Cancer research最新文献

{"title":"White matter injury fuels early progression of glioblastoma","authors":"Keon Woo Kim, Hyun Jin Choi, Jeong Ho Lee","doi":"10.1158/0008-5472.can-25-4362","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-4362","url":null,"abstract":"Glioblastoma (GBM) is the most aggressive and devastating primary brain cancer in adults. Most GBMs are diagnosed at an advanced stage with therapy resistance, posing a major obstacle to understanding the tumor microenvironment (TME) at the earliest stages of disease development. A precise characterization of early-stage GBM and its TME could provide critical insights into tumor progression and inform new therapeutic strategies. In a recent issue of Nature, Clements and colleagues demonstrated that white matter (WM) injury, induced by early tumor cells, constitutes a key TME factor driving GBM progression. Using somatic mouse models, patient-derived xenografts (PDXs), and human tissues, they showed that early glioma cells preferentially infiltrate WM tracts, inducing SARM1-mediated Wallerian degeneration (WD) that propagates into distal WM regions. Remarkably, WM injury induced by axonal transection significantly accelerated GBM progression at distal sites, whereas this effect was abolished by Sarm1 knockout, confirming that axonal injury followed by WD drives distal tumor progression. Collectively, these findings reveal a previously unrecognized evolutionary process in GBM development and highlight potential targets for therapeutic intervention.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"109 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203093","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 B052: Trends in Thromboembolism-Related Mortality Among Patients with Pancreatic Cancer in the United States: A CDC WONDER Analysis (1999–2023)","authors":"Sravani Bhavanam, Hakim Wazir, Nayanika Tummala, Amna Amjad, Diya Rathi, Aqsa Shaikh, Yassar Ul. Mulk","doi":"10.1158/1538-7445.pancreatic25-b052","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b052","url":null,"abstract":"Background: Pancreatic cancer and thromboembolism frequently coexist, posing significant challenges in clinical management. The interplay between these conditions can exacerbate hemodynamic instability and influence treatment outcomes. This study aims to assess or evaluate the impact of thromboembolism related mortalities among patients with pancreatic cancer. Methods: We analyzed adults aged >25 years death certificates from the CDC-WONDER database with pancreatic cancer (ICD-10 codes: C25) and thromboembolism (ICD-10 codes: I26, I80, and I82) from 1999-2023. Age-adjusted mortality rates (AAMR) per 100,000 were calculated, and trends were analyzed by gender, race, region and metropolitan status. Join-point regression was used to calculate annual percentage changes (APC) with 95 % confidence intervals (CI). Results: A total of 24,870 deaths were attributed to pancreatic cancer and thromboembolism related mortalities in individuals from 1999 to 2023. The AAMR increased from 0.31 in 1999 to 0.42 in 2011 (APC: 2.7; 95% CI: 1.91-3.5), then decreased to 0.4 in 2015 (APC: -1.34; 95% CI: -6.77 to 4.40), and ultimately increased to 0.65 in 2023 (APC: 7.39; 95% CI: 6.0-8.81) with an overall AAPC (3.55; 95% CI: 2.48-4.62). In terms of gender, both sexes show increment with higher AAMRs (1999-2023) in males from 0.35 to 0.76 (AAPC: 3.4; 95% CI: 2.84-3.97) compared to females from 0.27 to 0.58 (AAPC: 3.61; 95% CI: 2.02-5.22). From 1999 to 2023, Non-Hispanic (NH) Black or African American displayed the highest AAMR (0.47-1.09), followed by NH White (0.29-0.64), and Hispanic or Latino (0.21-0.45). Geographically, The AAMR for the Northeast ranged from 0.35 in 1999 to 0.67 in 2023, followed by the Midwest (0.31-0.67), the South (0.3-0.67), and the West (0.29-0.6). Metropolitan areas had the highest overall AAMR (0.4) while Nonmetropolitan areas had the lowest (0.38). Conclusion: Mortalities related to pancreatic cancer and thromboembolism have increased, with highest rates among males, Black population, and those in Northeastern and urban U.S., requiring targeted, equitable public health strategies. Citation Format: Sravani Bhavanam, Hakim Wazir, Nayanika Tummala, Amna Amjad, Diya Rathi, Aqsa Shaikh, Yassar Ul. Mulk. Trends in Thromboembolism-Related Mortality Among Patients with Pancreatic Cancer in the United States: A CDC WONDER Analysis (1999–2023) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr B052.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"17 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183155","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 A067: βIII-tubulin is a dual cell therapeutic target in pancreatic cancer and regulates sensitivity to TRAIL through a DR5-dependent mechanism","authors":"Grace Schulstad, John Kokkinos, Janet Youkhana, Aparna S. Raina, Meagan E. Davis, Oliver S.M. Arkell, Keilah Garcia Netto, Cyrille Boyer, David Goldstein, Koroush S. Haghighi, George Sharbeen, Joshua A. McCarroll, Phoebe A. Phillips","doi":"10.1158/1538-7445.pancreatic25-a067","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a067","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) urgently requires novel, effective therapies as its 5-year survival rate remains at just 13%. Our group has previously shown that silencing βIII-tubulin induced chemosensitisation and apoptosis in vitro, and reduced metastasis and tumour growth in vivo (McCarroll et al, Oncotarget, 2015). Recently, we have demonstrated that βIII-tubulin regulates the extrinsic (caspase-8) apoptosis pathway in PDAC cells, where silencing βIII-tubulin increased PDAC cell sensitivity to TNF-related apoptosis-inducing ligand (TRAIL). Extrinsic apoptosis is activated when TRAIL binds to its receptors, death receptor 4 (DR4) or 5 (DR5). This study expanded on these findings to assess whether these effects (i) are dependent on DR4 or DR5 signaling; (ii) occur in PDAC cancer-associated fibroblasts (CAFs); (iii) are therapeutically relevant in an in vivo setting. Aims: 1) Determine the effect of (a) DR5 knockout and (b) DR4 and DR5 agonists on βIII-tubulin knockdown-mediated sensitization of PDAC cells to TRAIL in vitro; 2) Evaluate the effect of βIII-tubulin knockdown on CAF proliferation and sensitivity to TRAIL-induced apoptosis in vitro; 3) Assess the therapeutic potential of silencing βIII-tubulin in combination with TRAIL in a xenograft PDAC mouse model. Methods: 1) MiaPaCa2 PDAC cells were treated with (a) CRISPR to knockout DR5 ± control or βIII-tubulin-siRNA ± TRAIL, or (b) control- or βIII-tubulin-siRNA ± TRAIL, DR4 or DR5 agonist, and apoptosis measured (Annexin V + DAPI via flow cytometry). 2) Patient-derived PDAC CAFs were transfected with control- or βIII-tubulin ± TRAIL and proliferation (IncuCyte S3), apoptosis (Annexin V + DAPI via flow cytometry) and senescence (β-galactosidase senescence stain) measured. 3) Subcutaneous PDAC tumours were treated with control- or βIII-tubulin-siRNA complexed to STAR 3 nanoparticles twice weekly (intravenous) ± TRAIL once weekly (intratumoural) for 4 weeks. Results: 1a) Knockout of DR5 in PDAC inhibited βIII-tubulin knockdown-mediated sensitization to TRAIL. 1b) βIII-tubulin knockdown combined with DR5 agonists induced apoptosis to a greater extent than DR4 agonists in PDAC. 2) Knockdown of βIII-tubulin reduced CAF proliferation and viability, and induced senescence. However, it did not induce apoptosis ± TRAIL. 3) Knockdown of βIII-tubulin in combination with TRAIL induced a significant increase in the frequency of responders, in comparison to either treatment alone. Conclusions: 1) Sensitization of PDAC cells to TRAIL mediated by βIII-tubulin knockdown is DR5-dependent; 2) βIII-tubulin knockdown inhibits both CAF and PDAC proliferation and sensitises PDAC cells to TRAIL-induced apoptosis. Citation Format: Grace Schulstad, John Kokkinos, Janet Youkhana, Aparna S. Raina, Meagan E. Davis, Oliver S.M. Arkell, Keilah Garcia Netto, Cyrille Boyer, David Goldstein, Koroush S. Haghighi, George Sharbeen, Joshua A. McCarroll, Phoebe A. Phillips. βIII-tubulin is a dual cell therap","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"19 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183207","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 B116: Integrative proteogeonomic profiling of PDAC reveals updated epithelial subtypes and cross-omic predictors of survival","authors":"Ferris Nowlan, Noor Shakfa, Tiak Ju Tan, Sibyl Drissler, Elizabeth Sunnucks, Jennifer L. Gorman, Chengxin Yu, Sheng-Ben Liang, Barbara Gruenwald, Ayelet Borgida, Edward L. Chen, Golnaz Abazari, Miralem Mrkonjic, Julie M. Wilson, Kieran R. Campbell, Robert C. Grant, Anne-Claude Gringas, Grainne M. O'Kane, Faiyaz Notta, Steve Gallinger, Hartland W. Jackson","doi":"10.1158/1538-7445.pancreatic25-b116","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b116","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) chemotherapy regimens are largely uniform, tailored mainly to patient fitness or rare genomic alterations. This strategy fails to capitalize on the disease’s substantial molecular heterogeneity, including variations in copy number alterations, immune infiltration, stromal composition, and cancer cell phenotypes. These features are not independent; they reflect interconnected biological processes and co-evolving pathways that shape tumour progression. Multi-omic integration is therefore essential—not only to capture the complexity of PDAC biology, but also to clarify the molecular basis of tumours classified as ‘intermediate’ by current stromal and cancer taxonomies, thereby enabling rational therapeutic targeting. To this end, we performed imaging mass cytometry on three serial sections of a PDAC tissue microarray (221 resected tumours, ∼4 cores each), generating >800 multiplexed images (40–43 channels) focused on epithelial, immune, or stromal biomarkers. We profiled 76 immune and stromal cell types and states (hypoxic, proliferative, apoptotic, under tension), as well as six tumour phenotypes defined by expression of epithelial transcription factors (GATA6, FOXA2, PDX1), classical markers (AGR2, TFF1, CEACAM6), basal markers (TP63, KRT5, S100A2, CAV1), and other PDAC-associated proteins (S100A4, MMP7, MUC16). These six cancer cell types captured the classical and basal PDAC signatures, along with four discrete “intermediate” states with distinct associations to stromal heterogeneity, RNA subtype (n = 92), tumour ploidy (n = 182), and patient outcome. These phenotypes are also detectable in unmatched single-cell RNA-seq data (n = 163), though with more overlap in marker expression. Using matched 30X whole genome sequencing (n = 182), we identified mutations and copy number alterations linked to shifts in cancer and stromal cell phenotypes, raising the question of which molecular axis best informs clinical prognosis. To address this, we applied a modified version of Stabl, a Lasso-based machine learning approach, to compare across omic layers and identify features most strongly associated with overall survival. Per-modality analysis showed that models incorporating omics outperformed those based on clinical features alone, with imaging data slightly outperforming genomics. Cross-omic integration revealed several prognostically relevant copy number aberrations, fibroblast phenotypes, and cancer cell states. By consolidating information on tumour phenotypes, stromal niches, and genomic alterations, this work aims to focus future drug discovery on the most clinically impactful molecular features in PDAC. Citation Format: Ferris Nowlan, Noor Shakfa, Tiak Ju Tan, Sibyl Drissler, Elizabeth Sunnucks, Jennifer L. Gorman, Chengxin Yu, Sheng-Ben Liang, Barbara Gruenwald, Ayelet Borgida, Edward L. Chen, Golnaz Abazari, Miralem Mrkonjic, Julie M. Wilson, Kieran R. Campbell, Robert C. Grant, Anne-Claude Gringas, ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"327 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183208","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 B026: Sustained KRAS-MAPK Inhibition Induces Interferon-mediated Epithelial-to-Mesenchymal Transition and Reveals a Potential Therapeutic Opportunity","authors":"Ashenfi S. Bulle, Timothy Hung-Po Chen, Iftikhar Khawar, Huaping Li, Vikas Somani, Lim Kian-Huat, Ashenfi S. Bulle","doi":"10.1158/1538-7445.pancreatic25-b026","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b026","url":null,"abstract":": Therapeutic targeting of the KRAS-MAPK pathway has been clinically unsuccessful in pancreatic ductal adenocarcinoma (PDAC) until recently, with the advent of KRAS inhibitors that have shown promising efficacy in clinical trials. However, treatment resistance remains a challenge. Analysis of human PDAC samples and patient-derived cell lines treated with the ERK inhibitor ulixertinib revealed prominent upregulation of interferon and epithelial-to-mesenchymal transition (EMT) signatures. We identify TRIM22, an interferon-inducible E3 ubiquitin ligase upregulated following KRAS and MAPK inhibition, as a key mediator that drives EMT, at least in part by promoting the degradation of IκBα and thus activating NF-κB signaling. We further show that TACSTD2, which encodes TROP2, is an NF-κB target gene that is upregulated following EMT. On this basis, combining ulixertinib or the KRAS^G12D inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan markedly suppresses the growth of PDAC patient-derived xenografts (PDXs). Together, our study uncovers TRIM22 as a molecular link between interferon signaling and EMT and nominates TROP2 as a druggable vulnerability that can be co-targeted to augment the therapeutic efficacy of KRAS-MAPK pathway inhibitors. Citation Format: Ashenfi S. Bulle, Timothy Hung-Po Chen, Iftikhar Khawar, Huaping Li, Vikas Somani, Lim Kian-Huat, Ashenfi S. Bulle. Sustained KRAS-MAPK Inhibition Induces Interferon-mediated Epithelial-to-Mesenchymal Transition and Reveals a Potential Therapeutic Opportunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr B026.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"105 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183303","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 A021: Examining the unconventional role of Ang–Tie2 signaling in pancreatic CAF/ECM unit function","authors":"Jaye C. Gardiner, Sergio Santos, Khoa A. Tran, Mariia Dmitrieva, Aleksandr Dolskii, Janusz Franco-Barraza, Caneta Brown, Tiffany Luong, Edna Cukierman","doi":"10.1158/1538-7445.pancreatic25-a021","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a021","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a five-year survival rate of ∼13%. Its aggressiveness is largely mediated by the expansive tumor microenvironment that includes functional units consisting of cancer-associated fibroblasts (CAFs) and CAF-generated extracellular matrix (ECM). Recent work from our lab identified that the synaptic neuronal protein, Netrin G1 (NetG1), is pathologically upregulated in pancreatic functional units, drives the unit’s pro-tumor functions, and correlated with poorer overall survival in PDAC patients with high fibroblastic NetG1 expression. The goal of this project is to determine whether comparisons of NetG1 high and low expressing CAFs could elucidate other novel pro-PDAC unit regulators. Using publicly available transcriptomic data of PDAC patient-matched normal-like fibroblasts and CAFs, CAFs were stratified into NetG1low or NetG1high expressing cohorts to identify differentially expressed genes (DEG). Computational analyses revealed a key network of 67 genes represented in 16 clusters from the initial 530 DEG input list. “Tie2 Signaling” was the largest enriched cluster, which is canonically known for being associated with endothelial cell function (e.g., angiogenesis) but has never been studied in association with pro-PDAC CAF/ECM units. Western blot analysis demonstrated that patient-derived pancreatic CAF/ECM units amply express Tie2 whose activity (denoted by phosphorylation) increases upon stimulation with the angiopoietin (Ang) ligands. Small molecule inhibition of CAF Tie2 can decrease both IL-6 and TGFβ secretion, to varying levels depending on patient background, suggesting that 1) loss of Tie2 signaling may affect CAF pro-tumorigenic functions and 2) there may be patient specific differences that contribute to CAF function. Indeed, we observed higher tumor burden in mice orthotopically co-injected with the most active patient-derived CAF line compared to the least active CAF. Transcriptomic data revealed, however, that our patient derived lines do not distinctly correlate with previously published CAF gene signatures. Studies determining whether repression of CAF Tie2 expression via CRISPRi can reduce this growth advantage in an orthotopic mouse model are underway. Collectively, these data suggest that Ang/Tie2-mediated signaling can influence CAF/ECM pro-tumorigenic functions and may provide a novel target to normalize the tumor-enabling microenvironment in PDAC patients. Citation Format: Jaye C. Gardiner, Sergio Santos, Khoa A. Tran, Mariia Dmitrieva, Aleksandr Dolskii, Janusz Franco-Barraza, Caneta Brown, Tiffany Luong, Edna Cukierman. Examining the unconventional role of Ang–Tie2 signaling in pancreatic CAF/ECM unit function [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"21 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183156","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 A012: Context-dependent role of TGM2 in Pancreatic Ductal Adenocarcinoma","authors":"Polina Wright, Parash Parajuli, Deanna Ward, Emma Cullen, Muhammad Akbar, Azeddine Atfi","doi":"10.1158/1538-7445.pancreatic25-a012","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a012","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, driven by accumulating genetic alterations and sustained by a fibrotic, immunosuppressive tumor microenvironment. We previously identified Transgultaminase 2 (TGM2), a stress-inducible enzyme involved in extracellular matrix remodeling and cell survival, as a critical downstream effector of oncogenic KRAS signaling. In the KrasG12D mouse model (KC), genetic deletion of Tgm2 almost completely protected mice from developing PDAC, establishing TGM2 as a key mediator of tumor initiation. PDAC progression, however, depends on additional genetic alterations in key tumor suppressor genes, such as TP53, SMAD4, and p16INK4A. That said, we next asked whether it could also contribute to PDAC progression. To address this, we initially examined TGM2 expression in representative KrasG12D-based mouse models carrying individual deletions in Trp53 (KPC), Smad4 (KSC), or p16Ink4a (KIC). TGM2 expression was markedly elevated in KPC mice, modestly increased in KIC mice, and unchanged in KSC mice. To functionally assess TGM2’s role in more aggressive disease resembling human PDAC, we made use of the KPC model to evaluate the impact of deleting Tgm2 on disease progression. Interestingly, while Tgm2 deletion in KPC mice led to a modest increase in survival, it did not prevent the development of aggressive PDAC. Histological analysis revealed that tumors from TGM2-deficient KPC mice (TKPC) retained the altered architecture and metastatic behavior characteristic of KPC tumors, indicating that TGM2 is dispensable for PDAC progression once the disease has advanced beyond the initiation stage. Mechanistically, the lack of TGM2 upregulation in KSC mice suggested a potential link between TGF-β signaling and TGM2 expression. Transcriptomic analyses of KC tumors using public datasets revealed that the upregulation in TGM2 expression strongly correlates with increased TGF-β signaling, and in vitro assays confirmed that TGF-β induces TGM2 expression in a Smad4-dependent manner, as shown using both wild-type and SMAD4-deleted human PDAC cells, Panc1. These findings were corroborated in primary tumor cell lines derived from KSC mice, providing compelling evidence that TGF-β signaling induces TGM2 expression, which in turn contributes to the initiation of PDAC in the KC mouse model of PDAC. Together, these data provide the first mechanistic evidence that TGM2 functions as a context-dependent effector in PDAC pathogenesis, being essential to tumor initiation but bypassed in advanced disease driven by loss of key tumor suppressors. As such, this discover could open up new opportunities for developing innovative therapeutic strategies to curb this devastating disease. Citation Format: Polina Wright, Parash Parajuli, Deanna Ward, Emma Cullen, Muhammad Akbar, Azeddine Atfi. Context-dependent role of TGM2 in Pancreatic Ductal Adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cance","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"4 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183210","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 A058: The Influence of WDR-62 in c-Jun-N-terminal Kinase on the Spatiotemporal Regulation of JNK Activation in Pancreatic Ductal Adenocarcinoma","authors":"SDANISH KADIR, Partha R. Laskar","doi":"10.1158/1538-7445.pancreatic25-a058","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-a058","url":null,"abstract":"c-Jun N-terminal kinase activation plays a significant role in dictating cell fate outcome. In response to cellular stress inducers, hydrogen peroxide. Biochemically, the p38 and JNK-MAPK can activate the SAPK (stress-activated protein kinase) pathways. This same stress granule can also reduce the SAPK apoptotic response. Where the RACK-1 (Receptor for C kinase-I) functions as a binding agent to initiate the stress granule signaling pathway. In normal human microenvironments, JNK isoforms have been found responsible for showcasing tumor suppressive characteristics. Similarly, the JNK and Harvey Rat Sarcoma Virus can also initiate genetic screenings in mice with the KRASG-12D allele and Pdx1-Cre transgene. Normally, PDAC is an aggressive malignancy with a survival rate of only 13%. The inactivation of the drug, multi-drug resistance, cell death inhibition (apoptosis suppression), altering in the drug metabolism, epigenetic changes, and changes in the drug targets can lead to the development of high resistance against oxaliplatin. This aggressive form of malignancy mostly results in missense mutation, especially at the thermodynamically active sequences of the Kirsten Rat Sarcoma Virus such as G12D, G12V, and Q61H. However, our primary focus is G12D. The oxaliplatin-led chemoresistance in both cell-autonomous and non-autonomous secretions of the 15dPGJ2 prostaglandin has been proposed to facilitate the development of the PDAC. Similar to JNK, the WD Repeat Domain 62 (WDR-62) may also lead to the development of pancreatic ductal adenocarcinoma (PDAC). WDR-62 functions as a novel JNK (c-Jun N-terminal kinase) binding protein, has only been expressed in heat-sensitive circumstances, and is a part of the mitogen-activated protein kinase pathway (MAPK). WDR-62 is a 175 kDa-long protein that binds to the JNK and alters the MAPK signaling cascade. As a novel scaffold protein, WDR-62 can bind with other scaffolds such as JIP-1, JIP-2, and JIP-3 to control the overexpression of stress granules in PDAC. The WDR-62 inhibits the AP-1 transcription through the recruitment of the JNK to a non-nuclear compartment. Moreover, JNK and WDR-62 can regulate the dynamic interplay between the stress granules, thereby mediating the mRNA-generated stresses. In general, the stress granules and 15d-PGJ2 prostaglandin have been suggested to regulate the regional and time-specific JNK activations. WDR-62 leads to phosphorylation, activating the classical, non-classical, and overexpression of the stress granules and the expression of TIA (tumor-induced angiogenesis) and TTP (thrombotic thrombocytopenic purpura). We hypothesize the knockdown of the WDR-62 can lead to the suppression of theOxaliplatin-resistant WDR62 gene-initiated DNA repairing system and the regulation of the normal cell signaling process of the MAPK, cell proliferation, apoptosis, and mRNA homeostasis in PDAC. However, in our studies we have found the less limited role of the WDR-62 in the development of PDAC,","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"21 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183258","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: Advancing early detection of pancreatic cancer with BlueSCAI, a novel high-sensitivity, multiplexed biomarker technology","authors":"Malcolm J. MacKenzie, Ilya Alexandrov, Matthew R. Preimesberger","doi":"10.1158/1538-7445.pancreatic25-b056","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b056","url":null,"abstract":"Introduction: There is an unmet need for a blood-based assay to detect Pancreatic Ductal Adenocarcinoma (PDAC) at an earlier, more treatable stage. To provide compelling clinical value and drive broad adoption, the assay must: i. display 80%+ sensitivity @ 99%+ specificity; ii. cost <$500; and iii. target higher risk cohorts to raise prevalence and obtain PPV >40%. Unfortunately, tests available or in development still fall short due to high false positives and negative rates, low early-stage sensitivity, and high cost. However, certain imperfect circulating markers, like CA19-9, are elevated in many individuals with PDAC, offering potential anchor markers. Leveraging orthogonal, complementary markers may augment insufficient anchor marker performance. But a more sensitive multiplex assay technology is needed to harness high potential but untapped markers. Background: We used our MPAD (Multiplexed Paired-antibody Amplified Detection) platform and PanDx multi-marker panel for PDAC. The PanDx panel combines CA19-9 with additional proteins selected for their non-correlated and complementary signal profiles. In a prior study of early-stage PDAC vs. non-cancer controls, PanDx panel displayed sensitivity of 76% at 99% specificity, a >20% point improvement over CA19-9 alone, PanDx AUC: 93% (95% CI: 89–97%) vs. 84% (95% CI: 74–90%) for CA19-9 alone; thus supporting the potential of a multiplexed, orthogonal biomarker strategy for early detection of PDAC. Methods and Results: We developed BlueSCAI (Serial-Capture, Adapter-Insertion), a next-generation assay technology that substantially enhances MPAD analytical performance. BlueSCAI works by 1) dramatically reducing assay background, improving signal-to-noise ratios and target LOD, and 2) tuning relative signal intensity across targets by modulating adapter concentration. This combination enables robust multiplexed profiling of low-abundance biomarkers (see poster), which we are combining with a novel pancreas-derived extracellular vesicle (EV) enrichment strategy. Increased sensitivity, with EV enrichment, enables detection of biologically informative EV-associated protein targets, often in low abundance, and below detection levels with conventional multiplex approaches. We also developed a rapid biomarker screening workflow using pooled plasma samples from PDAC and various non-PDAC control cohorts. By generating a weighted average signal for each candidate biomarker, this approach enables identification of cohort-level differences without the need to analyze individual samples, and allows for efficient assessment of multiple targets, and high-throughput prioritization based on effect size and orthogonality to CA19-9. Top-performing markers are then validated in individual samples for integration into the PanDx panel. Conclusion: Together, novel BlueSCAI technology, EV enrichment, and the biomarker screening platform provide a flexible, scalable system for refining a multi-marker pan","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"53 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183070","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 B002: Effects of Proglumide with Chemotherapy on the Pancreatic Tumor Microenvironment: Phase 1 PROGEM Trial","authors":"Jill P. Smith, Gakiza Christal . Nkulikiyimana, Hong Cao, Wenqiang Chen, Bhaskar Kallakury, John Kwagyan, Benjamin A. Weinberg","doi":"10.1158/1538-7445.pancreatic25-b002","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic25-b002","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and resistance to therapy that is attributed to its desmoplastic and immunosuppressive tumor microenvironment (TME). In animal models of PDAC, the cholecystokinin-B receptor (CCK-BR) antagonist, proglumide, was shown to decrease tumoral fibrosis, alter the tumor immune cell signature, and allow increased uptake of chemotherapy and T-cells into tumors resulting in decreased metastases and improved survival. The purpose of this Phase 1 clinical trial was to study the safety of proglumide in combination with standard of care chemotherapy with gemcitabine/nab-paclitaxel (GEM-NAB-P) in subjects with metastatic PDAC. The secondary aim was to study the combined effects of proglumide with GEM-NAB-P on the TME with tumor biopsies and a blood biomarker assay. Methods: The study was an open-labeled Phase 1 trial in gemcitabine-naïve subjects with metastatic PDAC with ECOG 0-1 performance status. The study was approved by the FDA, IRB and registered on the clinicaltrials.gov website (NCT05827055). Subjects were treated with standard of care GEM-NAB-P with oral proglumide 1200mg/day until progression. Safety was assessed with adverse events according to CTCAE criteria. Tumor biopsies were obtained at baseline and again at week-8 on therapy and analyzed by histology and multiplex immunohistochemistry for changes in the TME. A liquid biopsy serum sample was collected at baseline, week-8 and at the end-of treatment (EOT) for analysis of a microRNA biomarker panel reflecting changes in the TME. McGill pain surveys were done at baseline, week 8 and at the EOT. Results: Six patients were enrolled and treated in the study and no AEs related to proglumide were reported. Compared to baseline, week-8 biopsies showed an 81% decrease in Ki67+ cells; a 75% decrease in M2-polarized tumor-associated macrophages; a 42% decrease in tumor collagen content, and a 13-fold increase in CD8 T-cells. A blood biomarker panel done before and on treatment showed changes that correlated with the histology and the clinical course. The anti-fibrotic markers (miR185, miR346, and miR378) and the inhibitors of epithelial to mesenchymal transition (miR200 and miR205) increased with therapy. MiR122 that regulates cell cycle and growth decreased initially but increased at the time of progression. The McGill pain survey showed reduced pain level at week 24 or EOT. Conclusion: These results showed that proglumide is safe in combination with chemotherapy for subjects with metastatic PDAC. A parallel shift occurs between the TME and circulating microRNA profiles offering a promising non-invasive biomarker panel for monitoring treatment response. Because proglumide monotherapy (and not gemcitabine) remodeled the TME in murine models of PDAC, our data suggest that proglumide also may alter the TME in human subjects with PDAC and warrants further investigation in a Phase 2 clinical trial. Citation Format: Jill P. Smith, Gakiza Ch","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"21 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183075","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}