Cancer research最新文献

{"title":"Abstract A128: Design of a Phase 2 basket trial to assess mifomelatide (TCMCB07) in GI cancer cachexia: A focus on pancreatic ductal adenocarcinoma (PDAC)","authors":"Meghan Joly, William Riedl, Wilmon Grant, LuAnn Sabounjian, Allison Gardner, Barry Badeau, Russell Potterfield, Daniel Marks","doi":"10.1158/1538-7445.pancreatic26-a128","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a128","url":null,"abstract":"Background: Cachexia is common in gastrointestinal (GI) cancers in general and pancreatic ductal adenocarcinoma (PDAC) in particular. PDAC has one of the highest prevalences and earliest onsets of cancer cachexia, affecting up to 90% of patients. Furthermore, the extent of weight lost among patients with PDAC exceeds that observed in most other tumor types. Cachexia-induced muscle mass and energy store depletion reduces chemotherapy tolerance, often leading to dose reductions, treatment delays/discontinuation, and poorer survival outcomes. Therefore, body weight preservation during chemotherapy may improve treatment effectiveness and outcomes for patients with PDAC. The central melanocortin (MC) system, including MC3 and MC4 receptors, plays an essential role in regulating appetite, body mass, and energy homeostasis and is a logical therapeutic target to prevent and treat cachexia. Mifomelatide is a novel peptide MC3R/MC4R dual antagonist that is being studied for cancer and chemotherapy-associated weight loss. Our previously published work showed that mifomelatide is safe and ameliorates cancer- and chemotherapy-associated cachexia in preclinical animal studies with mice, rats, and pet dogs. In a Phase 1 trial with healthy volunteers, mifomelatide was well tolerated; the only adverse events were low-grade injection-site reactions. In addition, while the trial was not powered for efficacy, mifomelatide treatment was associated with a modest increase in body weight and hunger compared with placebo, warranting further clinical development. Methods: The randomized, double-blind, placebo-controlled Phase 2 basket trial of mifomelatide (NCT06937177) is enrolling participants initiating first-line chemotherapy for newly diagnosed, unresectable PDAC and cachexia or newly diagnosed, unresectable colorectal cancer (CRC) and < 10% body weight loss in the past 6 months. Participants, grouped into 2 cohorts by tumor type, are randomly assigned to receive subcutaneous mifomelatide (12.5, 25, or 50 mg) or placebo daily for 12 weeks. Following double-blind treatment, eligible participants may enroll in an open-label extension phase and receive mifomelatide 25 mg daily for up to an additional 26 weeks. Primary endpoints are change from baseline in body weight at 12 weeks and safety. Secondary endpoints are focused on changes in anorexia/cachexia-related PROs and BMI. This Phase 2 basket trial will generate robust insights into the benefit–risk profile of MC3R/MC4R dual antagonism with mifomelatide to treat cachexia across GI cancers and inform optimal dose selection, endpoints, sample size, and other key design elements for a planned pivotal trial in PDAC. Citation Format: Meghan Joly, William Riedl, Wilmon Grant, LuAnn Sabounjian, Allison Gardner, Barry Badeau, Russell Potterfield, Daniel Marks. Design of a Phase 2 basket trial to assess mifomelatide (TCMCB07) in GI cancer cachexia: A focus on pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proce","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"6 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048765","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 A120: Tumor-intrinsic MYC promotes a skeletal muscle-involving wasting phenotype in pancreatic ductal adenocarcinoma","authors":"Tingting Zhang, Faming Zhao, Xiaoyan Wang, Colin Daniel, Melissa Cunningham, Zheng Xia, Aaron J. Grossberg, Rosalie C. Sears","doi":"10.1158/1538-7445.pancreatic26-a120","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a120","url":null,"abstract":"Cancer cachexia is defined by an ongoing loss of skeletal muscle mass, with or without loss of adipose tissue, and is particularly prevalent and severe in pancreatic ductal adenocarcinoma (PDAC). However, whether muscle and adipose wasting represent separable components of cachexia and are differentially shaped by tumor-intrinsic programs remains unclear. Here, we quantified a muscle wasting score (MWS) and a fat wasting score (FWS) from computed tomography images in 212 patients with resected PDAC, 178 of whom had matched tumor bulk RNA-sequencing data for pathway activity analyses associated with MWS and FWS. MWS and FWS were not significantly correlated (r = 0.01, p = 0.92, n = 212), indicating that muscle and adipose wasting can be uncoupled in PDAC cachexia. Increasing MWS was associated with enrichment of multiple inflammatory pathways, including TNFA/NF-κB signaling. Hallmark MYC Targets V1/V2 programs were also enriched with increasing MWS, whereas their associations with FWS were substantially weaker. Consistently, tumors from patients with muscle wasting, either alone or accompanied by adipose wasting, exhibited higher MYC activity than tumors from patients with adipose-only wasting. For functional validation, primary PDAC cells derived from spontaneous Ptf1aCreERT2; KrasG12D; c-Myc (KMC) tumors were transduced with control (shNC) or MYC-targeting (shMYC) shRNA and orthotopically transplanted into syngeneic C57BL/6 mice. Mice bearing shNC tumors developed progressive body-weight loss and had significantly shorter survival than mice bearing shMYC tumors. To minimize confounding by metastatic burden, mice were compared at a pre-metastatic stage with matched primary-tumor volumes. At this stage, shNC tumors induced approximately 20% loss of both gastrocnemius and tibialis anterior muscle mass, together with approximately 40% loss of epididymal white adipose tissue, whereas shMYC tumors caused approximately 18% adipose loss without measurable muscle wasting. Following metastatic progression, shNC tumors produced severe muscle wasting (∼35%) and near-complete adipose depletion (∼80%), compared with substantially milder losses in the shMYC group (∼8.5% muscle and ∼55% adipose loss). Thus, MYC suppression largely preserved skeletal muscle, whereas substantial adipose loss persisted. Consistent with these phenotypes, shNC tumors exhibited enhanced inflammatory and cachexia-related transcriptional programs, including increased expression of Il6, Il11, Cxcl1, Inhba, Angptl4, and Igfbp3. shNC tumors also developed more liver metastases and showed markedly increased phosphorylated STAT3 in both metastatic lesions and adjacent liver parenchyma, consistent with enhanced tumor–host inflammatory signaling. Collectively, these findings show that muscle and adipose wasting have distinct relationships with tumor-intrinsic MYC in PDAC cachexia. Tumor MYC promotes the emergence of a muscle-involving cachexia phenotype in the setting of ongoing adipose wasti","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"103 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048777","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 B128: Urolithin A enhances chemotherapy efficacy and preserves intestinal barrier integrity in pancreatic ductal adenocarcinoma","authors":"Varunkumar Krishnamoorthy, Vineet K. Gupta, Nitu R. Heggade, Siddharth Mehra, Sweta Ghosh, Sana I. Oroumieh, Daysi D. Manrique, Rohan Moniruzzaman, Kamalpreet K. Sandha, Sanjana Shrivatsa, Rimpi Khurana, Venkatakrishna R. Jala, Yuguang Ban, Nipun Merchant, Austin R. Dosch, Peter J. Hosein, Nagaraj Nagathihalli","doi":"10.1158/1538-7445.pancreatic26-b128","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b128","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) is commonly treated with standard chemotherapy regimens such as Gemcitabine/Paclitaxel (Gem+PTX) and FOLFIRINOX (FFX), which are cytotoxic agents. However, treatment-associated gastrointestinal toxicity limits dose intensity and clinical benefit. Urolithin A (UroA), a gut microbiome-derived metabolite that promotes epithelial mitochondrial fitness, is untested as a chemotherapy adjuvant in PDAC. We investigated whether UroA could improve antitumor efficacy while protecting against chemotherapy-induced intestinal injury in preclinical PDAC models. Methods: We used genetically engineered PKT (Ptf1a Cre/+ ; LSL-Kras G12D/+ ; Tgfbr2 flox/flox ) or orthotopically implanted KPC6694 cells in C57BL6 mice that were treated with vehicle, UroA, Gem+PTX, or (Gem+PTX)+UroA; parallel studies evaluated FFX±UroA and MRTX1133+(Gem+PTX)+UroA. Pancreatic tumor burden was quantified. Intestinal barrier function was evaluated by measuring colon length, multiplex immunofluorescence, and transepithelial electrical resistance (TEER) plus FITC-dextran permeability in 3D human EpiIntestinal organoids. GeoMx digital spatial transcriptomics was used to assess the tight junction regions. Survival was analyzed by Kaplan-Meier. Results: Adding UroA to Gem+PTX significantly reduced pancreatic tumor burden and increased preservation of normal pancreatic parenchyma compared with Gem+PTX alone. Similar antitumor benefits were observed in FFX-treated mice, in which UroA further enhanced therapeutic responses while improving normal pancreatic architecture. Chemotherapy shortened colons, disrupted ZO-1 continuity, and increased inflammatory cell infiltration; UroA restored colon length and ZO-1 architecture, reduced inflammatory cell infiltration, improved barrier function in human organoids as measured by TEER, and normalized FITC-dextran permeability. Colonic spatial profiling revealed UroA-associated normalization of tight junction programs and attenuation of the chemotherapy-driven inflammatory signature. Uro A and Gem+PTX improve survival when compared to mice treated with Gem+PTX alone. The addition of the clinical-stage KRAS inhibitor MRTX1133 further improved outcomes, more than doubling survival compared with Gem+PTX+UroA. Conclusions: Urolithin A enhances chemotherapy's antitumor activity, protects the intestinal barrier, and further extends survival when combined with KRAS inhibition, supporting UroA as a translationally ready PDAC-combination adjuvant. Citation Format: Varunkumar Krishnamoorthy, Vineet K. Gupta, Nitu R. Heggade, Siddharth Mehra, Sweta Ghosh, Sana I. Oroumieh, Daysi D. Manrique, Rohan Moniruzzaman, Kamalpreet K. Sandha, Sanjana Shrivatsa, Rimpi Khurana, Venkatakrishna R. Jala, Yuguang Ban, Nipun Merchant, Austin R. Dosch, Peter J. Hosein, Nagaraj Nagathihalli. Urolithin A enhances chemotherapy efficacy and preserves intestinal barrier integrity in pancreatic ductal adenocarcinoma [abstract]. In: Proceedin","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"542 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048860","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 IA012: A New Perspective: Clinical Trials in the Era of RAS Inhibitors","authors":"C. Benedikt Westphalen","doi":"10.1158/1538-7445.pancreatic26-ia012","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-ia012","url":null,"abstract":"The demonstration of an overall survival benefit for RAS(ON) multi-selective inhibition in previously treated metastatic pancreatic ductal adenocarcinoma (RASolute 302) establishes the first randomised evidence for RAS-directed therapy in this disease. Previously, biomarker-directed treatment in PDAC reached a minority of patients and was derived largely from tumour-agnostic approvals, with germline BRCA1/2 constituting the only ESCAT tier I-A alteration. RAS mutations, present in more than 90% of tumours, now satisfy tier I-A criteria, extending biomarker-defined treatment to most patients. More than forty RAS-directed agents across eight mechanistic classes are in clinical development, at least nine of them in phase 3 and sponsored by multiple organisations. These trials differ in eligible population, comparator and chemotherapy backbone, and share few common design elements. Reported response rates range from 33% to 82%, a spread determined predominantly by treatment line, allele selection and backbone rather than by pharmacological activity; within a single study, investigator-selected backbones yielded divergent response rates in cohorts differing substantially at baseline. ESMO-MCBS v2.0 grades single-arm data to a maximum of grade 3, leaving the grades that denote substantial benefit unattainable without a comparator. This presentation examines the methodological consequences: the limited discriminatory capacity of objective response rate where disease control approaches 90%; the case for qualifying ctDNA molecular response as an early efficacy endpoint; the promotion of patient-reported outcomes and sustained relative dose intensity to co-primary status; master-protocol architectures with shared control arms and pre-specified randomisation at progression; and prospective characterisation of resistance. Citation Format: C. Benedikt Westphalen. A New Perspective: Clinical Trials in the Era of RAS Inhibitors [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 IA012.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"39 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048764","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 A033: Gangliosides as regulators of the hybrid epithelial-mesenchymal phenotype in pancreatic ductal adenocarcinoma","authors":"Ali G. Moursy, Zachary Klamer, Alfredo Reyes-Oliveras, Chongfeng Gao, Thomas Goralski, Ash Fletcher, Chanjuan Shi, Joshua Jang, Peter Allen, Brian Haab","doi":"10.1158/1538-7445.pancreatic26-a033","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a033","url":null,"abstract":"Despite advances in cancer research, the five-year survival rate for pancreatic ductal adenocarcinoma (PDAC) remains only 13%, largely due to early metastasis, the lack of effective treatments against metastatic cancer, and the absence of reliable biomarkers. PDACs and other cancers gain metastatic capability and heightened treatment resistance through high plasticity between epithelial and mesenchymal states, driven mainly by cells that undergo a partial epithelial/mesenchymal transition (pEMT) to adopt a hybrid state. Treatments to target the cells in a hybrid state and their ability to undergo epithelial/hybrid/mesenchymal (E/H/M) state transitions have been hindered by the lack of identification and definition of persistent hybrid cancer cells in primary tumors. We investigated whether hybrid cancer cells have distinct metabolic, transcriptional, and cell-surface glycan and protein profiles that enable the definition of such cells in primary tumors and in-vitro systems. We used 13C tracing, metabolomics, and transcriptional profiling to identify newly produced glycans in epithelial-mesenchymal transitions and multiplexed glycan/protein immunofluorescence and spatial transcriptomics to determine cell-surface glycan and protein profiles in primary tumors and cell culture. We found that cells undergoing EMT increase glycolysis, increase glucose commitment to sialic acid and glycosphingolipid production, and increase transcriptional support of ganglioside and a2,6 sialic acid production. In primary tumors, specific E, H, and M cancer cell subpopulations had distinct cell-surface glycan and protein profiles, and spatially linked clusters of cancer cells with high heterogeneity in E/H/M states had increased ganglioside and a2,6 sialic acid display. In cell culture, such features identified cells in stable hybrid states. Specific gangliosides were associated with highly migratory cells, and knockdown of the B4GALNT1 gene that contributes to ganglioside production induced reversion from the hybrid to the epithelial state. Therefore, cell-surface glycan and ganglioside features identify specific hybrid subpopulations of PDAC cells and potential drivers of E/H/M state transitions. The further characterization of these subpopulations may reveal methods to prevent E/H/M plasticity and reduce the metastatic and treatment-resistant capabilities of PDAC. Citation Format: Ali G. Moursy, Zachary Klamer, Alfredo Reyes-Oliveras, Chongfeng Gao, Thomas Goralski, Ash Fletcher, Chanjuan Shi, Joshua Jang, Peter Allen, Brian Haab. Gangliosides as regulators of the hybrid epithelial-mesenchymal phenotype in pancreatic ductal adenocarcinoma [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 A033.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"6 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048814","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 B061: Epigenetic EZH2 dependency in KRAS inhibitor-resistant PDAC cells","authors":"Gonçalo Outeiro-Pinho, Aref Hosseini, Maciej Garczyk, Stephan von. Gunten, Beat Gloor, Anna Silvia. Wenning, Hannah L. Williams, Martin Wartenberg, Georgia Konstantinidou","doi":"10.1158/1538-7445.pancreatic26-b061","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b061","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, mainly due to limited therapeutic options, late diagnosis and rapid development of drug resistance. Recently, multiple pan- and mutation-selective KRAS inhibitors have been developed, showing significant survival benefit, including the KRASG12D inhibitor MRTX1133. Unfortunately, as observed with the KRASG12C inhibitors, resistance mechanisms often limit its long-term efficacy. Epigenetic remodeling, particularly via the histone methyltransferase enhancer of zeste homolog 2 (EZH2), has been implicated in cell plasticity and therapy resistance by repressing epithelial programs while inducing more aggressive cellular states. Here, we investigated the mechanisms driving resistance to MRTX1133 in PDAC. We established three MRTX1133-resistant (MRTX1133_R) cell lines through chronic exposure to escalating drug concentrations. After, we employed bulk RNA sequencing followed by gene set enrichment analysis to reveal alterations between MRTX1133_R and parental counterparts. We then performed multiple functional assays to characterize the mechanisms driving the resistant phenotype. Additionally, we stained human samples from a tissue microarray by immunohistochemistry to assess the translation of our findings. We found that KRAS inhibitor-resistant cells exhibited profound molecular rearrangements, including loss of epithelial markers (E-cadherin, Claudin-1), and increased expression of mesenchymal players (N-cadherin, Slug), concomitantly with enhanced PI3K-mTOR pathway activity. RNA sequencing analysis revealed enhanced cellular plasticity and enrichment of neuroendocrine (NE) and EZH2-associated transcriptional programs, marked by higher expression of several NE markers, including ASCL1, CHGA, NKX2-2, and PAX6. Importantly, treatment with an EZH2 inhibitor – Tazemetostat – markedly reduced the proliferation of MRTX1133_R cells, abolished H3K27me3 protein levels and decreased expression of NE markers. Combined treatment of Tazemetostat and MRTX1133 re-sensitized resistant cells, leading to a significant reduction in cell viability alongside cell death induction. Remarkably, Tazemetostat synergized with the dual mTOR/PI3K inhibitor Dactolisib to significantly reduce cell viability, providing an alternative therapeutic option. Importantly, in human samples, high percentage of EZH2+ cells significantly associated with advanced stages, lymph node-positive cases, as well as recurrence at distant sites, particularly in the lung. Overall, our findings uncover an epigenetically-driven resistance mechanism in which EZH2 promotes NE differentiation and provides a bypass signaling under KRAS inhibition. Targeting EZH2 may therefore represent a promising therapeutic strategy to overcome KRAS inhibitor resistance and improve the clinical outcome for PDAC patients. Citation Format: Gonçalo Outeiro-Pinho, Aref Hosseini, Maciej Garczyk, Stephan von. Gunten, Beat Gloor, Anna Silvia. Wenning, H","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"72 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048605","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 B109: Proteomics analysis of histotripsy ablated pancreatic tumors in C57BL/6 mice","authors":"Joshua L. Perez, Tamalika Paul, Irving Coy. Allen","doi":"10.1158/1538-7445.pancreatic26-b109","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b109","url":null,"abstract":"Background: Histotripsy is a non-invasive, non-thermal focused ultrasound ablation technology that mechanically disrupts tumor tissue while stimulating anti-tumor immune responses. Although histotripsy enhances immune cell infiltration and has demonstrated systemic immunologic effects, the mechanisms linking tumor destruction to adaptive immunity remain incompletely understood. We hypothesized that histotripsy alters major histocompatibility complex (MHC) class I antigen presentation and remodels the tumor immunopeptidome. Methods: Pan02 pancreatic tumors were established in C57BL/6 mice and treated with partial histotripsy ablation or left untreated as controls. Tumors were harvested 2 hours and 21 days following treatment. MHC-associated peptides were enriched using the semi-automated SAPrIm immunopeptidomics workflow and analyzed by liquid chromatography coupled with variable-window data-independent acquisition mass spectrometry. Peptide identification and quality-control analyses were performed using PEAKS software. Results: Twenty-two mass spectrometry analyses generated 413,653 frames, 282,397 precursor ions, 180,243 extracted features, and 68,966 peptide-spectrum matches, yielding 1,127 unique peptides derived from 40 proteins. Replicate analyses demonstrated reproducible peptide recovery across experimental conditions, supporting the robustness of the workflow. A conserved core immunopeptidome was identified across treatment groups, while additional peptide populations varied according to histotripsy treatment and collection time point. These treatment-associated peptide signatures suggest dynamic remodeling of antigen presentation following histotripsy. Chromatographic quality assessment also identified opportunities to improve peptide recovery and expand immunopeptidome coverage in future studies. Conclusions: Mass spectrometry-based immunopeptidomics is a feasible approach for characterizing antigen presentation following histotripsy in pancreatic cancer. These preliminary findings provide evidence that histotripsy remodels the MHC class I immunopeptidome and establish a foundation for mechanistic studies investigating how altered antigen presentation contributes to histotripsy-induced anti-tumor immunity and may inform future combination immunotherapy strategies.Generative AI was used to improve the clarity and organization of this abstract. All authors reviewed and verified the accuracy and integrity of the final submitted content. Citation Format: Joshua L. Perez, Tamalika Paul, Irving Coy. Allen. Proteomics analysis of histotripsy ablated pancreatic tumors in C57BL/6 mice [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 B109.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"43 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048609","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 B080: Maturation-dependent sensing of microenvironmental cues drives divergent neutrophil polarity in pancreatic cancer","authors":"Anna Bianchi, Manan Patel, Da Yin, Andrew M. Adams, Haleh Amirian, Karthik Rajkumar, Beatrice Awasthi, Anuroop Allena, Harper M. Marsh, Elena Shersher, William L. Hwang, Peter J. Hosein, Jashodeep Datta","doi":"10.1158/1538-7445.pancreatic26-b080","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b080","url":null,"abstract":"Tumor-associated neutrophils exhibit functional heterogeneity, with distinct immunosuppressive and antigen-presenting states described across cancer types. Yet these populations have largely been characterized as isolated observations rather than as opposing fates arising from a common developmental decision point, and the mechanisms that specify each remain poorly understood. Here, using pancreatic ductal adenocarcinoma (PDAC) and its highly neutrophil-enriched tumor microenvironment (TME) as the disease context, we show that TGFβ-driven Siglec-F/8+ immunosuppressive and interferon-driven MHC-II+ antigen-presenting neutrophils represent opposing terminal fates governed by a binary transcriptional switch enforced by Zeb1 and Ets1. Competence to acquire each fate is gated by discrete windows of neutrophil maturation, which directs their segregation into spatially distinct niches within the PDAC TME and encodes divergent functional consequences for antitumor immunity. The resulting polarity is reflected in the circulating neutrophil compartment, where the balance between these states correlates with pathological response to neoadjuvant chemotherapy in patients with localized PDAC; pharmacological inhibition of the Siglec-F+ suppressive program improves chemosensitivity and survival in vivo, implicating neutrophil fate reprogramming as a novel immunomodulatory strategy in PDAC. Citation Format: Anna Bianchi, Manan Patel, Da Yin, Andrew M. Adams, Haleh Amirian, Karthik Rajkumar, Beatrice Awasthi, Anuroop Allena, Harper M. Marsh, Elena Shersher, William L. Hwang, Peter J. Hosein, Jashodeep Datta. Maturation-dependent sensing of microenvironmental cues drives divergent neutrophil polarity 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 B080.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"83 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048615","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 B013: Interrogating and modeling progression of early pancreatic intraepithelial neoplasia","authors":"Tana Gazdik, Madeline Kuhn, Kyra Lindley, Aaron Doe, Brian Mau, Ellen M. Langer","doi":"10.1158/1538-7445.pancreatic26-b013","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b013","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with one of the lowest five-year survival rates of all cancers. Low grade, premalignant pancreatic intraepithelial neoplasias (PanINs) are common in the general population, but despite expression of mutant KRAS, the vast majority of these lesions will never progress to cancer. Understanding how additional genetic or epigenetic changes as well as changes to the tumor microenvironment contribute to PanIN to PDAC progression is critical and has the potential to reveal mechanisms of interception for this deadly disease. To better understand how specific alterations to epithelial or microenvironmental cell states impact progression of human PanINs, we are (1) analyzing the composition, organization, and cellular states of early human PanIN lesions and (2) designing manipulable in vitro co-culture models that mimic early human lesions. To understand the cell types, cell states, and spatial organization of PanIN lesions, we have collected >25 organ donor pancreata from people without cancer diagnoses. We histologically assessed multiple regions from the head, body, and tail of each pancreas to select ROIs for further genomic, transcriptomic, and proteomic analysis. We performed spatial transcriptomics on 72 ROIs selected from 13 donors, representing distinct age, BMI, and other lifestyle characteristics. Ongoing spatial transcriptomic analysis is determining the cellular composition and pathway usage among epithelial, stromal, and immune cell types across these different lesions, and these will be compared to the cell type and state changes observed in later stage lesions and pancreatic cancer. In order to build in vitro models testing hypotheses derived from this analysis, we have also created epithelial organoid and fibroblast lines from many of the normal pancreata. Using these primary derived cell lines along with additional purchased primary or immortalized cell lines, we are generating complex 3D bioprinted co-culture models of early disease progression. We are comparing phenotypic, proteomic, and transcriptomic changes to the epithelial cells and the microenvironment following distinct combinations or genetic perturbations of the different cell types. These models will be used to interrogate and understand the crosstalk that can permit progression of pancreatic cancer and to identify and test targets to intercept this process. Citation Format: Tana Gazdik, Madeline Kuhn, Kyra Lindley, Aaron Doe, Brian Mau, Ellen M. Langer. Interrogating and modeling progression of early pancreatic intraepithelial neoplasia [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 B013.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"19 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048637","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 B065: Bioactive Compounds Derived from Alcea rosea Suppress KRAS-Driven Signaling and Cancer Stem Cell Plasticity in Pancreatic Ductal Adenocarcinoma","authors":"Ruhban Ansar. Parry","doi":"10.1158/1538-7445.pancreatic26-b065","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b065","url":null,"abstract":"Background: Activating KRAS mutations occur in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases and are major drivers of tumor progression, therapeutic resistance, and poor clinical outcomes. Persistent activation of the RAF/MEK/ERK signaling cascade promotes cancer stem cell (CSC) maintenance and tumor plasticity, limiting the efficacy of current targeted therapies. This study evaluated the therapeutic potential of bioactive compounds isolated from Alcea rosea to target KRAS-driven signaling and CSC-associated phenotypes in PDAC. Methods: Bioactive compounds isolated from the ethyl acetate extract of Alcea rosea were evaluated in KRAS-mutant human PDAC cell lines. Cytotoxicity was assessed by MTT assay, while colony formation, wound healing, and 3D spheroid assays evaluated tumorigenicity and stemness. Apoptosis was analyzed by DAPI/PI and AO/EtBr staining, ROS generation, mitochondrial membrane potential, and flow cytometry. Western blotting assessed p-MEK, p-ERK, Caspase-3, and PARP expression. Molecular docking against KRAS, MEK1, and ERK2 evaluated binding affinities, followed by 100 ns molecular dynamics simulations to assess complex stability, conformational dynamics, RMSD, RMSF, and hydrogen-bonding interactions. Results: Alcea rosea-derived compounds significantly reduced PDAC cell viability, clonogenic growth, migration, and 3D spheroid formation, indicating impaired cancer stem cell (CSC) self-renewal. Treatment increased ROS generation, disrupted mitochondrial membrane potential, and induced apoptosis, as evidenced by Caspase-3 activation and PARP cleavage. Western blot analysis demonstrated 1.3-fold and 2.2-fold reductions in MEK and ERK phosphorylation, respectively. Molecular docking revealed favourable binding of the bioactive compounds to KRAS, MEK1, and ERK2, while 100 ns molecular dynamics simulations confirmed stable ligand–protein complexes through consistent RMSD, RMSF, and hydrogen-bonding profiles. Conclusions: Alcea rosea-derived bioactive compounds exhibit potent anti-tumor activity against KRAS-mutant PDAC by inhibiting KRAS/MAPK signaling and disrupting cancer stem cell-associated plasticity. These findings, supported by both experimental and computational analyses, warrant further preclinical investigation of Alcea rosea-derived small molecules as potential therapeutics to overcome resistance in KRAS-driven pancreatic cancer. Agreement on Use of Generative AI: Generative artificial intelligence was used exclusively to improve the language, grammar, and structure of text written by the authors. No AI tools were used in the study design, data collection, experimentation, analysis, interpretation of results, or preparation of the scientific content. Citation Format: Ruhban Ansar. Parry. Bioactive Compounds Derived from Alcea rosea Suppress KRAS-Driven Signaling and Cancer Stem Cell Plasticity in Pancreatic Ductal Adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Fro","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"13 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048681","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}