Cancer research最新文献

{"title":"Abstract B060: From Resistance to Rescue: Allele-Informed Salvage Therapy Following Daraxonrasib Resitance in Pancreatic Cancer","authors":"Thomas McFall, Daniel Dorbin, Juliannie Herrera, Raven Davidson, Douglas B. Evans, Susan Tsai, K. Nikki, Y. David Seo, Razelle Kurzrock, G. Aaron Hobbs, Mandana Kamgar","doi":"10.1158/1538-7445.pancreatic26-b060","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b060","url":null,"abstract":"Background: Clinical-grade RAS(ON) inhibitors have transformed treatment of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC), but acquired resistance is universal and post-progression treatment selection remains empiric. Whether specific KRAS alleles impose distinct constraints on the adaptive resistance network, and whether these constraints can be exploited therapeutically, is unresolved. Methods: We compared resistance mechanisms to daraxonrasib, a multi-selective RAS(ON) inhibitor, between isogenic PDAC models harboring KRAS G12D versus KRAS G12R, alleles with divergent RAS network dynamics. Signaling was characterized by RAS activity assays, biochemical profiling of the mutant/wild-type RAS ratio, and cyclophilin A (CypA) expression. Findings were extended to a KRAS G12R PDAC patient who progressed after 10 months of daraxonrasib, using biochemical profiling of resected tumor and rapid 3D-bioprinted patient-derived toroids to model candidate salvage regimens. Results: Daraxonrasib inhibited mutant KRAS primarily through steric occlusion of effector binding while engaging wild-type RAS only modestly (∼20%). KRAS G12R was unable to transactivate wild-type RAS, and daraxonrasib-resistant KRAS G12R cells instead adopted EGFR/wild-type RAS-GTP signaling as the dominant adaptive route. In contrast, KRAS G12D resistance arose through retained mutant KRAS-GTP signaling accompanied by loss of CypA, the binding partner required for daraxonrasib activity. The shift toward EGFR/wild-type RAS dependence in the G12R setting conferred sensitivity to trametinib. Consistent with the preclinical data, the patient's resected tumor showed intratumoral EGFR/wild-type RAS activation at progression, and patient-derived toroids predicted sensitivity to trametinib-based combination therapy. Despite an aggressive disease course and lack of response to the two immediately preceding lines of therapy, sixth-line trametinib-based combination therapy achieved approximately 5 months of disease control, and the patient ultimately achieved 40 months of overall survival, substantially exceeding the 8–12 month median for metastatic PDAC. Conclusions: KRAS allele identity dictates the topology of the adaptive resistance network following RAS(ON) inhibitor therapy, generating allele-specific and therapeutically actionable vulnerabilities. These data establish a mechanistic and translational framework, validated with a rapid patient-derived toroid platform, for rational, mechanism-informed salvage therapy selection in patients who progress on RAS inhibitors. Citation Format: Thomas McFall, Daniel Dorbin, Juliannie Herrera, Raven Davidson, Douglas B. Evans, Susan Tsai, K. Nikki, Y. David Seo, Razelle Kurzrock, G. Aaron Hobbs, Mandana Kamgar. From Resistance to Rescue: Allele-Informed Salvage Therapy Following Daraxonrasib Resitance in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"10 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048604","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 B056: SOAT1 inhibition by a covalent metabolite mimetic targets RAS maturation and pancreatic cancer","authors":"Wenjun Lan, Shoujun Sun, Nitin Pawar, Jérémy Nigri, Juliene Hinds, Astrid Deschênes, Lesley Ferguson, Cristina Lopez, Sangjun Yoon, Yijian Qiu, Victoria Gaeth, Sara Pawlak, Clementina Strozek, Michelle Saoi, Ritchie Ly, Shaheen Khan, Rachel Rubino, Youngkyu Park, Scott Lyons, Adam Moorhouse, Michael Lukey, Shozeb Haider, Hiro Furukawa, Paolo Cifani, Justin Cross, Michael Murphy, John Moses, David Tuveson","doi":"10.1158/1538-7445.pancreatic26-b056","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b056","url":null,"abstract":"Oncogenic KRAS requires prenylation for membrane localization and cellular transformation, but extensive efforts to inhibit this process for cancer therapy have failed. We report that Sterol o-acyl transferase 1 (SOAT1) stimulates Pancreatic Ductal Adenocarcinoma (PDAC) cells by enhancing isoprenoid synthesis to increase RAS membrane localization and mitochondrial function. Acute loss of SOAT1 attenuates PDAC transformation, nominating the therapeutic potential of targeting this non-essential enzyme. Since existing SOAT1 inhibitors lacked selectivity in PDAC cells, we developed SOAT1 covalent metabolite mimetic antagonists. Our lead compound elicits SOAT1 degradation and collapses RAS signaling and mitochondrial function in PDAC cells, demonstrating potent anti-neoplastic activity while sparing normal tissues in multiple murine PDAC models. Therefore, SOAT1 targeting provides a new means to attenuate RAS maturation and oncogenicity in PDAC. Citation Format: Wenjun Lan, Shoujun Sun, Nitin Pawar, Jérémy Nigri, Juliene Hinds, Astrid Deschênes, Lesley Ferguson, Cristina Lopez, Sangjun Yoon, Yijian Qiu, Victoria Gaeth, Sara Pawlak, Clementina Strozek, Michelle Saoi, Ritchie Ly, Shaheen Khan, Rachel Rubino, Youngkyu Park, Scott Lyons, Adam Moorhouse, Michael Lukey, Shozeb Haider, Hiro Furukawa, Paolo Cifani, Justin Cross, Michael Murphy, John Moses, David Tuveson. SOAT1 inhibition by a covalent metabolite mimetic targets RAS maturation and 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 B056.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"56 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048639","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 A139: SUMOylation Inhibition Synergizes with Irinotecan and Daraxonrasib to Treat Pancreatic Cancer","authors":"Asimina Courelli, Mia MacDonald, Ponmathi Panneerpandian, Leonie Ren, Jonathan Weitz, Herve Tiriac, Yuan Chen, Andrew M. Lowy","doi":"10.1158/1538-7445.pancreatic26-a139","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a139","url":null,"abstract":"Introduction: Pancreatic cancer (PDAC) has a poor response to standard cytotoxic chemotherapy, necessitating improved treatment options. SUMOylation is a post-translational modification (PTM) that modulates cell cycle replication, cell proliferation, and DNA damage repair pathways. We hypothesized that SUMOylation inhibition agent (SUMOi; SB-4826) would synergize with cytotoxic chemotherapies and daraxonrasib (DARA) to increase cancer cell death. Methods: In Vitro Synergy: Human PDAC organoid lines(hf44, hf23, hT1- primary tumor; hm1a, hm1e, hm1f- lung metastases; hm19b- liver metastases) screened with 5-Fluorouracil, Irinotecan (IRI), Oxaliplatin, Gemcitabine, Paclitaxel in combination with SUMOi (100nM max concentration for all drugs). KPC46, FC1245, FC1245-Gem Resistant murine PDAC cells treated with IRI and/or SUMOi (500nM max concentration for all drugs; viability measured using cell titer glo; synergy plots generated using Combenefit. Western Blots (WB): KPC46 and hf44 treated with SUMOi and/or IRI; staining for γ-H2AX and cleaved caspase-3 (CC3). Animal Experiments: NSG and B6 mice underwent orthotopic KPC46, FC1245, and FC1245-GemR cell injections—IP injections with SUMOi, and/or IRI; tumor volume (TV) assessed with ultrasound. Human PDAC Cultures: patient tumor slices incubated in SUMOi 100 mg/kg biweekly, DARA 20 mg/kg daily, and/or IRI 12.5 mg/kg qweek. Enrollment upon tumors reaching 3-5 mm diameter (measured by ultrasound); IF was conducted for EdU and γH2AX. Human single cell RNA sequencing (scRNASeq): using the Human Pancreatic Cancer Single-Cell Atlas to identify SUMO2/3 expressing cells. Results: In vitro synergy between SUMOi+IRI was consistently observed at concenctrations ≤ 50nM for both organoid and murine cell lines. Synergistic cytotoxicity of SUMOi+IRI treatment in vivo resulted in significantly decreased tumor growth in KPC46, FC1245, and FC1245-GemR lines compared to monotherapy and untreated groups in NSG mice. WB using KPC 46 and hf44 (organoid) showed the greatest increase in ϒ- H2AX and CC3 occurred for SUMOi+IRI compared to SUMOi and IRI alone. In tumor slices, SUMOi+IRI treatment yielded the greatest decrease in EdU and increase in γH2AX staining . Human tumor scRNASeq showed SUMO2/3 is highly expressed PDAC primary tumor cells as compared to adjacent normal tissue and that SUMO2/3 expressing cancer cells persist after FOLFIRINOX and Gemcitabine/Paclitaxel treatment. B6 mice with orthotopic FC1245 and FC1245-GemR tumors showed the longest survival and smallest tumors with DARA+IRI+SUMOi treatment compared to DARA alone and IRI+SUMOi. Conclusion: SUMOi+IRI shows synergistic cytotoxicity observed in both murine and human PDAC models. SUMO proteins and PTMs are highly expressed in human PDAC tumors compared to normal tissue. Addition of SUMOi+IRI to DARA leads to improved tumor growth control and survival compared to DARA alone in aggressive murine models. Clinically, SUMOi+IRI could be combined with DARA as a second ","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":"149048643","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 B088: Targeting bile acids mitigates PDAC Tumor Burden and induces anti-tumor immunity","authors":"Erin Gibbons, Rahul Shinde, Gauri Mirji, Sajad Bhat, Wujuan Zhang, Aaron Goldman, Behnaz Mansoori","doi":"10.1158/1538-7445.pancreatic26-b088","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b088","url":null,"abstract":"It is well appreciated that dietary metabolites can influence health outcomes. However, the various mechanisms by which some dietary metabolites influence health and treatment responses remain unknown. One metabolite subgroup that warrants further investigation is bile acids, which are derived from cholesterol in the liver and can be converted into secondary bile acids by the gut microbiome. They are dysregulated in many diseases such as cancer and are upregulated in pancreatic adenocarcinoma (PDAC) patients. Pancreatic cancer has an average five-year survival rate of 13%, and patients do not respond well to conventional chemotherapy and immunotherapy, highlighting the need for novel therapeutic strategies. In addition to metabolites, our lab is broadly focused on the immune microenvironment with a concentration on macrophages. Macrophages make up a significant portion of the immune cells in PDAC patient tumors and are often immunosuppressive. We performed spatial transcriptomics on tumor tissue from mice with PDAC, focusing on macrophage-high regions of the tumors, and found increased bile acid metabolism gene pathways in treatment-resistant compared to treatment-responsive tumors. This suggested that bile acid signaling could impact macrophages to make a more immunosuppressive tumor microenvironment that is less responsive to treatment. One way to target bile acid signaling in PDAC is through z-guggulsterone (zGS), a plant-derived FXR (bile acid receptor) antagonist. This drug has been shown to induce apoptosis in pancreatic cancer cell lines, but research on its impact on the immune microenvironment in PDAC is lacking. Therefore, we treated mice with PDAC with zGS and chemotherapy and found the combination strategy to be the most effective at tumor growth reduction, and that zGS boosts immune activation. We also observed larger orthotopic PDAC tumors in mice on a high cholesterol diet (HCD) and significant increases in secreted fecal bile acids, particularly lithocholic acid (LCA) derivatives. Treating mice with LCA decreased tumor growth and increased immune activation in cells, including macrophages. To study the impacts of LCA on macrophages specifically, we isolated bone-marrow-derived macrophages (BMDMs) from mice and cultured them in the presence or absence of LCA and tumor cell-derived supernatant (TCS) to mimic the tumor microenvironment. We collected RNA from these macrophages and found that LCA reduced immunosuppressive mRNAs by real-time quantitative PCR. RNA sequencing of these samples displayed increases in interferon pathway genes indicating that LCA may exert its anti-tumor effects through interferons in macrophages. Overall, we have found that targeting specific bile acids and their signaling can decrease tumor growth, showing potential as novel treatment modalities for PDAC and other cancers. Citation Format: Erin Gibbons, Rahul Shinde, Gauri Mirji, Sajad Bhat, Wujuan Zhang, Aaron Goldman, Behnaz Mansoori. Targeting bile acids","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":"149048679","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 A110: The Identification of IGFBP-3 as a Clinically Relevant Target in the Treatment of PDAC-induced Skeletal Muscle Wasting and Testing the Efficacy of an Anti-IGFBP-3 Neutralizing Antibody","authors":"Calvin L. Cole, Zachary R. Sechrist","doi":"10.1158/1538-7445.pancreatic26-a110","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a110","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, causes skeletal muscle wasting (SMW) in 80–85% of patients which accounts for ∼30% of patient deaths. In these patients, SMW reduces treatment tolerance and overall survival. However, no FDA-approved therapies exist. Our laboratory recently demonstrated that tumor-secreted insulin-like growth factor-binding protein 3 (IGFBP-3) is necessary and sufficient to induce SMW in murine PDAC models. Consistent with this, datasets show elevated IGFBP-3 expression in human PDAC tumors which is associated with reduced overall survival. These findings suggest that IGFBP-3 may be a promising therapeutic target. Thus, laboratory developed a novel neutralizing anti-IGFBP-3 antibody (NmAb). Here, we determine if IGFBP-3 is upregulated in the serum of patients with pancreatic cancer, evaluate the efficacy of our NmAb to attenuate SMW in a murine model of PDAC and neutralize human PDAC tumor-derived IGFBP-3, and test whether the secretion of IGFBP-3 by CAPAN-1 cells induce SMW in a xenograft mouse model. Methods: Serum and tumor samples from 7 patients with PDAC and 3 non-tumor bearing patients, were obtained from the URMC Biobank for IGFBP-3 ELISA and IHC analysis. Female C57BL/6 8-week-old mice (n=10) were inoculated with PDAC tumor cells and randomly assigned to treatment groups (vehicle control vs. NmAb treated (40mg/kg)). 8-week-old male and female NU/J nude mice were randomized to sham surgery or orthotopic injection of 5×105 CAPAN-1 cells (n=4/group/sex). Lean mass was assessed in all animals by dual-energy X-ray absorptiometry (DEXA). Murine C2C12 myotubes were treated with CAPAN-1 conditioned media (CM) for 24 hours and stained for myosin heavy chain to assess myotube diameter. Lastly, a chimeric anti-IGFBP-3 NmAb developed in our laboratory was added to CAPAN-1 CM to evaluate its neutralizing efficacy. Results: Patients with PDAC displayed significantly higher serum IGFBP-3 levels than control patients (p<0.01). In tumor-bearing patients, IGFBP-3 trended higher in stage III versus stage I–II disease (p=0.1637). IHC also showed increased IGFBP-3 protein expression in tumor vs. adjacent non-pathologic pancreas. Treatment with IGFBP-3 NmAb improved survival in treated animals compared to vehicle controls (Log-rank p<0.0001) and significantly attenuated SMW (p≤0.001). In C2C12 myotubes, CAPAN-1 CM treatment significantly reduced myotube diameter (p<0.05), which was attenuated with anti-IGFBP-3 NmAb treatment (p<0.05). Lastly, male and female NU/J mice bearing orthotopic CAPAN-1 tumors exhibited significant muscle loss beginning at week 6 versus non-tumor controls, as measured by DEXA (p<0.05). Conclusions: These findings suggest that serum IGFBP-3 is elevated in human PDAC patients and promotes SMW in clinically relevant in vitro and in vivo models. Moreover, our novel NmAb shows efficacy in improving survival and attenuating SMW ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"30 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048708","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 A062: SFRP2 Silencing Restrains Pancreatic Cancer Growth and Enhances Survival Through Remodeling of the Tumor Microenvironment","authors":"Olivia Sweatt, Lillian Hsu, Lety Reyes Angeles, David Wang, Rachel Burge, Rupak Mukherjee, Jack Hyland, Eleanor Hilliard, Shikhar Mehrotra, Michael Ostrowski, Denis Guttridge, Peggi Angel, Nathaniel Dolloff, Nancy Klauber-DeMore","doi":"10.1158/1538-7445.pancreatic26-a062","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a062","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options. Secreted frizzled-related protein 2 (SFRP2) has emerged as an important mediator of tumor progression by promoting tumor cell survival, immune exhaustion, and angiogenesis. In human PDAC, elevated SFRP2 expression is associated with worse clinical outcomes and is regulated by KRAS. We hypothesized that SFRP2 plays a critical role in PDAC progression and represents a therapeutic target. Methods: SFRP2 knockout (KO) and scrambled control cell lines were generated from a KPC-derived murine PDAC cell line using CRISPR/Cas9 gene editing. Successful gene silencing was confirmed by Western blot. Scrambled control and SFRP2 KO cells were orthotopically implanted into the pancreas of C57BL/6J mice. Tumors were harvested 17 days after implantation, weighed, fixed in formalin, and embedded in paraffin (FFPE). Apoptosis was assessed using the TUNEL assay. Multiplex immunofluorescence (IF) identified tumor-associated macrophages (TAM). M1 macrophages were identified using F4/80, CD80, CD86, and iNOS, while M2 macrophages were identified using F4/80, CD206, and CD163. Images were analyzed using inForm software and validated with Phenochart. Targeted proteomic imaging was performed to evaluate extracellular matrix (ECM) proteins. In a separate study, mice bearing scrambled control or SFRP2 KO tumors were monitored for survival and analyzed using Kaplan-Meier methodology. Results Western blot confirmed successful SFRP2 silencing, with KO cells demonstrating a 75% reduction in SFRP2 protein expression compared with scrambled controls. In vivo, SFRP2 KO tumors were significantly smaller than controls, with mean tumor weights reduced from 1.79 ± 0.15 g to 0.40 ± 0.06 g in SFRP2 KO (n = 6, p < 0.01). TUNEL analysis demonstrated a 3.5-fold increase in apoptosis in SFRP2 KO tumors (26.44 ± 2.23 apoptotic cells per 20× field) compared with controls (8.00 ± 1.80; n = 3, p < 0.0001). Multiplex IF revealed significantly fewer M2 macrophages in SFRP2 KO tumors, with counts decreasing from 71 ± 13 cells in controls to 12 ± 9 cells in KO tumors (n = 4, p < 0.02); with no change in M1 TAM cell counts. The ECM proteome demonstrated significant remodeling following SFRP2 deletion. SFRP2 KO tumors exhibited a 2.3-fold increase in collagen type I alpha 2 (Col1a2) expression (p < 0.005), accompanied by a twofold decrease in collagen type I alpha 1 (Col1a1) expression (p < 0.005). Loss of SFRP2 also significantly improved survival, with mice bearing scrambled control tumors surviving 14 ± 0 days versus 25.08 ± 0.82 days for the SFRP2 KO group (n = 11, p < 0.001). Conclusions Genetic deletion of tumor-derived SFRP2 increases apoptosis, suppresses tumor growth, remodels the ECM, reduces immunosuppressive M2 macrophage infiltration, and prolongs survival in an orthotopic PDAC mouse model. These findings identify SFRP2 as a key regu","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"164 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048753","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 IA008: Spatial transcriptomics on a diverse pancreatic cancer cohort reveals Black African Americans display reduced classical and increased intermediate tumor subtype","authors":"Nina Steele, Yuesong Wu, Daniel Sålas-Escabillas","doi":"10.1158/1538-7445.pancreatic26-ia008","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-ia008","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy 20% more likely to develop in Black African Americans (BAA), compared to Non-African Americans (NAA). Large-scale gene expression signatures of tumor subtypes and cellular microenvironments in a diverse PDAC cohort has not been rigorously evaluated. Here we present, for the first time, a multi-omics interrogation of BAA versus NAA PDAC using whole exome sequencing, spatial transcriptomics (ST), and spatial proteomics, cell-state and tertiary lymphoid structure (TLS) distribution validated in independent cohorts. Whole exome sequencing confirmed patient ancestry and showed no significant differences in driver mutations between race groups. For ST analysis, we examined 7 BAA and 15 NAA PDAC samples, combining our cohort (n=6 BAA, n=6 NAA) with Human Tumor Atlas Network (HTAN) (n=1 BAA, n=9 NAA) data. BAA PDAC tumors had significantly fewer classical molecular subtype cells with no change in more aggressive basal-like cells. Instead, BAA patients showed a significant enrichment of the intermediate/hybrid subtype compared to NAA patients. BAA tumors also displayed increased B cell and reduced myeloid cell interactions compared to NAA tumors. Conclusions: Our findings show BAA tumors exhibited an increased intermediate molecular subtype signature at the expense of cells with a classical subtype, accompanied by a distinct immune cell composition and spatial distribution. This study highlights health disparities in patients of different ancestry may have a molecular basis that influences tumor aggressiveness and the immune response that may inform therapeutic efficacy and options. Citation Format: Nina Steele, Yuesong Wu, Daniel Sålas-Escabillas. Spatial transcriptomics on a diverse pancreatic cancer cohort reveals Black African Americans display reduced classical and increased intermediate tumor subtype [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 IA008.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"52 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048759","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 IA007: Getting ahead of the tumor: Interception approaches for pancreas cancer","authors":"Ben Stanger, Minh Than, Lucie Dequiedt, Noah Cheng, Ashley Kiemen, Robert Vonderheide","doi":"10.1158/1538-7445.pancreatic26-ia007","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-ia007","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) emerges from precursor lesions (PanINs and IPMNs) that harbor mutations in the KRAS oncogene. Once thought to be untargetable, the KRAS oncoprotein can now be inhibited with small molecule compounds that bind to either the active or inactive form of the protein. KRAS inhibitors are in various stages of clinical development and stand to change the therapeutic landscape for advanced PDAC. Given the prevalence of KRAS mutations in PanIN precursors, we hypothesized that KRAS inhibition could decrease the amount of premalignant neoplasia in the pancreas, thereby “intercepting” the lesions before they can progress to advanced PDAC. To this end, we used the KPC mouse model of PDAC in which pancreas-directed mutations in KRAS and TP53 result in the formation of PanIN lesions and invasive carcinoma with reproducible kinetics. Short term KRAS inhibition led to PanIN regression via apoptosis and a modest delay in tumor onset, whereas prolonged inhibition – achieved via a metronomic on/off dosing schedule – led to a near-tripling over overall survival across multiple agents. These results underscore the feasibility of bringing KRAS inhibition forward from the malignant setting to intercept disease at the premalignant stage. Citation Format: Ben Stanger, Minh Than, Lucie Dequiedt, Noah Cheng, Ashley Kiemen, Robert Vonderheide. Getting ahead of the tumor: Interception approaches for pancreas 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 IA007.","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":"149048760","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 IA010: From Multi-Omics to Autonomous AI Agents: AI-HOPE-Pancreas for Precision Oncology","authors":"Enrique Velazquez Villarreal","doi":"10.1158/1538-7445.pancreatic26-ia010","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-ia010","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive molecular heterogeneity, complex pathway interactions, stromal remodeling, and variable responses to systemic therapy. Although KRAS and TP53 represent major genomic drivers, the broader signaling architecture underlying age- and treatment-specific differences remains incompletely understood. We developed a conversational artificial intelligence (AI) agent framework to enable rapid, clinically contextualized interrogation of multiple oncogenic pathways and establish a foundation for autonomous AI-driven multi-omic precision oncology in pancreatic cancer. Methods: Clinical and genomic data from 184 PDAC tumors were analyzed after stratification by age at diagnosis and gemcitabine exposure. A specialized AI-HOPE-Pancreas conversational artificial intelligence agent, developed at the Velazquez-Villarreal Lab and targeting the RTK-RAS, MAPK, TP53, PI3K, TGFβ, and JAK/STAT pathways, was used to dynamically construct clinically defined cohorts and perform pathway- and gene-level analyses. AI-generated findings were subsequently confirmed using conventional statistical approaches. Molecular alteration patterns and their associations with overall survival were evaluated across age- and treatment-specific subgroups. Results: Distinct pathway architectures emerged across clinical contexts. Within RTK-RAS/MAPK signaling, ERBB2 & RET mutations were enriched among gemcitabine-treated late-onset tumors, whereas early-onset disease demonstrated treatment-associated differences involving CACNA2D family genes, FLNB, and TP53. TP53 alterations were more frequent in gemcitabine-treated early-onset compared with late-onset PDAC, while PI3K pathway alterations were enriched in late-onset gemcitabine-treated tumors. TGFβ alterations occurred in approximately one-quarter to one-third of tumors across subgroups and were predominantly driven by SMAD4. TGFBR2 mutations were significantly enriched in gemcitabine-treated versus untreated late-onset PDAC. In contrast, genomic alterations affecting JAK/STAT signaling were uncommon and showed no significant age- or treatment-associated differences. Importantly, among late-onset patients who did not receive gemcitabine, the absence of RTK-RAS/MAPK, TP53, or PI3K pathway alterations was associated with improved overall survival. Conclusions: Integrated interrogation of multiple signaling pathways reveals that PDAC molecular architecture is strongly dependent on clinical context, including age at diagnosis and treatment exposure. These findings extend molecular characterization beyond individual driver genes and demonstrate how specialized conversational AI agents can rapidly integrate data with potential prognostic and therapeutic relevance. This framework provides a foundation for expanding from genomic analyses toward multi-omic integration and increasingly autonomous AI agents capable of coordinating genomic, transcriptomic, microbiome, spat","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"40 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048762","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 A047: Mechanistic dissection and inhibitor targeting of nutrient scavenging in pancreatic cancer","authors":"Sarah E. Ackermann, Seamus E. Degan, Wen-Hsuan Chang, Ryan Robb, Mallory K. Roach, Jonathan M. DeLiberty, Khalilah E. Taylor, Runying Yang, Clint A. Stlanecker, Kirsten L. Bryant","doi":"10.1158/1538-7445.pancreatic26-a047","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a047","url":null,"abstract":"Mutational activation of the KRAS oncogene occurs in over 90% of pancreatic ductal adenocarcinoma (PDAC) patients, and plays a crucial role in tumor initiation, progression, and tumor maintenance. Historically considered undruggable, there has recently been a surge in efforts to develop and improve drugs that target RAS. RAS inhibitors are well-tolerated, with promising clinical efficacy against RAS-driven PDAC; however, adaptive and acquired resistance develops upon inhibition of RAS alone. Multiple genomic- and signaling-based compensatory mechanisms have been proposed and account for approximately 50% of the cases in which resistance emerges. We determined that inhibition of the RAS pathway increased autophagy, a process of \"self-eating\" whereby cancer cells degrade defective organelles and recycle macromolecules for energy. Our studies established the provocative concept that concurrent treatment with an autophagy stimulating small molecule (e.g., RAS inhibitors) enhanced the anti-tumor activity of the autophagy inhibitors chloroquine/ hydroxychloroquine (CQ/HCQ). Moving forward, we propose studies to facilitate and improve the clinical advancement of this therapeutic strategy, as well as further elucidate the metabolic changes associated with acute RAS inhibition and RAS inhibitor resistance. The only FDA-approved autophagy inhibitor, HCQ, has poor potency and bioavailability. Thus, we evaluated other therapeutic strategies to block autophagy in PDAC. The Unc-51-like autophagy activating serine/threonine kinases 1 and 2 (ULK1/2) are essential for the initiation of autophagosome biogenesis, making ULK1/2 an attractive potential anti-autophagy therapeutic target. However, we found that inhibition of ULK1/2 antagonizes RAS inhibition in multiple PDAC models. Ongoing studies are focused on delineating the mechanism underlying the antagonism between RAS and ULK inhibition. We recently discovered that autophagy upregulation associated with acute RAS pathway inhibition is transient and that the nutrient scavenging process, macropinocytosis, is upregulated following prolonged RAS inhibition and in RASi-resistant cells. RASi resistant cells also display increased abundance of macropinocytosis-related proteins. Mechanistically, this adaptive phenotype is mediated through PI3K-, FAK-, and TEAD-associated signaling dependencies that support macropinocytic uptake in subsets of RASi-resistant cells, revealing that this process can be enhanced through multiple compensatory routes that likely converge on cytoskeletal remodeling and RAC1-dependent macropinosome formation. Ongoing analyses are focused on determining whether upregulated macropinocytosis is a driver of RASi-resistance and to what extent autophagy contributes to the viability of RASi-resistant PDAC models. Overall, we aim to elucidate how autophagy and macropinocytosis mediate adaptation to acute RAS inhibition and promote RAS inhibitor resistance with the goal of discovering targets and delinea","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"59 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048817","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}