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Abstract A009: Characterizing the pre-metastatic liver in PDAC patients using scRNA-seq of FFPE tissue 摘要:利用FFPE组织scRNA-seq表征PDAC患者的转移前肝脏
IF 11.2 1区 医学
Cancer research Pub Date : 2025-09-28 DOI: 10.1158/1538-7445.pancreatic25-a009
Ryan Humphrey, Ash Fletcher, Julia Button, Daniel Nussbaum, Erika Crosby
{"title":"Abstract A009: Characterizing the pre-metastatic liver in PDAC patients using scRNA-seq of FFPE tissue","authors":"Ryan Humphrey, Ash Fletcher, Julia Button, Daniel Nussbaum, Erika Crosby","doi":"10.1158/1538-7445.pancreatic25-a009","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a009","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains an essentially incurable disease. Even among patients considered for curative-intent surgery and chemotherapy, recurrence persists in nearly all patients, and 5-year PDAC survival remains at only 8%. Hepatic metastases tend to occur earlier than metastases to other sites, and patients with liver involvement have the worst survival outcomes, even when compared to those with multisite disease. A critical need exists for novel, scalable diagnostic metrics capable of identifying and characterizing patients at high risk for metastatic spread of PDAC, particularly to the liver. The tumor microenvironment (TME) plays a critical role in tumorigenesis, progression, and metastasis, and the varied immune and stromal cell populations within the TME represent promising targets to serve as biomarkers for the early diagnosis of cancer, as they undergo characteristic phenotypic changes during disease onset and progression. With this in mind, we built a unique biorepository to bank pre-metastatic liver samples collected at the time of curative-intent surgery, aiming to identify features of the microenvironment present in the liver of PDAC patients prior to metastatic spread. Clinical follow-up for patients in this biorepository has since matured, allowing us to bin patients based on time to hepatic recurrence. We utilized a recently developed Flex assay from 10X Genomics for performing single-cell RNA sequencing (scRNA-seq) on formalin-fixed, paraffin-embedded (FFPE) tissues, an approach well-suited for retrospective analysis. Herein, we demonstrate the feasibility of applying this method to FFPE liver samples from PDAC patients across various disease states by profiling the immune landscape of the pre-metastatic liver. Specifically, we profiled liver samples from patients with no recurrence, early recurrence, or confirmed PDAC liver metastases, and conducted comparative transcriptional analysis against healthy liver samples. This analysis revealed multiple distinct immune cell populations within the liver, including myeloid cells such as Kupffer cells, macrophages, dendritic cells, and granulocytes, lymphoid cells such as CD4+ and CD8+ T cells, B cells, and NK cells, and relevant stromal populations such as fibroblasts and sinusoidal endothelial cells. These populations exhibited unique, patient-specific, and disease state-specific expression patterns. Additionally, we identified distinct zonal hepatocyte populations, which will allow us to query transcriptional changes in fundamental liver cell types. Furthermore, through gene set enrichment analysis (GSEA), we observed pathway-level changes characteristic of these cell populations within the liver. Together, these findings demonstrate the applicability of this scalable approach and its potential to meaningfully supplement existing PDAC diagnostics by enabling earlier characterization of the liver’s pre-metastatic niche to assess recurrence risk. Citation Format: ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"119 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract A126: Tumor-informed ctDNA, ddPCR, CA19-9, and CEA to evaluate early treatment dynamics in patients with metastatic pancreatic cancer 摘要:肿瘤信息ctDNA、ddPCR、CA19-9和CEA评估转移性胰腺癌患者早期治疗动态
IF 11.2 1区 医学
Cancer research Pub Date : 2025-09-28 DOI: 10.1158/1538-7445.pancreatic25-a126
James Lee, Amber Habowski, Baho Sidiqi, Adrianna Kapusta, Jenna Battaglia, Daniel King, James Lee
{"title":"Abstract A126: Tumor-informed ctDNA, ddPCR, CA19-9, and CEA to evaluate early treatment dynamics in patients with metastatic pancreatic cancer","authors":"James Lee, Amber Habowski, Baho Sidiqi, Adrianna Kapusta, Jenna Battaglia, Daniel King, James Lee","doi":"10.1158/1538-7445.pancreatic25-a126","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a126","url":null,"abstract":"Introduction Blood-based biomarkers may enable earlier assessment of treatment response than imaging in patients with metastatic pancreatic cancer. Tumor-informed circulating tumor DNA (ctDNA) approaches may be more sensitive, whereas tumor-naïve ctDNA profiling using KRAS mutations may offer a cheaper and faster alternative for most patients with PDAC. CA19-9 and CEA are also commonly used as tumor markers for PDAC treatment monitoring. We hypothesized that ctDNA, ddPCR, CA19-9, and CEA dynamics would be associated with treatment response. Methods: In this prospective, single-center study, patients with metastatic PDAC were monitored using blood-based biomarkers with high temporal resolution. Signatera (a ctDNA reporter panel informed by whole-exome sequencing) and digital droplet PCR (ddPCR of KRAS codon 12/13 mutations) were used along with standard CA19-9 and CEA. Blood markers were drawn at baseline and after 2, 4, and 8 weeks of treatment. Treatment response was measured by the RECIST 1.1 criteria or clinical deterioration. The primary objective was to evaluate the association of progression-free survival (PFS) with biomarker changes from baseline to 2 or 4 weeks. Results: Nineteen patients were enrolled, comprising 11 starting first-line (1L) therapy and 8 starting 2L. Sufficient tissue was available for tumor-informed ctDNA profiling in 12 of 19 patients (63%). ddPCR data were evaluated in 14 of the 19 patients and CA19-9 & CEA were evaluated in 19 of 19 patients. Overall median PFS was 3.5 months (1.9 - 4.3 months). A ctDNA reduction of at least 20% compared to baseline by week 2 and week 4 of treatment was associated with longer PFS (p=0.002 and p<0.001, respectively). Fluctuations in ddPCR by week 2 and week 4 compared to baseline were not associated with longer PFS at any threshold (all p-values>0.10 and p-values>0.19, respectively). Fluctuations in CA19-9 by week 2 of treatment were not associated with longer PFS at any threshold (all p-values>0.05); however, an increase of CA19-9 greater than 50% by week 4 of treatment was associated with worse PFS (p=0.002). Fluctuations in CEA by week 2 of treatment and week 4 of treatment were not associated with longer PFS at any threshold (all p-values>0.05). Among patients without a ctDNA increase at week 2, those who demonstrated a >80% reduction in ddPCR had significantly longer PFS (p<0.0001). Conclusions: Early reduction in ctDNA levels as early as 2-weeks and CA19-9 increases by week 4 of treatment were associated with worse PFS. These findings suggest utility of blood-based biomarkers for early treatment monitoring and could inform a prospective interventional trial evaluating ctDNA dynamics to inform early treatment decisions. Citation Format: James Lee, Amber Habowski, Baho Sidiqi, Adrianna Kapusta, Jenna Battaglia, Daniel King, James Lee. Tumor-informed ctDNA, ddPCR, CA19-9, and CEA to evaluate early treatment dynamics in patients w","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"11 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract A056: Targeting the Protein Regulator of Cytokinesis 1 (PRC1) Pathway in Pancreatic Cancer A056:靶向胰腺癌细胞分裂1 (PRC1)通路的蛋白调节因子
IF 11.2 1区 医学
Cancer research Pub Date : 2025-09-28 DOI: 10.1158/1538-7445.pancreatic25-a056
Amnon Peled, Michal Abraham, Lika Gamaev, Orly Eizenberg, Arnon Aharon
{"title":"Abstract A056: Targeting the Protein Regulator of Cytokinesis 1 (PRC1) Pathway in Pancreatic Cancer","authors":"Amnon Peled, Michal Abraham, Lika Gamaev, Orly Eizenberg, Arnon Aharon","doi":"10.1158/1538-7445.pancreatic25-a056","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a056","url":null,"abstract":"Pancreatic cancer (PDAC) is a major cause of cancer mortality worldwide, largely due to its high recurrence rate and chemoresistance. We found that the microtubule-associated protein regulator of cytokinesis 1 (PRC1) is implicated in PDAC progression, associated with poor prognosis, enhanced cancer proliferation, stemness, metastasis, and chemoresistance. PRC1 functions as an oncogenic driver, particularly in PDAC cases with elevated expression. Using siRNA and the small molecule BKT300 that inhibits PRC1 function, we found that downmodulation of PRC1 induces G2/M cell cycle arrest and triggered mitotic catastrophe and apoptosis. Interestingly, BKT300 targeted PRC1 by arresting it in a phosphorylated state at T481, concurrently downregulating CDC25C and upregulating p21. siRNA-mediated suppression of PRC1 in cancer cells prevented the activity of BKT300, indicating that BKT300’s efficacy is dependent on PRC1 expression. Direct binding of BKT300 to PRC1 was further confirmed through multiple assays. Importantly, BKT300 synergized with 5FU and irinotecan to induce cancer cell death, both agents are the standard of care for treatment of pancreatic cancer patients. In vivo studies in PDAC mouse models demonstrated significant tumor growth inhibition and tumor regression, underscoring the therapeutic promise of BKT300 for PDAC. Overall, BKT300 presents a novel approach to tackling PDAC by directly targeting PRC1, potentially improving outcomes in PDAC cases with high PRC1 expression and resistance to conventional therapies. Citation Format: Amnon Peled, Michal Abraham, Lika Gamaev, Orly Eizenberg, Arnon Aharon. Targeting the Protein Regulator of Cytokinesis 1 (PRC1) Pathway in Pancreatic Cancer [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): nr A056.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"4 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract B008: Ex-vivo organotypic tumor model of metastatic core biopsy serve as a pragmatic platform for real-time personalized therapy in pancreatic adenocarcinoma 摘要B008:转移性核心活检离体器官型肿瘤模型可作为胰腺腺癌实时个性化治疗的实用平台
IF 11.2 1区 医学
Cancer research Pub Date : 2025-09-28 DOI: 10.1158/1538-7445.pancreatic25-b008
Naveen Chandrashekhar, Jason Yuan, Natalie Stasny, Mohammed Aldakkak, Mandana Kamgar, Thomas McFall, Nikki Lytle, Jenny Grewal, Anna Stark, Olivia Guerra, Alexandria Phan, William A. Hall, Beth A. Erickson, Anai Kothari, Callisia N. Clarke, Kathleen Christians, William Rilling, Parag Tolat, Douglas B. Evans, Yongwoo D. Seo
{"title":"Abstract B008: Ex-vivo organotypic tumor model of metastatic core biopsy serve as a pragmatic platform for real-time personalized therapy in pancreatic adenocarcinoma","authors":"Naveen Chandrashekhar, Jason Yuan, Natalie Stasny, Mohammed Aldakkak, Mandana Kamgar, Thomas McFall, Nikki Lytle, Jenny Grewal, Anna Stark, Olivia Guerra, Alexandria Phan, William A. Hall, Beth A. Erickson, Anai Kothari, Callisia N. Clarke, Kathleen Christians, William Rilling, Parag Tolat, Douglas B. Evans, Yongwoo D. Seo","doi":"10.1158/1538-7445.pancreatic25-b008","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b008","url":null,"abstract":"Background: Metastases are common in patients with pancreatic ductal adenocarcinoma (PDAC) and are often associated with a significantly poorer prognosis. Current tissue-based models for personalized therapy, such as patient derived organoids or xenografts, remain technically and logistically burdensome. To address this critical need, we have developed a pragmatic ex vivo organotypic tumor model from core biopsies of metastases with testable and replicable conditions as a potential avenue for evaluating sensitivity to neoadjuvant chemotherapies. Methods: Standard-of-care image-guided 16G core biopsies of metastases were obtained from patients with PDAC undergoing clinically indicated biopsies through our Surgical Oncology Tissue Bank protocol. 3mm-4mm cut slices of cores were grown in sterile RPMI media on cell culture inserts in 24-well plates, with every 2 day media changes for a minimum of five days. Viability was assessed with a colorimetric MTS assay. After incubation with control or investigational agents, slices were fixed in formalin and examined using H&E and immunohistochemistry (IHC). Results: 10 core biopsies were obtained and processed (7 liver, 2 peritoneum, 1 lung) from March to June 2025; median number of 3mm slices created per sample was 5.5 [range 2-17]. All patients' samples had viable tumor in control conditions at 48 hours or greater confirmed on MTS and H&E stains. Based on individual patient’s known prior sensitivity to first or second-line chemotherapy, we tested a range of chemotherapeutic treatments (e.g. FOLFIRINOX, gemcitabine/paclitaxel) and targeted agents (e.g. pan-RAS inhibitor RMC-7977 and MEK inhibitor trametinib) against negative control (DMSO). In one patient with KRAS q61h mutation and known resistance to FOLFIRINOX (developed liver metastasis after 8 cycles of neoadjuvant therapy), 48 hour incubation experiment demonstrated MTS viability of 111% for FOLFIRINOX (compared to negative control), vs. 74% for gem/paclitaxel and interestingly 53% for RMC-7977. In another metastatic patient with KRAS wildtype and BRAF V487 mutation and long-term control of liver disease on FOLFIRINOX, 48 hour incubation demonstrated viability of 5% for FOLFIRINOX and 19% for trametinib; interestingly, this patient was subsequently switched to a MEK inhibitor and demonstrated normalization of CA19-9 after 2 months of targeted therapy. Quantification of tumor microenvironment dynamics are underway with IHC for cleaved caspase-3, Ki-67, and CD45. Conclusions: Our organotypic tumor culture system using patient-derived core biopsies represents a novel and pragmatic approach to real-time personalized therapy in metastatic PDAC. While it relies on presumed homogeneity of tissue across the core biopsy, this system is cost-effective, does not rely on take rate (as in organoids or xenograft models), and allows for preliminary viability readouts within days of biopsy. Further work is ongoing to validate viability signals with protein si","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"10 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract A088: Genomic Scar to Immune Signals: Translational Insights from the POLAR Trial Reveal POLQ-Driven Immunogenicity in HRD Pancreatic Cancer 基因疤痕到免疫信号:POLAR试验的翻译见解揭示了polq驱动的HRD胰腺癌免疫原性
IF 11.2 1区 医学
Cancer research Pub Date : 2025-09-28 DOI: 10.1158/1538-7445.pancreatic25-a088
Wungki Park, Catherine O'Connor, Marc Hilmi, Shigeaki Umeda, Roshan Sharma, Kevin Soares, Joshua Schoenfeld, Nuray Tezcan, Anupriya Singhal, Kenneth Yu, Joanne Chou, Olca Basturk, Nadeem Riaz, Walid Chatila, Chaitanya Bandlamudi, Vinod Balachandran, Dana Pe'er, Benjamin Greenbaum, Christine Iacobuzio-Donahue, Eileen M. O'Reilly
{"title":"Abstract A088: Genomic Scar to Immune Signals: Translational Insights from the POLAR Trial Reveal POLQ-Driven Immunogenicity in HRD Pancreatic Cancer","authors":"Wungki Park, Catherine O'Connor, Marc Hilmi, Shigeaki Umeda, Roshan Sharma, Kevin Soares, Joshua Schoenfeld, Nuray Tezcan, Anupriya Singhal, Kenneth Yu, Joanne Chou, Olca Basturk, Nadeem Riaz, Walid Chatila, Chaitanya Bandlamudi, Vinod Balachandran, Dana Pe'er, Benjamin Greenbaum, Christine Iacobuzio-Donahue, Eileen M. O'Reilly","doi":"10.1158/1538-7445.pancreatic25-a088","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a088","url":null,"abstract":"BACKGROUND: Pancreatic cancer (PC) remains largely unresponsive to immunotherapy, underscoring the need for biomarker-guided approaches. In the Phase II POLAR trial, 63 participants with metastatic PC and disease control after platinum-based chemotherapy received maintenance pembrolizumab and olaparib. Participants were prospectively stratified into three molecular cohorts: Cohort A (BRCA1/2 or PALB2-mutated homologous recombination–deficient [HRD], N=33), Cohort B (non-core HRD, N=15), and Cohort C (platinum-sensitive without HRD mutations, N=15). Cohort A used a two-stage design with co-primary endpoints of objective response rate (ORR) and 6-month progression-free survival (PFS). Cohort A demonstrated promising activity, with an ORR of 35% (95% CI: 15–59), a 6-month PFS of 64% (95% CI: 49–82), and a 2-year overall survival of 56% (95% CI: 41–76), where responses in Cohorts B and C were infrequent. These results prompted investigation into molecular features underlying immunogenicity and resistance. METHODS: We performed integrated genomic and immune profiling of POLAR trial samples (WES N=40, cfDNA, mIF), along with an independent multi-omic iPC cohort (WES N=71; snRNA-seq N=23, 59,771 nuclei). A POLQ Deletion Footprint (PDF) score was developed based on the frequency and length of short deletions to infer theta-mediated end joining (TMEJ) activity. Associations between PDF, neoantigen burden and quality, immune infiltration, tumor cell DNA repair evolution were assessed. RESULTS: Tumors with high PDF exhibited were marked by enriched short deletions, increased high-quality neoantigens (R=0.75, p=0.0013), and infiltration by cytolytic CD8+T cells (PRF1hiGZMBhiGNLYhi), suggesting immune engagement. In contrast, PDF-low tumors displayed ongoing replication stress leading to R-loop accumulation (p=4.8e–14) and a trend toward whole-genome doubling (p=0.072). Along a neoantigen pseudotime trajectory, POLQ-dependent TMEJ activity peaked during early HRD tumor evolution and waned over time, giving rise to STING activation and subsequent type I interferon signaling, which in turn fostered immune diversification and ultimately drove neoepitope editing. In the POLAR trial, patients lacking PDF-derived neoantigens had significantly worse progression-free and overall survival (log-rank p=0.0007 and 0.018, respectively). These findings highlight PDF reflects accumulation of past POLQ activity and informs functional quality of the tumor neoantigens and promotes T cell–mediated tumor recognition. CONCLUSIONS: The POLQ Deletion Footprint (PDF) score identifies a distinct subset of HRD pancreatic tumors shaped by prior POLQ-mediated repair. PDF encodes scars, enriched for immunogenic neoantigens and immune infiltration. Absence of PDF in HRD PC is associated with poor outcomes and unresolved replication stress. These findings establish PDF as a mechanistic biomarker that links replication dynamics, DNA repair and immune recognition, and may guide future precis","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract A026: Hereditary chronic pancreatitis induced plasticity cooperates with mutant Kras in early pancreatic carcinogenesis 摘要:遗传性慢性胰腺炎诱导的可塑性与突变Kras在早期胰腺癌发生中的协同作用
IF 11.2 1区 医学
Cancer research Pub Date : 2025-09-28 DOI: 10.1158/1538-7445.pancreatic25-a026
Tanvi V. Inamdar, Ferdinand Krannich, Nico Hesselbarth, Atul Verma, Teresa Vauti, Ghanem El Kassem, Jasmine Hillmer, Michael Boettcher, Ivonne Regel, Heidi Griesmann, Irene Esposito, Markus Glaß, Monika Hämmerle, Patrick Michl, Helmut Laumen, Jonas Rosendahl
{"title":"Abstract A026: Hereditary chronic pancreatitis induced plasticity cooperates with mutant Kras in early pancreatic carcinogenesis","authors":"Tanvi V. Inamdar, Ferdinand Krannich, Nico Hesselbarth, Atul Verma, Teresa Vauti, Ghanem El Kassem, Jasmine Hillmer, Michael Boettcher, Ivonne Regel, Heidi Griesmann, Irene Esposito, Markus Glaß, Monika Hämmerle, Patrick Michl, Helmut Laumen, Jonas Rosendahl","doi":"10.1158/1538-7445.pancreatic25-a026","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a026","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer with hereditary chronic pancreatitis (CP) conferring a significantly increased risk. Hereditary CP is caused by mutations in genes, such as PRSS1, SPINK1, CTRC, or CPA1 and presents with variable onset. However, the underlying mechanisms through which CP contributes to oncogenic transformation remain poorly understood. To elucidate this, we generated a genetically engineered mouse model carrying CP-associated human p.N256K carboxypeptidase A1 (CPA1) mutation and oncogenic Kras mutation resulting in Ptf1a Cre ;Kras LSL-G12D ;Cpa1 N256K (KC-Cpa1) mouse strain. Histological analyses of the KC-Cpa1 pancreas revealed accelerated development of early steps of PDAC including acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN) lesions, and extensive fibrosis. Ex vivo 3D acinar cultures from 8-week-old KC-Cpa1 mice pancreata demonstrated enhanced ADM formation compared to Ptf1a Cre (Cre), Cpa1 N256K/N256K (Cpa1), and Ptf1a Cre ;Kras LSL-G12D (KC). These findings suggest that inflammation induced by the Cpa1 N256K mutation synergizes with oncogenic Kras mutation to promote the early initiation of PDAC. To explore the cellular heterogeneity and transcriptional program of metaplastic cells, we performed single cell RNA sequencing of pancreata of KC-Cpa1, KC, Cpa1, and Cre which revealed Cpa1 N256K -induced exocrine plasticity marked by an early ADM state and inflammatory phenotype of ductal cells (iDucts). Furthermore, single cell RNA sequencing also suggested disease-specific signaling between ductal cells, granulocytes, and fibroblasts. These results support the utility of KC-Cpa1 mouse model for studying early stages of CP-induced PDAC. Citation Format: Tanvi V. Inamdar, Ferdinand Krannich, Nico Hesselbarth, Atul Verma, Teresa Vauti, Ghanem El Kassem, Jasmine Hillmer, Michael Boettcher, Ivonne Regel, Heidi Griesmann, Irene Esposito, Markus Glaß, Monika Hämmerle, Patrick Michl, Helmut Laumen, Jonas Rosendahl. Hereditary chronic pancreatitis induced plasticity cooperates with mutant Kras in early pancreatic carcinogenesis [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): nr A026.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"4 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract B112: HMGA2 Predicts Treatment Outcome in Pancreatic Cancer B112: HMGA2预测胰腺癌的治疗结果
IF 11.2 1区 医学
Cancer research Pub Date : 2025-09-28 DOI: 10.1158/1538-7445.pancreatic25-b112
Naomi Yamamoto, Stephanie Dobersch, Ian Loveless, Annie N. Samraj, Gun Ho Jang, Miki Haraguchi, Liang-I Kang, Marianna B. Ruzinova, Kiran R. Vij, Jacqueline L. Mudd, Thomas Walsh, Rachael A. Safyan, E. Gabriela Chiorean, Sunil R. Hingorani, Nathan M. Bolton, Li Li, Ryan C. Fields, David G. DeNardo, Faiyaz Notta, Howard C. Crawford, Nina G. Steele, Sita Kugel
{"title":"Abstract B112: HMGA2 Predicts Treatment Outcome in Pancreatic Cancer","authors":"Naomi Yamamoto, Stephanie Dobersch, Ian Loveless, Annie N. Samraj, Gun Ho Jang, Miki Haraguchi, Liang-I Kang, Marianna B. Ruzinova, Kiran R. Vij, Jacqueline L. Mudd, Thomas Walsh, Rachael A. Safyan, E. Gabriela Chiorean, Sunil R. Hingorani, Nathan M. Bolton, Li Li, Ryan C. Fields, David G. DeNardo, Faiyaz Notta, Howard C. Crawford, Nina G. Steele, Sita Kugel","doi":"10.1158/1538-7445.pancreatic25-b112","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b112","url":null,"abstract":"The recognition of distinct transcriptional subtypes in pancreatic ductal adenocarcinoma (PDAC) has defined a group of poorly differentiated tumors with worse prognosis, but these findings have yet to reach clinical application. These tumors, termed “basal,” are unique for their loss of epithelial identity and relative chemoresistance compared to “classical” tumors. To develop a prognostic biomarker for the basal subtype, we have identified that the chromatin architectural protein HMGA2 is highly expressed in this subset of cancers. Using a tumor microarray of 580 primary biopsies from a diverse set of PDAC patients undergoing surgical resection, we performed multiplex immunohistochemistry for HMGA2, previously published markers of basal and classical disease, and immune subsets. We then associated patient outcome and known clinical data from 491 of these samples to staining patterns. We found that expression of HMGA2, but not published basal markers CK5 or CK17, predicted overall survival in our cohort. Combination of HMGA2 status with GATA6 status allowed for identification of two key study groups: an HMGA2+/GATA6- cohort with worse survival, decreased CD8+ T cells, and poorer response to gemcitabine-based chemotherapies (n=94, median survival = 11.2 months post-surgery); and an HMGA2-/GATA6+ cohort with improved survival, increased CD8+ T cell infiltrate, and improved survival with gemcitabine-based chemotherapy (n=198, median survival = 21.7 months post-surgery). Importantly, these findings were also true for Black patients, who have been underrepresented in previous subtyping studies. HMGA2 was also predictive of overall survival in RNA sequencing from metastatic tumors in an independent cohort. As a positive nuclear marker for basal disease, HMGA2 complements GATA6 as a dual-indicator test for disease subtype in PDAC. We aim to introduce this novel biomarker in a prospective multi-center clinical trial to further validate its use in selecting chemotherapy regimens and across other under-represented racial groups. Citation Format: Naomi Yamamoto, Stephanie Dobersch, Ian Loveless, Annie N. Samraj, Gun Ho Jang, Miki Haraguchi, Liang-I Kang, Marianna B. Ruzinova, Kiran R. Vij, Jacqueline L. Mudd, Thomas Walsh, Rachael A. Safyan, E. Gabriela Chiorean, Sunil R. Hingorani, Nathan M. Bolton, Li Li, Ryan C. Fields, David G. DeNardo, Faiyaz Notta, Howard C. Crawford, Nina G. Steele, Sita Kugel. HMGA2 Predicts Treatment Outcome in Pancreatic Cancer [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): nr B112.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"21 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract B055: A Multimodal Machine Learning Approach for Early Detection of Pancreatic Cancer B055:胰腺癌早期检测的多模态机器学习方法
IF 11.2 1区 医学
Cancer research Pub Date : 2025-09-28 DOI: 10.1158/1538-7445.pancreatic25-b055
Dan-Ni Wu, Joey Jen, Chao-Ping Hsu, Yu-Ting Chang, Chun-Mei Hu
{"title":"Abstract B055: A Multimodal Machine Learning Approach for Early Detection of Pancreatic Cancer","authors":"Dan-Ni Wu, Joey Jen, Chao-Ping Hsu, Yu-Ting Chang, Chun-Mei Hu","doi":"10.1158/1538-7445.pancreatic25-b055","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b055","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer, primarily due to late diagnosis and a lack of effective biomarkers. Our prior research has focused on the critical roles of metabolic dysregulation and the tumor microenvironment in the early stages of PDAC. We've shown that RRM1 O-GlcNAcylation disrupts sugar metabolism, leading to genomic instability and the development of oncogenic KRAS mutations. Furthermore, we identified a key signaling pathway: Muc4 overexpression in KrasG12D/+ pancreatic cells promotes fibroblast recruitment and pancreatic intraepithelial neoplasia (PanIN) formation via Activin A secretion. Activin A also mediates tumor-fibroblast interactions that drive metastasis. Importantly, blocking Activin A with Follistatin effectively inhibits PanIN progression and PDAC malignancy in our mouse models. To address the limitations of current early diagnostic methods, we developed a novel multimodal machine learning framework. This integrated strategy combines comprehensive serum metabolomic profiles, clinical information, and the Activin A protein biomarker. This approach demonstrates highly accurate and reproducible early detection of PDAC, offering a promising strategy to improve patient outcomes and with potential for broader applications in cancer diagnostics. Citation Format: Dan-Ni Wu, Joey Jen, Chao-Ping Hsu, Yu-Ting Chang, Chun-Mei Hu. A Multimodal Machine Learning Approach for Early Detection of Pancreatic Cancer [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): nr B055.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"95 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract A071: Immune biomarkers of response in a phase 1 trial of combined MEK/STAT3/PD-1 inhibition in metastatic pancreatic ductal adenocarcinoma (PDAC) 摘要:MEK/STAT3/PD-1联合抑制转移性胰腺导管腺癌(PDAC)的1期试验免疫生物标志物反应
IF 11.2 1区 医学
Cancer research Pub Date : 2025-09-28 DOI: 10.1158/1538-7445.pancreatic25-a071
Peter Joel. Hosein, Sayan Chakraborty, Anna Bianchi, Yolanda Justal, Nkiruka Ezenwajiaku, Maria Vanessa. Yow, Chloe Brown, Melinda Boone, Edmond Box, Juan Pablo. Vaccario, Paolo Serafini, Jashodeep Datta, Nipun Merchant
{"title":"Abstract A071: Immune biomarkers of response in a phase 1 trial of combined MEK/STAT3/PD-1 inhibition in metastatic pancreatic ductal adenocarcinoma (PDAC)","authors":"Peter Joel. Hosein, Sayan Chakraborty, Anna Bianchi, Yolanda Justal, Nkiruka Ezenwajiaku, Maria Vanessa. Yow, Chloe Brown, Melinda Boone, Edmond Box, Juan Pablo. Vaccario, Paolo Serafini, Jashodeep Datta, Nipun Merchant","doi":"10.1158/1538-7445.pancreatic25-a071","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a071","url":null,"abstract":"Background: PDAC remains resistant to immune checkpoint inhibition (ICI), in part due to a suppressive tumor microenvironment (TME) driven by oncogenic RAS and stromal interactions. Our preclinical data demonstrate that combined MEK and JAK/STAT3 inhibition reprograms the TME, reduces immunosuppressive myeloid cell populations, and restores effector T cell function, facilitating ICI sensitivity. Based on these findings, we conducted a phase 1 trial (NCT05440942) to evaluate the safety, preliminary efficacy, and immune biomarkers of trametinib (MEKi), ruxolitinib (JAK/STAT3i), and retifanlimab (anti–PD-1) (TRRf), in patients with metastatic PDAC as second or third-line therapy. Methods: The trial consisted of a dose escalation phase (Part 1, N=8) and an expansion phase (Part 2, N=20) at the target dose level (trametinib 2 mg PO daily, ruxolitinib 15 mg PO BID, retifanlimab 500 mg IV every 28 days). Peripheral blood and core biopsies were collected at baseline and after Cycle 1 of treatment cycle for biomarker analyses, including high-dimensional flow cytometry, cytokine profiling, and CODEX spatial immune profiling. Results: No dose-limiting toxicities were observed across all dose levels. The most common grade 3/4 adverse events (AE’s) were fatigue (32%), anemia (29%) and transaminase increase (18%). Among 20 patients in part 2, 2 achieved partial responses and 5 had stable disease for over 16 weeks (objective response rate 10%; disease control rate 35%). In-depth immune profiling of 5 responders (defined as having disease control) and 5 non-responders after Cycle 1 revealed that responders exhibited expansion of CD4+ early effector and memory T cells with increased levels of Granzyme B and CD107a, consistent with enhanced cytotoxic potential. Responders also demonstrated a reduction in monocytic myeloid-derived suppressor cells (M-MDSCs) and regulatory B cells, along with increases in mature NK cells. In contrast, non-responders showed expansion of total CD19+ B cells along with their CD20+ subset of memory B cells and downregulation of CD38 on CD4+ T cells, suggestive of impaired activation. Notably, plasma IL-12p70 and IFN-γ levels were significantly elevated after one treatment cycle in all six patients tested, regardless of response status, supporting TRRf-induced systemic Th1 immune polarization. Conclusions: TRRf therapy was well tolerated in patients with metastatic PDAC and induced a distinct immune reprogramming in responders characterized by activation of memory/effector CD4+ T cells, innate cytotoxicity via NK cell expansion, and systemic Th1 cytokine induction. These circulating immune phenotypes and cytokine profiles may serve as predictive biomarkers and provide mechanistic insight into response to MEK/STAT3-targeted immunotherapy in PDAC. Citation Format: Peter Joel. Hosein, Sayan Chakraborty, Anna Bianchi, Yolanda Justal, Nkiruka Ezenwajiaku, Maria Vanessa. Yow, Chloe Brown, Melinda Boone, Edmond Box, Juan Pablo. Vaccario, Paolo ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"120 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract A023: Fibroblast STAT3 activation drives organ-specific premetastatic niche formation 摘要:成纤维细胞STAT3激活驱动器官特异性转移前生态位的形成
IF 11.2 1区 医学
Cancer research Pub Date : 2025-09-28 DOI: 10.1158/1538-7445.pancreatic25-a023
Emily L. Lasse Opsahl, Carlos E. Espinoza, Alberto Olivei, Jude Ogechukwu. Okoye, Megan Hoffman, Faith Avritt, Ahmed M. Elhossiny, Allison C. Bischoff, Katelyn L. Donahue, Mary Poggi, Padma Kadiyala, Nandini Arya, Jiaqi Shi, Kyoung Lee, Yaqing Zhang, Eileen S. Carpenter, Julianne M. Szczepanski, Timothy L. Frankel, Marina Pasca di Magliano
{"title":"Abstract A023: Fibroblast STAT3 activation drives organ-specific premetastatic niche formation","authors":"Emily L. Lasse Opsahl, Carlos E. Espinoza, Alberto Olivei, Jude Ogechukwu. Okoye, Megan Hoffman, Faith Avritt, Ahmed M. Elhossiny, Allison C. Bischoff, Katelyn L. Donahue, Mary Poggi, Padma Kadiyala, Nandini Arya, Jiaqi Shi, Kyoung Lee, Yaqing Zhang, Eileen S. Carpenter, Julianne M. Szczepanski, Timothy L. Frankel, Marina Pasca di Magliano","doi":"10.1158/1538-7445.pancreatic25-a023","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a023","url":null,"abstract":"Pancreatic cancer is associated with a high rate of metastasis and poor prognosis. The formation of a premetastatic niche (PMN) facilitates cancer cell spread and contributes to cancer mortality. Using murine pancreatic cancer models based on expression of oncogenic KRAS in the pancreas epithelium, we discovered that remodeling of the lung microenvironment occurs in mice bearing pancreatic precursor lesions prior to cancer formation. This early lesion premetastatic niche (EL-PMN) resembles the PMN in cancer-bearing mice, and both anticipate characteristics of overt metastasis, such as transcriptional reprogramming, activation of fibroblast STAT3 signaling and infiltration of immunosuppressive Arginase 1+ macrophages. Serum IL6 drives lung fibroblast STAT3 activation; in turn, fibroblast STAT3 activation is necessary for lung metastasis establishment. Interestingly, fibroblast reprogramming did not occur in the liver, pointing to organ-specific PMN formation. The formation of an early lesion premetastatic niche may underlie early dissemination of pancreatic cancer. Citation Format: Emily L. Lasse Opsahl, Carlos E. Espinoza, Alberto Olivei, Jude Ogechukwu. Okoye, Megan Hoffman, Faith Avritt, Ahmed M. Elhossiny, Allison C. Bischoff, Katelyn L. Donahue, Mary Poggi, Padma Kadiyala, Nandini Arya, Jiaqi Shi, Kyoung Lee, Yaqing Zhang, Eileen S. Carpenter, Julianne M. Szczepanski, Timothy L. Frankel, Marina Pasca di Magliano. Fibroblast STAT3 activation drives organ-specific premetastatic niche formation [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): nr A023.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"30 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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