Cancer research最新文献

{"title":"Abstract A138: The Association between Food Swamps and Pancreatic Cancer Mortality in Georgia","authors":"Malcolm Bevel, Jabrena Marshall, Victoria Ayodele, Arianna Iribhogbe, Meng-Han Tsai, Samantha R. Jones, Justin X. Moore","doi":"10.1158/1538-7445.pancreatic26-a138","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a138","url":null,"abstract":"Purpose: We investigated the association between food swamps and pancreatic cancer mortality in Georgia counties over a ten-year span. Background: Pancreatic cancer is the 4th leading cause of cancer death in the state of Georgia. As one of 13 obesity-related cancers, consumption of a healthy diet with emphasis on fresh produce is a vital protective factor against pancreatic cancer is. Living in areas where unhealthy food outlets outnumber healthy food retailers (i.e., food swamps) reduces access to healthy foods, potentially leading to worse cancer outcomes. However, the association between food swamps and pancreatic cancer mortality remains understudied. Method ology: We conducted a cross-sectional ecological study by linking county-level pancreatic cancer mortality data (2010-2020) from the Centers for Disease Control and Prevention (CDC) WONDER with food environment data (2012 – 2020) from the United States Department of Agriculture (USDA). Food swamp scores was the exposure of interest and was defined as the ratio of fast-food and convenience stores to grocery stores and farmer’s markets. Food swamp scores then categorized as low or high, with higher scores indicating counties with poorer healthy food resources. Pancreatic cancer mortality rates (outcome of interest) were based on underlying cause of death (UCD) ICD-10 codes, and were categorized as low vs. high. Multivariable-adjusted, multilevel generalized mixed-effects models were used to estimate the aforementioned association among eligible Georgia counties (N = 94). Results: Compared with counties with low pancreatic cancer mortality, counties with high pancreatic cancer mortality had a higher proportion of non-Hispanic (NH)-Black residents (28.7% vs. 20.0%), higher poverty rates (20.2% vs. 13.6%), higher adult smoking rates (18.9% vs. 16.7%), and higher food swamp scores (8.11 vs. 6.92) (p-value < 0.0001). After adjusting for age, race, poverty rates, and physician density, the odds of Georgia counties with high food swamp scores had more than two-fold higher odds of high pancreatic cancer mortality than counties with low food swamp scores (AOR = 2.63; 95% CI =1.02–6.77). Conclusion: Georgia counties with high food swamp scores had significantly higher odds of high pancreatic cancer mortality. These findings highlight the need for scalable interventions that improve healthy food access, including community gardens and controlled-environment agriculture initiatives such as rooftop gardens, alongside nutrition education and policy efforts to reduce disparities in pancreatic cancer mortality across Georgia. Citation Format: Malcolm Bevel, Jabrena Marshall, Victoria Ayodele, Arianna Iribhogbe, Meng-Han Tsai, Samantha R. Jones, Justin X. Moore. The Association between Food Swamps and Pancreatic Cancer Mortality in Georgia [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Phil","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"21 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048644","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}

{"title":"Abstract B129: Repurposed T-Box-Targeting Drug in Liposomal Formulation Shows Synergistic Efficacy Against PDAC","authors":"Susan Immanuel, Serala Karabo, Sharon Prince, Joshua Reineke","doi":"10.1158/1538-7445.pancreatic26-b129","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b129","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, largely due to late diagnosis, limited therapeutic response, and its dense desmoplastic stroma, which limits drug penetration. To address the need for more effective treatments, we investigated a repurposed small-molecule inhibitor targeting T-box transcription factors (TBX2/TBX3), emerging drivers of PDAC progression. In PDAC, TBX factors promote extracellular matrix (ECM), stiffening and remodeling, enhancing invasion, survival, and chemoresistance. Because developing new drugs is costly and slow, repurposing an existing compound offers a faster translational path while enabling targeted disruption of a key transcriptional program underlying PDAC desmoplasia. Methods: The significance of TBX2/TBX3 was investigated in human PDAC cell lines using SA-β-gal assay, Annexin-V/PI staining, transwell invasion, immunocytochemistry, and western blotting. The lead compound (name withheld pending IP protection) from a high-throughput drug repurposing screen was evaluated for cytotoxicity using MTT assays in PDAC cell lines (PANC-1, BxPC-3) and non-malignant epithelial and stromal cells (HPNE, HPaSteC). To model the desmoplastic tumor microenvironment, we generated 3D pancreatic cancer spheroids from the co-culture of PANC-1 and HPaSteC cells and quantified treatment-induced changes using SpheroidSizer®. A liposomal formulation was produced using hydrogenated soybean phosphatidylcholine, cholesterol, and helper lipids via cross-flow mixing, followed by characterization of particle size, polydispersity index (PdI), and encapsulation efficiency (EE). Results: When TBX3 was stably knocked down, the cells underwent senescence and had reduced proliferative ability. Interestingly, TBX2 levels increased in the TBX3-knockdown PDAC cells, and depleting TBX2 in these cells inhibited their migration and invasion. These results demonstrated that TBX2 and TBX3 have distinct oncogenic functions in PDAC and that any effective anti-PDAC drug will need to inhibit them both. Treatment with drug X in 3D desmoplastic models showed that initial exposure caused limited penetration, damaging mainly the outer layers, resulting in shedding in an onion-like manner. Subsequent treatments resulted in deeper penetration and complete disruption of the spheroid core at higher concentrations. Conclusion: The repurposed compound shows strong cytotoxicity against PDAC cells and effectively disrupts desmoplastic 3D spheroids with repeated dosing. The successful development of liposomal formulation further supports its potential as a therapeutic candidate, warranting future evaluation—particularly in combination with other chemotherapies—for PDAC treatment. Citation Format: Susan Immanuel, Serala Karabo, Sharon Prince, Joshua Reineke. Repurposed T-Box-Targeting Drug in Liposomal Formulation Shows Synergistic Efficacy Against PDAC [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: Ne","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048675","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}

{"title":"Abstract IA011: Decoding actionable tumor ecosystems through spatial multi-omics and AI","authors":"Linghua Wang","doi":"10.1158/1538-7445.pancreatic26-ia011","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-ia011","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) evolves within highly organized and dynamic tumor ecosystems in which malignant, stromal, and immune cell populations continuously interact in space. We conceptualize this spatial organization as a “cellular language,” where the identity, state, and spatial arrangement of individual cells collectively define the functional architecture of the tumor. Decoding this language may reveal how PDAC progresses, metastasizes, evades immunity, and responds to or resists therapy. In this presentation, I will discuss computational frameworks that integrate digital pathology, spatial multi-omics, multiplexed imaging, and artificial intelligence to resolve PDAC ecosystems across multiple biological scales. These approaches connect tumor-cell states and lineage plasticity with the organization of cancer-associated fibroblasts, immune populations, and multicellular neighborhoods, enabling us to define recurrent spatial niches and ecosystem states during tumor progression and metastatic evolution. Longitudinal and treatment-associated analyses further reveal how these ecosystems are remodeled by therapy and identify spatial features associated with therapeutic response and resistance. By integrating gigapixel histopathology with high-dimensional molecular and cellular measurements, AI provides an opportunity to move beyond descriptive spatial maps toward scalable models that recognize clinically relevant ecosystem states in routine tissue specimens. Together, these studies illustrate how moving beyond descriptive spatial maps to decode the functional grammar of PDAC ecosystems can uncover mechanisms of progression and therapeutic resistance, identify actionable multicellular interactions, and enable spatially informed precision oncology. The concepts and computational strategies presented here provide a broadly applicable framework for moving from high-dimensional spatial data to biologically interpretable and clinically actionable hypotheses, with relevance to studies of pancreatic cancer and other solid tumors. Citation Format: Linghua Wang. Decoding actionable tumor ecosystems through spatial multi-omics and AI [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2): nr IA011.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"17 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048763","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}

{"title":"Abstract B094: CDK12 inhibition activates cGAS-STING-mediated antitumor immunity and enhances immune checkpoint blockade in basal-like PDAC","authors":"Dosuke Iwadate, Keisuke Yamamoto, Hiroyuki Kato, Hiroaki Hujiwara, Mitsuhiro Fujishiro","doi":"10.1158/1538-7445.pancreatic26-b094","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b094","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited effective therapies. Using a patient-derived organoid-based drug screen, we identified cyclin-dependent kinase 12 (CDK12) as a promising therapeutic target, particularly in basal-like PDAC. CDK12 is a transcription-associated cyclin-dependent kinase involved in gene expression regulation at multiple levels and has recently gained attention as a therapeutic target in several cancer types. However, the therapeutic impact and potential of CDK12 inhibition in pancreatic cancer remain poorly understood. Both pharmacological and genetic inhibition of CDK12 exerted potent antitumor activity in vitro and in subcutaneous xenograft models using immunodeficient mice, inducing DNA double-strand breaks and apoptosis. To elucidate the underlying antitumor mechanism, we established FKBP12F36V (dTAG) knock-in PDAC cell lines, enabling rapid depletion of endogenous CDK12. Quantitative image-based cytometry and time-lapse imaging revealed that CDK12 ablation induced mitotic arrest followed by DNA damage and apoptosis. Mechanistically, loss of CDK12 kinase activity during S phase perturbed DNA replication, leading to spindle assembly checkpoint activation and subsequent mitotic catastrophe. Furthermore, CDK12 inhibition markedly increased micronuclei formation in vitro, resulting in robust activation of a type I interferon response through the cGAS-STING pathway and increased expression of T-cell-recruiting chemokines. Consistent with these findings, pharmacological inhibition of CDK12 in a syngeneic orthotopic tumor model increased intratumoral CD8+ T-cell infiltration and enhanced the efficacy of combined anti-PD-1 and anti-CTLA-4 therapy. Collectively, our results demonstrate that targeting CDK12 not only induces tumor cell-intrinsic cytotoxicity but also activates antitumor immunity, highlighting the therapeutic potential of combining CDK12 inhibition with immune checkpoint blockade in basal-like PDAC. Citation Format: Dosuke Iwadate, Keisuke Yamamoto, Hiroyuki Kato, Hiroaki Hujiwara, Mitsuhiro Fujishiro. CDK12 inhibition activates cGAS-STING-mediated antitumor immunity and enhances immune checkpoint blockade in basal-like PDAC [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2): nr B094.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"65 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048783","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}

{"title":"Abstract A105: The PASS-01 Challenge: Comparing Biomarkers for Treatment Selection in Advanced Pancreatic Cancer in a Randomized Controlled Trial","authors":"Wei Quan, David Henault, Syeda Mariam Hasnain, Daniela Bevacqua, Amy Zhang, Gun Ho Jang, Yangqing Deng, Julie Wilson, Anna Dodd, Andrew Aguirre, David Tuveson, Elizabeth Jaffee, Steven Gallinger, Faiyaz Notta, Jennifer J. Knox, Robert C. Grant","doi":"10.1158/1538-7445.pancreatic26-a105","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a105","url":null,"abstract":"Background: Predictive biomarkers for first-line treatment selection in advanced pancreatic ductal adenocarcinoma (PDAC) have been proposed, but none have been validated using data from a randomized controlled trial (RCT), which is the only design capable of unbiased assessment of differential treatment effect (DTE). Methods: We launched the PASS-01 Challenge, a rigorous, arms-length comparison of predictive and prognostic algorithms in PDAC using clinical, whole-genome, transcriptomic, and digitized histopathology data from PASS-01, a randomized phase II trial of FFX versus GnP in previously untreated metastatic PDAC. Participating groups receive de-identified multi-modal data, generate predictions independently, and submit locked predictions for centralized, blinded linkage to outcome data. The primary endpoint is concordance-for-benefit (C4B) for progression-free survival (PFS) in the per-protocol population; secondary endpoints include C4B and hazard ratios for overall survival (OS) and objective response (ORR), as well as the concordance index (C-index) for prognostic predictions. Participants can publish the performance of their predictions immediately after submission. Results: Here, we report four initial approaches under the Challenge: a multimodal machine-learning model (MULTIPL) that we developed and three previously published biomarkers (PurIST, hENT1 expression, HRDetect). MULTIPL, PurIST, and HRDetect were prognostic for OS (best C-index 0.595 [MULTIPL], P<0.001). In contrast, none of the four approaches achieved statistically significant treatment-selection performance by C4B for OS, ORR, or PFS, although exploratory subgroup analysis identified longer OS among MULTIPL-predicted GNP-favored patients treated with GnP versus FFX (HR 0.47, 95% CI 0.28–0.82, P=0.007). Conclusions: The PASS-01 Challenge enables rigorous, centrally-adjudicated, RCT-based validation of treatment-selection algorithms in PDAC, providing the first head-to-head benchmark of leading biomarker approaches. While the biomarkers evaluated so far are prognostic, treatment selection remains an unmet need. The Challenge remains open for submissions (hpb-research.ca) and invites investigators to test new and existing algorithms to accelerate progress in precision treatment selection for PDAC. Citation Format: Wei Quan, David Henault, Syeda Mariam Hasnain, Daniela Bevacqua, Amy Zhang, Gun Ho Jang, Yangqing Deng, Julie Wilson, Anna Dodd, Andrew Aguirre, David Tuveson, Elizabeth Jaffee, Steven Gallinger, Faiyaz Notta, Jennifer J. Knox, Robert C. Grant. The PASS-01 Challenge: Comparing Biomarkers for Treatment Selection in Advanced Pancreatic Cancer in a Randomized Controlled Trial [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2): nr A105.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048789","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}

{"title":"Abstract B011: HMGA2 controls fibroblast skewing and immune infiltration in basal pancreatic cancer","authors":"Naomi Yamamoto, Stephanie Dobersch, Tess M. Robertson, Jae Hyung Sim, Adrianne Wallace-Povirk, Nayvin W. Chew, Alex E. Orellana, Joana Aggrey-Fynn, Liberalis Debraj . Boila, Aidan Schutter, Ian M. Loveless, Gun Ho Jang, Shayan Avanessian, Gregory L. Beatty, Sunil R. Hingorani, Camilla Rydberg Millrud, Nina G. Steele, Debora Barbosa Vendramini-Costa, Ralph Francescone, Howard C. Crawford, Faiyaz Notta, Kevin C. Barry, Sita Kugel","doi":"10.1158/1538-7445.pancreatic26-b011","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b011","url":null,"abstract":"The basal-like subtype of pancreatic ductal adenocarcinoma (PDAC) is associated with poor outcomes and increased chemoresistance. Expression of high mobility group AT-hook 2 (HMGA2), a chromatin architectural protein, marks basal PDAC cells. Recent efforts to understand the tumor microenvironment (TME) of PDAC have extensively characterized both immune and stromal compartments. In previous work, we have shown that HMGA2+ basal-like pancreatic tumors are associated with higher fibroblastic activation and lower CD8+ T cell infiltrate than HMGA2- classical tumors. To mechanistically determine how HMGA2 expression alters the TME, we implemented three independent data sets; single-cell, microdissected and bulk RNA sequencing and found that HMGA2+ cancer cells also had high expression of ILA. Expression of HMGA2 by tumor cells leads to upregulation of the immunosuppressive markers interleukin 6 (IL6) and leucine-rich repeat containing protein 15 (LRRC15) in associated fibroblasts. Mechanistically, HMGA2 in the tumor cell binds the interleukin 1 alpha (IL1α) promoter, displaces histone linker H1 and upregulates transcription, increasing IL1α in the TME. In vivo, a genetically engineered mouse model with high levels of tumoral HMGA2 also displayed high IL6+ LRRC15+ fibroblast content and low CD8+ T cell content in tumors compared to HMGA2low littermates. We then orthotopically implanted murine KrasLSL-G12D/+, Trp53L/+, Pdx1-Cre, Rosa26YFP/YFP (KPCY) engineered to overexpress HMGA2 (oeHMGA2) or empty vector. oeHMGA2 accelerated disease course, increased metastases, and was sufficient to remodel the TME, including lower CD8+ T cell, and higher NK cell, and Treg populations. These TME changes were all prevented when oeHMGA2 cells were implanted into IL1R1 knock-out mice. Finally, we find that preclinical interruption of the IL1R pathway was sufficient to reverse IL6 and LRRC15 skewing in basal conditioned media-treated human PSCs and naïve murine fibroblasts and in vivo. Blockade of the IL1α signaling axis disrupts this tumor-driven microenvironment phenotype and combines with inhibitors of oncogenic KRAS to improve tumor control. These data demonstrate the role of tumoral HMGA2 expression in controlling an immunosuppressive TME, highlight a potential biomarker to determine TME phenotype in PDAC patients and introduce a novel subtype-specific immunomodulatory therapy. Citation Format: Naomi Yamamoto, Stephanie Dobersch, Tess M. Robertson, Jae Hyung Sim, Adrianne Wallace-Povirk, Nayvin W. Chew, Alex E. Orellana, Joana Aggrey-Fynn, Liberalis Debraj . Boila, Aidan Schutter, Ian M. Loveless, Gun Ho Jang, Shayan Avanessian, Gregory L. Beatty, Sunil R. Hingorani, Camilla Rydberg Millrud, Nina G. Steele, Debora Barbosa Vendramini-Costa, Ralph Francescone, Howard C. Crawford, Faiyaz Notta, Kevin C. Barry, Sita Kugel. HMGA2 controls fibroblast skewing and immune infiltration in basal pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"2 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048824","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}

{"title":"Abstract B114: Distinct Oncogenic KRAS Mutations Shape Tumor Immunity in Pancreatic Cancer","authors":"Huanhuan Sun, Andrew Wenger, KAtherine Bacchi, Rohit Chandwani, Kawther Abdilleh, Lukas Dow, Despina C. Siolas","doi":"10.1158/1538-7445.pancreatic26-b114","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b114","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is generally considered an immune-suppressive malignancy, yet the tumor-intrinsic programs that determine its immune microenvironment remain incompletely defined. KRAS mutations are a known driver of pancreatic cancer, occuring in over 90% of tumors. Historically, all oncogenic KRAS mutations were assumed to be biologically equivalent. However, emerging clinical and molecular data suggest otherwise: KRASG12R tumors, which represent approximately 20% of PDACs, are associated with the most favorable clinical outcomes, while KRASG12D tumors are associated with the worst outcomes, suggesting the presence of biologically distinct tumor subtypes. To understand the basis of the clinical observation, we analyzed human RNA-sequencing datasets from more than 600 patients and found significant enrichment of immune-related pathways in KRASG12R PDAC compared with KRASG12D PDAC. To mechanistically investigate this observation, we generated mutation-defined PDAC organoid models expressing either KRASG12R or KRASG12D. Although the models proliferated similarly in vitro, orthotopic implantation into immunocompetent mice demonstrated that KRASG12R tumors grew more slowly and exhibited an immune-active tumor microenvironment. Mechanistically, KRASG12R tumors exhibited enhanced antigen-presentation programs, suggesting that KRAS mutation status identity may regulate tumor immunogenicity. Spatial single-cell profiling of human PDAC specimens confirmed these findings, revealing enrichment of antigen-presenting cells and immune activation markers in KRASG12R tumors. Our data identify oncogenic KRAS mutation subtype as a determinant of immune microenvironment in PDAC and provide a rationale for mutation-informed therapeutic strategies Citation Format: Huanhuan Sun, Andrew Wenger, KAtherine Bacchi, Rohit Chandwani, Kawther Abdilleh, Lukas Dow, Despina C. Siolas. Distinct Oncogenic KRAS Mutations Shape Tumor Immunity in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2): nr B114.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"35 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048859","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}

{"title":"Abstract B127: Synthetic Lethality Through Combined BET and CDK9 Inhibition in MYC-Amplified Pancreatic Ductal Adenocarcinoma","authors":"Paulina N. Esguerra, Michela Cadarso, Sasha Livingwell, Md Shahadat Hossan, Olivia Wong, Jeremy D. Kratz","doi":"10.1158/1538-7445.pancreatic26-b127","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b127","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality and comprises molecular subtypes characterized by MYC amplification (14%) or MYC overexpression (40%), both of which drive tumor proliferation, metabolic reprogramming, and cellular plasticity. MYC dysregulation is associated with poor clinical outcomes and resistance, but its direct targeting remains a challenge. Here, we investigate the response of a patient-derived cancer organoid (PCO) model of PDAC as a function of MYC amplification to evaluate the synthetic lethality of dual transcriptional inhibition through BET inhibition (ZEN3694) and CDK9 inhibition (SLS009). Methods: A MYC-amplified PCO (Copy number 35) was treated with ZEN3694 (500nM), SLS009 (200nM) or the combination. Apoptosis and necrosis were assessed at 72h with caspase-3/7 and TO-PRO staining, respectively with cycloheximide (200 μM) as a positive control. One-way ANOVA followed by Tukey's post hoc test was used to compare mean percentage of area stained between treatment groups. Dose-response combination matrices were generated and viability was measured at 144h using 3D CellTiter-Glo (CTG, 50% v/v). Drug Synergy was quantified via SynergyFinder 3.0 (Zero Interaction Potency (ZIP), Bliss Independence (Bliss), Highest Single Agent (HSA)). Protein was isolated at 24h for Western blot analysis of total and Ser2/Ser5-phosphorylated RNA polymerase II, MYC and MCL-1. Blots were imaged using the LI-COR Odyssey imaging system and quantified with Image Studio software. Results: Following 72h treatment with SLS009 or ZEN3694 there was an observed mean Caspase-3/7 stained area of 14.78% and 5.178%, and mean TO-PRO staining of 15.68% and 5.131%, respectively. The combination of ZEN3694 and SLS009 further increased Caspase-3/7 staining to 25.65% (p< 0.001) and TO-PRO staining to 22.84% (p< 0.001). Dual treatment achieved synergy scores ranging between 17-21 indicating increased therapeutic activity. Western blot analysis showed on-target activity for the combination including reduced phosphorylation of RNA Pol II (Ser2/Ser5) (p< 0.0002 and p< of 0.0015) and decrease in T-Rpb1 (NTD) (p< 0.0162) consistent with transcriptional pausing. Furthermore, expression of short-lived transcription factors MYC and MCL-1 were both downregulated (both p< 0.0001). Conclusions: This study demonstrates that dual BET and CDK9 inhibition promotes transcriptional pausing and suppresses key regulators in transcriptionally driven cancers. Additionally, combining ZEN3694 and SLS009 exhibited in vitro synergy in and induced both apoptosis and necrosis, as well as demonstrating on-target transcriptional inhibition. Notably, these effects were achieved using ZEN3694 at a concentration substantially below physiological values, suggesting that SLS009 can potentiate the activity of BET inhibition. Ongoing studies are exploring this combination in other PDO models with diverse muta","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"93 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048861","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}

{"title":"Abstract B126: Targeting USP36 as a therapeutic strategy for high-MYC expressing pancreatic ductal adenocarcinoma","authors":"Assmaa Elsheikh, Pingchuan Zhang, Xiaoyan Wang, Yanping Li, Xiao-Xin Sun, Melissa Cunningham, Jonathan Brody, Sanjay Malhotra, Mushui Dai, Rosalie Sears","doi":"10.1158/1538-7445.pancreatic26-b126","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b126","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by poor therapeutic response and aggressive disease progression driven heavily by the c-MYC oncoprotein. Ubiquitin-specific protease 36 (USP36) is a nucleolar deubiquitinating enzyme that enhances the stability of critical nucleolar proteins, including c-MYC. Consequently, targeting USP36 represents a compelling therapeutic vulnerability in high-MYC-expressing PDAC tumors that are resistant to standard-of-care therapy. To identify novel therapeutic agents, a target-based high-throughput screening of a library containing 1,430 FDA-approved compounds was conducted utilizing a Ub-AMP fluorescence assay. In this biochemical assay, active USP36 cleaves ubiquitin from the substrate to generate a fluorescent signal; effective inhibitors are identified by a corresponding decrease in fluorescence intensity. From this screen, napabucasin, originally characterized as a cancer stemness inhibitor that blocks STAT3 phosphorylation and subsequent transcription of tumor-survival genes, was identified as a top candidate USP36 inhibitor. To validate this finding, well-established human PDAC cell lines (MIA PaCa-2 and Capan) were treated with napabucasin, demonstrating a robust time- and dose-dependent downregulation of c-MYC expression in both lines. Furthermore, in vitro cell viability assays demonstrated that napabucasin inhibits the proliferation of KMC murine PDAC cells, derived from tumors initiated through deregulated constitutive expression of MYC and mutant KRAS in adult pancreatic acinar cells, in a dose-dependent manner. Notably, cells with reduced MYC expression (MYC knockdown) exhibited significantly less sensitivity to napabucasin compared to shMYC control cells, supporting a MYC-dependent mechanism of action. To further validate these findings in patient-derived models, napabucasin was evaluated in patient-derived cell lines (PDCLs) established from primary human PDAC tumors. PDCLs possessing a high-MYC gene signature, as determined by bulk RNA-sequencing analysis, demonstrated heightened sensitivity to USP36 inhibition compared to cell lines with low-MYC signatures. Finally, to evaluate in vivo efficacy, napabucasin was administered in an orthotopic KMC PDAC mouse model. Tumors from this KMC model histologically and molecularly recapitulate the heterogeneity observed in human PDAC. Mice treated with napabucasin exhibited a significant reduction in average tumor volume compared to vehicle-treated controls. Furthermore, combining napabucasin with the pan-KRAS inhibitor RMC-6236 demonstrated superior efficacy in suppressing tumor growth compared to RMC-6236 monotherapy. Collectively, these data demonstrate that USP36 inhibition by napabucasin effectively impairs PDAC tumor growth in a MYC-dependent manner. These findings underscore the potential of USP36-targeted therapies, particularly when paired with pan-KRAS inhibition, as a promising strategy to over","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"80 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048858","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}

{"title":"Abstract A109: Urinary Metabolomic Signatures of Pancreatic Cancer Generalize Across Japanese and Thai Populations Despite Profound Baseline Divergence","authors":"Taisuke Baba, Masaki Sunagawa, Masamichi Hayashi, Kokuryo Toshio, Takashi Mizuno, Shunsuke Onoe, Nobuyuki Watanabe, Mihoko Yamada, Shoji Kawakatsu, Yosuke Ochiai, Hizuru Amano, Akinari Hinoki, Hiroo Uchida, Vasin Thanasukarn, Watcharin Loilome, Tomoki Ebata","doi":"10.1158/1538-7445.pancreatic26-a109","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a109","url":null,"abstract":"Background. Urine is an attractive noninvasive matrix for pancreatic ductal adenocarcinoma (PDAC) biomarkers, but whether metabolomic signatures generalize across populations differing in ethnicity and diet is unknown. Methods. Global urinary metabolomics (Metabolon) was performed on 182 samples: Japanese discovery cohort A (60 PDAC, 44 controls), Japanese validation cohort B (21, 18), and a Thai cohort (Khon Kaen University; 19, 20). Osmolality-corrected, log2-transformed peak areas were analyzed. Fifteen bridging specimens (identical urines assayed in both batches) were included, and all disease analyses used within-cohort PDAC-versus-control contrasts, in which batch effects cancel. Cross-cohort agreement was assessed by the rank correlation of z scores, tested against a permutation null that breaks metabolite correspondence between cohorts. Generative artificial intelligence (AI) assisted in writing the analysis code; all analyses were specified and verified by the authors. Results. Baseline populations diverged profoundly: among healthy controls, 251 of 1,106 metabolites (23%) differed between Thai and Japanese subjects (false discovery rate (FDR) <0.05; median 2.2-fold), whereas none differed in the 15 bridging specimens. This population effect exceeded the PDAC-versus-control effect itself (1.6-fold), and controls alone were almost fully separable by nationality (leave-one-out cross-validated area under the curve (AUC), 0.997). Despite this, the PDAC signature generalized: agreement between Japanese cohort A and the Thai cohort (r = 0.499; permutation P = 0.0002) matched that between the two Japanese cohorts (r = 0.531). Generalization was bidirectional: a Thai-derived score separated PDAC from controls in Japanese cohort A (AUC, 0.827), and a Japan-derived score did so in the Thai cohort (AUC, 0.811). Twenty-nine metabolites moved concordantly in all three cohorts, all elevated in PDAC and representing multiple metabolic pathways. Discordance tracked clinical state, not ethnicity: metabolite-inferred biliary obstruction differed across cohorts (Thai, 74%; Japan A, 40%; Japan B, 5%), and 86% of Japan-B PDAC had received neoadjuvant chemotherapy. Stratifying cohort A by clinical state, correlation with the Thai cohort ranged from 0.643 (treatment-naive, obstructed) to 0.208 (postchemotherapy, nonobstructed). Conclusions. Urinary PDAC signatures generalize across populations whose healthy metabolic baselines are themselves almost fully discriminable. Cross-cohort discordance reflected clinical state at sampling, namely biliary drainage and neoadjuvant therapy, rather than ethnicity. Detection of pancreatic cancer from urine is robust to differences in diet and ethnicity. Generative AI (Claude, Anthropic) was used to draft and edit the text of this abstract. Citation Format: Taisuke Baba, Masaki Sunagawa, Masamichi Hayashi, Kokuryo Toshio, Takashi Mizuno, Shunsuke Onoe, Nobuyuki Watanabe, Mihoko Yamada, Shoji Kawakatsu, Yosuke Ochiai, ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048707","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}