311.

BackgroundPreviously, we identified ITIH5 as a suppressor of pancreatic ductal adenocarcinoma (PDAC) metastasis in experimental models. Expression of ITIH5 correlated with decreased cell motility, invasion and metastasis without significant inhibition of primary tumour growth. Here, we tested whether secretion of ITIH5 is required to suppress liver metastasis and sought to understand the role of ITIH5 in human PDAC.MethodsWe expressed mutant ITIH5 with deletion of the N-terminal secretion sequence (ITIH5Δs) in highly metastatic human PDAC cell lines. We used a human tissue microarray (TMA) to compare ITIH5 levels in uninvolved pancreas, primary and metastatic PDAC.ResultsSecretion-deficient ITIH5Δs was sufficient to suppress liver metastasis. Similar to secreted ITIH5, expression of ITIH5Δs was associated with rounded cell morphology, reduced cell motility and reduction of liver metastasis. Expression of ITIH5 is low in both human primary PDAC and matched metastases.ConclusionsMetastasis suppression by ITIH5 may be mediated by an intracellular mechanism. In human PDAC, loss of ITIH5 may be an early event and ITIH5-low PDAC cells in primary tumours may be selected for liver metastasis. Further defining the ITIH5-mediated pathway in PDAC could establish future therapeutic exploitation of this biology and reduce morbidity and mortality associated with PDAC metastasis.

Extradomain-B Fibronectin (EDB-FN) is an oncomarker that can be visualized with magnetic resonance molecular imaging (MRMI) to detect pancreatic ductal adenocarcinoma (PDAC) metastasis. In this study, we sought to assess the expression of EDB-FN in clinical samples of PDAC and to evaluate MRMI of PDAC metastasis with an EDB-FN-specific gadolinium-based contrast agent (MT218) in an orthotopic KPC-GFP-Luc mouse model. EDB-FN expression was evaluated in PDAC tissue samples through immunohistochemistry. RNA-Seq data obtained from the GEPIA2 project was evaluated to demonstrate EDB-FN expression in large patient cohorts. FLASH-3D MRI at 3 T of the KPC-GFP-Luc metastasis model was performed following injection of MT218. Tumor enhancement in MR images was correlated to postmortem distribution of KPC-GFP-Luc tumors using fluorescent and bright-field cryo-imaging and anatomical landmarks. EDB-FN immunohistochemical staining scores of human metastatic tumor stroma, (2.17 ± 0.271), metastatic tumor parenchyma (2.08 ± 0.229), primary tumor stroma (1.61 ± 0.26), and primary tumor parenchyma (1.61 ± 0.12) were significantly (p < 0.0001) higher than normal pancreas stroma (0.14 ± 0.10) and normal pancreas parenchyma (0.14 ± 0.14). EDB-FN mRNA expression in tumors is 4.98 log2(TPM + 1) and 0.18 log2(TPM + 1) in normal tissue (p < 0.01). A mouse model of EDB-FN rich PDAC metastasis exhibited T1-weighted contrast to noise (CNR) changes of 21.80 ± 4.34 in perimetastatic regions and 8.38 ± 0.79 in metastatic regions identified through cryo-imaging, significantly higher (p < 0.05) than CNR changes found in normal liver (−6.43 ± 0.92), mesentery (2.24 ± 0.92), spleen (−3.06 ± 2.38) and intestine (1.08 ± 2.15). We conclude that EDB-FN is overexpressed in metastatic and primary PDAC tumors and MRMI with MT218 enables the detection of metastatic and perimetastatic tissues.

Background: Pancreatic ductal adeno-carcinoma (PDAC) ranks among the most lethal of human malignancies. We have demonstrated that ATDC is overexpressed in PDAC and promotes pancreatic cancer growth by activation of Wnt/β-catenin signaling (Cancer Cell, 2009). However, the role of ATDC during PDAC initiation and progression is incompletely understood. Hence, we developed a new transgenic mouse model to evaluate the impact of ATDC overexpression on PDAC formation. Methods: To genetically engineer a mouse ubiquitously overexpressing ATDC, a Flag-ATDC construct was subcloned into a pCAGGS vector containing a CMV enhancer/chicken β-actin (CAG) promoter. ATDC mice were bred onto a FVB/n background. Mice were genotyped by multiplex PCR. ATDC, β-catenin, Zeb1 and PTEN were measured by immunohistochemical staining. Results: ATDC overexpression resulted in acinar atypia with a long latency but was not sufficient to induce pancreatic intraepithelial neoplasia (PanIN) formation. We then analyzed the impact of ATDC overexpression in the context of KrasG12D by crossing of ATDC mice with LSL-KrasG12D;p48-Cre (KC) mice to generate ATDC;LSL-KrasG12D;p48-Cre (AKC) triple transgenic mice. KC mice developed PanINs with a long latency, and PDAC was not observed until mice reached an age of 15 months or greater. However, ATDC overexpression combined with KrasG12D accelerated PanIN progression and resulted in the development of invasive and widely metastatic PDAC with a high penetrance. 45% of AKC (0% KC) mice exhibited PanIN2or 3 as early as 2 months of age. 85% of AKC mice at 6-8 months of age developed highly invasive and metastatic PDAC, whereas none of the age-matched KC mice displayed those lesions. The evolution of PDAC in AKC mice recapitulated the histopathological manifestations of human PDAC, possessing a proliferative stromal component (Ki67 and collagen positive) and glandular architecture (CK19 and E cadherin positive) with a propensity for some tumors to advance to a poorly differentiated state (CK19, E cadherin and mucin negative). ATDC and β-catenin were upregulated in these primary and metastatic PDAC lesions. Furthermore, epithelial-to-mesenchymal transition (EMT) markers, ZEB1 and vimentin, were significantly upregulated in invasive PDAC and liver metastasis from AKC mice. In 2 separate cell lines developed from the AKC primary tumors, increased ATDC expression was found to not only correlate with upregulated β-catenin signaling and expression of the EMT markers ZEB1 and vimentin, but also loss of PTEN expression. Downregulation of PTEN expression by ATDC was determined to be due to ATDC-mediated methylation of the PTEN promoter. Loss of PTEN expression was observed in pancreatic tumors arising in the AKC mice. Conclusions: Here we demonstrate that ATDC, when coupled with oncogenic Kras, accelerates PanIN progression and the development of invasive pancreatic cancer that mimics human PDAC. ATDC may mediate these effects by alterations in the β-catenin and PTEN signaling pathways. This novel mouse model provides a platform for an improved understanding the pathogenesis of PDAC and for development of targeted treatment strategies. Citation Format: Lidong Wang, Huibin Yang, Filip Bednar, Yaqing Zhang, Jacob Leflein, Taylor Detzler, Gina M. Ney, Marina Pasca di Magliano, Diane M. Simeone. ATDC synergizes with oncogenic Kras to induce invasive pancreatic adeno-carcinoma in transgenic mice. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B49.

The majority of pancreatic ductal adenocarcinoma (PDAC) patients are metastatic at presentation with limited treatment options and a poor overall 5-year survival of 3%. The liver is the predominant site of distant metastasis in PDAC. Our group has previously shown that aerobic exercise can inhibit tumorigenesis in a primary PDAC mouse model by promoting anti-tumor immunity, however, the effects of exercise in the metastatic setting have not been explored. As such, we developed a model of PDAC liver metastasis by isolating primary pancreatic and liver metastatic cell lines from 18–20-week-old LSL-KRasG12D/+; LSL-Trp53R172H/+; p48Cre; Rosa26LSL-tdTomato/+ (KPCTpancreas or KPCTliver, respectively) mice. KPCTpancreas cells were surgically implanted into the pancreata of syngeneic wild-type mice. One week after pancreatic implantation, KPCTliver cells were implanted into the liver either by direct injection into the parenchyma or via the portal vein. The portal vein method enables us to account for the extravasation step of the metastatic cascade, while the direct parenchymal injection offers a less invasive surgery. Both models preserve the spleen, which is the largest secondary lymphoid organ and essential to the immune response. Treadmill running was initiated in the aerobic exercise cohort 5 days per week for 2 weeks or mice were allowed to rest. Endpoint analysis revealed that aerobic exercise treatment decreased tumor burden in both primary tumors and liver metastasis as measured by tumor weights and tdTomato fluorescence imaging when compared to the rested controls. Immune profiling of the liver metastases revealed elevated IL-15Rɑ+ CD8+ T cells as well as CD19+ B cells in the exercise cohort. While identification of IL-15Rɑ+ CD8+ T cells is consistent with the immune changes we have previously reported in the primary pancreatic tumor of exercised mice, the latter changes reveal organ specific immune cell recruitment not observed in the primary pancreatic tumor of exercised mice. The combined immune profiling and phenotypic changes suggest that aerobic exercise reduces PDAC metastatic growth by modulating systemic and intra-tumoral immunity. The induction of an anti-tumorigenic immune response by aerobic exercise could open avenues for potential pharmacological intervention in downstream pathways to aid in the treatment of metastatic PDAC. Citation Format: Mansour E. Riachi, Carolina G. Alcantara Hirsch, Erica Ma, Beny Shapiro, Ammar Javed, Christopher L. Wolfgang, Dafna Bar-Sagi. Exercise stimulates anti-tumoral immunity in metastatic 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 A018.

Pancreatic ductal adenocarcinoma (PDA) is characterized by aggressive local invasion and metastatic spread, leading to high lethality. Although driver gene mutations during PDA progression are conserved, no specific mutation is correlated with the dissemination of metastases1–3. Here we analysed RNA splicing data of a large cohort of primary and metastatic PDA tumours to identify differentially spliced events that correlate with PDA progression. De novo motif analysis of these events detected enrichment of motifs with high similarity to the RBFOX2 motif. Overexpression of RBFOX2 in a patient-derived xenograft (PDX) metastatic PDA cell line drastically reduced the metastatic potential of these cells in vitro and in vivo, whereas depletion of RBFOX2 in primary pancreatic tumour cell lines increased the metastatic potential of these cells. These findings support the role of RBFOX2 as a potent metastatic suppressor in PDA. RNA-sequencing and splicing analysis of RBFOX2 target genes revealed enrichment of genes in the RHO GTPase pathways, suggesting a role of RBFOX2 splicing activity in cytoskeletal organization and focal adhesion formation. Modulation of RBFOX2-regulated splicing events, such as via myosin phosphatase RHO-interacting protein (MPRIP), is associated with PDA metastases, altered cytoskeletal organization and the induction of focal adhesion formation. Our results implicate the splicing-regulatory function of RBFOX2 as a tumour suppressor in PDA and suggest a therapeutic approach for metastatic PDA.

Dysbindin promotes pancreatic ductal adenocarcinoma metastasis by activating NF-κB/MDM2 via miR-342-3p.

ETV4 promotes pancreatic ductal adenocarcinoma metastasis through activation of the CXCL13/CXCR5 signaling axis.

Background: Survival for patients with pancreatic ductal adenocarcinoma (PDAC) remains dismal and the majority of patients succumb to metastatic disease. Even for those with localized PDAC, most will die from metastatic disease despite margin-negative resection and adjuvant therapy. Therefore, these patients must harbor occult metastatic PDAC at presentation. There is a compelling need for the development of preclinical models that efficiently recapitulate occult metastatic liver PDAC to identify molecular and cellular pathways that drive metastatic cellular survival and growth. Towards this aim, we have developed a PDAC model of occult liver metastases using patient-derived xenografts (PDXs) to study the growth of PDAC within the metastatic environment and evaluated the effect of MEK inhibitor therapy on tumor progression. Methods and Results: Extensively characterized patient-derived KRAS-mutant (Tumors 608, 366, and 654) and wild-type (Tumors 738 and 215) PDAC cells were transduced with luciferase and injected into the spleens of athymic, nude mice, allowed to circulate for 10 minutes, after which a splenectomy was performed. To evaluate metastatic cell growth kinetics in the liver, tumor burden was monitored by sequential bioluminescent imaging. All mice exhibited defined phases of survival/dormancy and the proliferative outgrowth; however, differential kinetics were observed for each tumor cell line. To evaluate the effect of MEK inhibition of occult metastatic PDAC cells in the liver, Tumor 608 cells were injected and mice either received the MEK inhibitor trametinib (0.3 mg/kg, daily) or vehicle control beginning 48 hour post-injection. Trametinib significantly reduced metastatic tumor burden, delayed time to proliferative outgrowth, and greatly prolonged survival as compared to control (med. survival: 114 vs. 43 days, p&amp;lt;0.001). In contrast, in an orthotopic model with 250-500 mm3 tumors trametinib led to no inhibition in tumor growth for Tumor 608. To characterize metastatic PDAC cells within the liver after similar treatment conditions, we isolated cells from the liver 48 and 72 hours, 10 and 28 days after splenic injection. Tumor 608 cells were injected and metastatic PDAC cells were retrieved from the liver at the aforementioned timepoints post injection using magnetic column separation with human EpCAM (CD326)-targeted magnetically labeled microbeads. Flow cytometric analyses of retrieved cells revealed that decreased cellular markers of proliferation and increased caspase-3 cleavage correlated with decreased tumor burden observed at these timepoints in mice treated with trametinib. Conclusions: In a model of occult liver metastatic PDAC, patient-derived tumors exhibit different growth kinetics in the liver environment. Furthermore, MEK inhibition with trametinib decreased metastatic cellular proliferation, increased apoptosis, prolonged metastatic tumor outgrowth, and significantly increased survival of mice harboring occult hepatic metastases from PDAC. This efficacy of single agent trametinib is unique to occult metastatic disease and is not seen in orthotopic models of advanced, established pancreatic tumors. This finding illustrates the importance of using specific preclinical models that best recapitulate the clinical aspects of patients who will be evaluated in future clinical trials. Further investigation into the cellular and molecular factors promoting PDAC cell survival within the hepatic microenvironment utilizing this model will lead to development of rational therapeutic strategies for patients with occult metastatic disease. Citation Format: Timothy Newhook, James Lindberg, Sara Adair, J. Thomas Parsons, Todd W. Bauer. In a patient-derived xenograft model of occult hepatic metastasis from pancreatic cancer the MEK inhibitor trametinib delays tumor outgrowth and prolongs survival. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B21.

The investigational agent daraxonrasib (RMC-6236) is an oral, RAS(ON) multi-selective, tri-complex inhibitor targeting GTP-bound mutant and wild-type RAS. A registrational clinical trial, RASolute 302 (NCT06625320), is currently ongoing to evaluate daraxonrasib as a second-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Oncogenic mutations in KRAS drive the initiation and maintenance of PDAC and are present in over 90% of PDAC cases, most frequently at codon 12 (G12X). Among these, KRAS G12R displays distinct biochemical properties from other G12X variants, including the slowest rate of intrinsic GTPase activity, leading to an accumulation of the active, GTP-bound (ON) state. Additionally, attenuated oncogenic features of KRAS G12R in disease progression and metastasis of PDAC have been reported. Here we describe a detailed characterization of the antitumor activity of daraxonrasib in preclinical models of PDAC harboring KRAS G12R mutations. Daraxonrasib effectively suppressed RAS(ON) signaling and displayed anti-proliferative activity in a panel of KRAS G12R PDAC cell lines in vitro. In KRAS G12R xenograft models, daraxonrasib induced objective responses in 10/14 KRAS G12R PDAC models surveyed, with a significantly improved durability of response as compared to control. The potent antitumor activity of daraxonrasib in KRAS G12R models contrasts with that of pan-KRAS inhibitors that bind preferentially to the inactive, GDP-bound (OFF) state of KRAS (pan-KRAS(OFF) inhibitors) which exhibited limited to no activity. This is anticipated, given the properties of KRAS G12R and the respective mechanisms of action of the inhibitors. The activities of daraxonrasib in combination with standard of care (SOC) chemotherapy, i.e. gemcitabine and nab-paclitaxel (GnP), or leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), or immune checkpoint inhibitors in KRAS G12R PDAC models, were also explored. The addition of either GnP or FOLFIRINOX to daraxonrasib exhibited combinational benefits in xenograft models, leading to improved depth and/or durability of response compared to single agents in vivo. Furthermore, when evaluated in a syngeneic KRAS G12R PDAC model resistant to anti-PD-1 immunotherapy, daraxonrasib favorably remodeled the tumor microenvironment with increased T cell infiltration and decreased granulocytic myeloid derived suppressor cells. Treatment with daraxonrasib sensitized the tumors to anti-PD-1, achieving 7 out 10 complete responses in this model. Overall, these data highlight the attractive antitumor activity of daraxonrasib in preclinical models of KRAS G12R PDAC, as both monotherapy and in combination with SOC chemotherapy or immune checkpoint inhibition. Daraxonrasib is currently being evaluated as monotherapy in patients with previously treated metastatic PDAC (NCT06625320), and in combination with SOC chemotherapy in treatment-naive metastatic PDAC patients (NCT06445062). Citation Format: Urszula N. Wasko-Kornberg, Jasmine Y. Lee, Xing Wei, Yongxian Zhuang, Enrico Payson, Stephanie Chang, Kyle Seamon, Lick P. Lai, Marie Menard, Lingyan Jiang, Mallika Singh, Elsa Quintana, Jingjing Jiang. Daraxonrasib, a RAS(ON) multi-selective inhibitor, exhibits potent antitumor activity and combinatorial benefit with standard of care chemotherapy and with anti-PD-1 in preclinical models of KRAS G12R PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A118.

Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer.

This study evaluated the incidence of venous thromboembolism (VTE) in patients with advanced pancreatic ductal adenocarcinoma (PDAC) at the authors' institution and analyzed the risk factors associated with VTE and the overall survival (OS). One hundred and seventy patients with locally advanced or metastatic PDAC who received palliative chemotherapy at Daegu Catholic University Medical Center from January 2011 to December 2020 were included. During a median follow-up period of 341 days, 24 patients (14.1%) developed VTE. Cumulative incidence values of VTE were 4.7% (95% confidence interval [CI], 2.39-9.22) at 90 days, 9.9% (95% CI, 6.14-15.59) at 180 days, and 16.9% (95% CI, 11.50-24.36) at 360 days. Multivariate analysis showed that a carbohydrate antigen 19-9 (CA 19-9) level over 1,000 U/mL (hazard ratio [HR], 2.666; 95% CI, 1.112-6.389; p=0.028) and a history of alcohol consumption (HR, 0.327; 95% CI, 0.109-0.981; p=0.046) were significant factors associated with VTE. Patients with VTE showed a shorter median survival (347 days vs. 556 days; p=0.041) than those without VTE. Multivariate analysis revealed VTE (HR, 1.850; 95% CI, 1.049-3.263; p=0.033) and CA 19-9 level over 1,000 U/mL (HR, 1.843; 95% CI, 1.113-3.052; p=0.017) to be significant risk factors associated with OS. The cumulative incidence of VTE in patients with advanced PDAC was 16.9% at 360 days. While a history of alcohol consumption was a protective factor, a high CA19-9 level was a risk factor for VTE. In addition, the occurrence of VTE was associated with poor prognosis.

ObjectivesTo develop and validate a contrast-enhanced MRI-based intratumoral heterogeneity (ITH) model for predicting lymph node (LN) metastasis in resectable pancreatic ductal adenocarcinoma (PDAC).MethodsLesions were encoded into different habitats based on enhancement ratios at arterial, venous, and delayed phases of contrast-enhanced MRI. Habitat models on enhanced ratio mapping and single sequences, radiomic models, and clinical models were developed for evaluating LN metastasis. The performance of the models was evaluated via different metrics. Additionally, patients were stratified into high-risk and low-risk groups based on an ensembled model to assess prognosis after adjuvant therapy.ResultsWe developed an ensembled radiomics–habitat–clinical (RHC) model that integrates radiomics, habitat, and clinical data for precise prediction of LN metastasis in PDAC. The RHC model showed strong predictive performance, with area under the curve (AUC) values of 0.805, 0.779, and 0.615 in the derivation, internal validation, and external validation cohorts, respectively. Using an optimal threshold of 0.46, the model effectively stratified patients, revealing significant differences in recurrence-free survival and overall survival (OS) (p = 0.004 and p < 0.001). Adjuvant therapy improved OS in the high-risk group (p = 0.004), but no significant benefit was observed in the low-risk group (p = 0.069).ConclusionWe developed an MRI-based ITH model that provides reliable estimates of LN metastasis for resectable PDAC and may offer additional value in guiding clinical decision-making.Critical relevance statementThis ensemble RHC model facilitates preoperative prediction of LN metastasis in resectable PDAC using contrast-enhanced MRI. This offers a foundation for enhanced prognostic assessment and supports the management of personalized adjuvant treatment strategies.Key PointsMRI-based habitat models can predict LN metastasis in PDAC.Both the radiomics model and clinical characteristics were useful for predicting LN metastasis in PDAC.The RHC models have the potential to enhance predictive accuracy and inform personalized therapeutic decisions.Graphical