Cancer research最新文献

{"title":"Abstract B009: Targeting HDAC7 to Overcome Enzalutamide Resistance in Prostate Cancer","authors":"Buse Cevatemre, Batuhan Mert. Kalkan, Ezgi Karyemez, Ipek Bulut, Hamzah Syed, David T. Miyamoto, Ceyda Acilan","doi":"10.1158/1538-7445.prostateca26-b009","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b009","url":null,"abstract":"Enzalutamide is widely used for advanced prostate cancer (PC), but acquired resistance drives progression and poor outcomes. To uncover therapeutic vulnerabilities associated with enzalutamide resistance, we established an enzalutamide-resistant derivative of LNCaP (EnzaR) through a dose-escalation approach. Transcriptomic profiling of EnzaR cells revealed hallmark features of resistance, including suppression of androgen response and enrichment of epithelial-mesenchymal transition (EMT), accompanied by increased invasiveness. For clinical relevance, intersecting EnzaR-upregulated genes with genes upregulated in circulating tumor cells isolated from human PC patients highlighted a central chromatin-remodeling module, nominating epigenetic control as a shared resistance axis. We therefore screened epigenetic targeting compounds and found HDAC inhibitors to be selectively effective in EnzaR but not parental cells, also sensitizing the innately resistant human PC line (MR49F) to enzalutamide. In-cell efficacy was confirmed by the increase in histone acetylation, consistent with on-target HDAC inhibition. Given this differential sensitivity, we revisited the transcriptome and found enrichment of “HDAC7 targets” with marked HDAC7 upregulation at mRNA and protein levels. shRNA-mediated HDAC7 silencing restored enzalutamide sensitivity and, by GSEA, reactivated androgen response (NES > 3) while attenuating EMT, shifting toward a parental-like state; induction of core histone genes (e.g., H2BC21, H4C8, H3C6) and HAT components (e.g., KAT2B, MEAF6) supported chromatin relaxation and transcriptional reactivation. Across patient datasets, HDAC7 expression was consistently elevated, including cases with biochemical recurrence, tumor presence, metastasis, and higher Gleason scores. Moreover, higher HDAC7 levels correlated with shorter progression-free and disease-free survival. These findings highlight HDAC7 as a clinically relevant, resistance-associated factor and, to our knowledge, the first study to propose it as a novel epigenetic target to reverse enzalutamide resistance in advanced PC. Citation Format: Buse Cevatemre, Batuhan Mert. Kalkan, Ezgi Karyemez, Ipek Bulut, Hamzah Syed, David T. Miyamoto, Ceyda Acilan. Targeting HDAC7 to Overcome Enzalutamide Resistance in Prostate Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl): nr B009.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005960","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 A020: Utilization of liquid biopsy in metastatic castrate resistant prostate cancer (mCRPC): patient characteristics, treatment selection, and mutational status","authors":"Matthew S. Hall, Kathryn L. Penney, Jiemin Liao, Sean Gordon, Brooke Overstreet, Michael Rossi, Jennifer R. Rider","doi":"10.1158/1538-7445.prostateca26-a020","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-a020","url":null,"abstract":"Background: Targeted therapies for metastatic castrate resistant prostate cancer (mCRPC) increasingly rely on genomic profiling, including liquid biopsy of circulating tumor DNA (ctDNA), to enable precision treatment. Integrating multi-patient ctDNA-derived molecular insights with deeply abstracted real-world clinical data offers the opportunity to improve biomarker identification, patient selection, and reverse translation. Methods: Data were obtained from the ConcertAI Translational360™ dataset. Specifically, mCRPC patients with overlapping liquid biopsy ctDNA testing results from Guardant Health were identified. Patient characteristics, timing of ctDNA testing, prior treatments, and the prevalence of specific mutations were described. Using all mCRPC patients in the cohort, treatment-agnostic univariate Cox proportional hazards models were trained on the 3 most frequent mutations and on maximum allele frequency. Results: Among 1,167 mCRPC patients from primarily community oncology practices (78.3%) with at least one ctDNA test, median age at mCRPC diagnosis was 68 (IQR: 60, 80) years; 72% of patients were white, 17% were Black, and 2% were Asian. The first ctDNA test occurred a median 2.2 years (IQR: 0.9, 5.0) after patients became castrate-resistant. For 200 patients with longitudinal testing, a median of 1.2 years (IQR: 0.6, 1.9) elapsed between the first and last ctDNA test. Treatment patterns shifted after ctDNA testing. Specifically, PARP inhibitor therapy increased from 5% of patients before ctDNA testing to 20% after ctDNA testing. Longitudinal changes in mutations were associated with treatment. Among patients who initiated PARP inhibitor therapy between their first and last ctDNA tests (n=22; median 5 prior lines of therapy (IQR: 3.2, 7.8)), the increase in mutation count was greater than in other patients: median increase of 8.5 unique mutations (IQR 5.0, 15.5) vs. 3 (IQR 0, 7.2), Wilcoxon rank-sum p<0.001. Forty-one distinct ctDNA genomic alterations were detected in 1% or more of mCRPC patients including single nucleotide variants (SNV), indel, splice, and copy number variants (CNV). The three most frequent genomic alterations — AR amplification (29%), EGFR amplification (11%), and AR p.L702H (11%) — were each associated with worse rwOS in univariate Cox proportional hazards models (p< 0.001; C-index: AR amplification = 0.61; EGFR amplification = 0.54; AR p.L702H = 0.53). By comparison, maximum allele frequency (MAF), a measure of total ctDNA burden, had greater discrimination for rwOS than the individual mutations (C-index = 0.64; hazard ratio per 1 SD increase = 1.41; 95% CI: 1.32-1.50). Conclusions: In this real world cohort of mCRPC patients with at least one ctDNA test, a shift toward targeted therapies occurred after the first ctDNA test and acquired mutations were apparent at the time of the subsequent ctDNA test. Both individual mutations and MAF were associated with rwOS, highlighting the opportunity to utili","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"10 5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006121","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 B040: Development of an immunocompetent murine model of PSMA-positive metastatic prostate cancer to study the impact of PSMA-targeted therapies on the immune response","authors":"Melissa Monterosso, Aneesha Jones, Kayden Kwah, Anna Amiss, Abby Sydes, Didier Boucher, Aimee Horsfall, Heather Green, Johannes Koehbach, Ralph Huebner, Yaowu He, Stephen Rose, Gary Li, Feifei Liu, Simon Puttick, Anna Karmann, John Hooper, Thomas Kryza","doi":"10.1158/1538-7445.prostateca26-b040","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b040","url":null,"abstract":"Background: Prostate cancer (PC) is the second leading cause of cancer-related death in men, with metastatic castration-resistant PC (mCRPC) remaining largely incurable. Prostate-specific membrane antigen (PSMA) is a validated target, with PSMA-directed radioligand therapy demonstrating survival benefit in mCRPC. Targeted alpha therapies (TAT) with isotopes Lead-212 (212Pb) and Actinium-225 (225Ac) are in clinical development and deliver high-linear-energy-transfer radiation, inducing potent cytotoxicity and potentially enhancing anti-tumour immunity. Current PSMA-positive preclinical models rely on xenografts or engineered murine cells, limiting evaluation of TAT-induced immune modulation thus far. Objective: To investigate the immune-modulatory effects of 212Pb-TAT in metastatic PC, we sought to establish (i) a syngeneic murine model of metastatic PC expressing murine PSMA (mPSMA), and (ii) a PSMA-directed TAT tool compound with high affinity for mPSMA. Methodology: Murine metastatic PC cells (RM1-BM), which recapitulate late-stage TP53-mutant disease, were engineered to express murine FOLH1 (mPSMA) using a PiggyBac transposon system. Expression of mPSMA was confirmed both in vitro and in vivo by western blotting and immunohistochemistry. The TAT agent 212Pb-PS0001 (AdvanCell) was assessed in biodistribution and efficacy studies in immunocompetent C57Bl/6 mice. Results: RM1-BM-mFolh1 cells expressed mPSMA comparably to human PSMA-positive C4-2 cells. 212Pb-PS0001 showed selective tumour uptake in RM1-BM-mFolh1 models, with minimal off-target accumulation. Therapeutic evaluation demonstrated that a single dose of 212Pb-PS0001 significantly suppressed RM1-BM-mFolh1 tumour growth in immunocompetent mice, while untreated controls exhibited progressive disease. Notably, several animals achieved durable tumour control, suggesting potential activation of an anti-tumour immune response. Conclusion: We established a syngeneic mPSMA-positive metastatic PC model suitable for studying the immune-modulatory effects of PSMA-targeted therapies. This model represents a robust platform for assessing therapeutic efficacy, elucidating immune mechanisms of action, and evaluating rational combination strategies, including integration with immune checkpoint blockade. Preliminary studies with 212Pb-PS0001 demonstrated selective PSMA targeting, rapid clearance, and potent anti-tumour activity, supporting its use as PSMA-TAT tool compound. Citation Format: Melissa Monterosso, Aneesha Jones, Kayden Kwah, Anna Amiss, Abby Sydes, Didier Boucher, Aimee Horsfall, Heather Green, Johannes Koehbach, Ralph Huebner, Yaowu He, Stephen Rose, Gary Li, Feifei Liu, Simon Puttick, Anna Karmann, John Hooper, Thomas Kryza. Development of an immunocompetent murine model of PSMA-positive metastatic prostate cancer to study the impact of PSMA-targeted therapies on the immune response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Canc","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"187 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006190","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 A053: Somatic mutations and outcomes of salvage radiation and hormonal therapy for prostate cancer recurrence after prostatectomy","authors":"Keisuke Otani, David J. Konieczkowski, Yukako Otani, Grace Cerrato, Shulin Wu, Philip J. Saylor, Douglas M. Dahl, Chin-Lee Wu, Sophia C. Kamran, Jason A. Efstathiou, David T. Miyamoto","doi":"10.1158/1538-7445.prostateca26-a053","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-a053","url":null,"abstract":"Purpose/Objectives: Radiotherapy (RT) +/- androgen deprivation therapy (ADT) plays a key role in salvage therapy of prostate cancer (PC) recurrent after radical prostatectomy. However, not all patients benefit, and there is an unmet need for biomarkers to distinguish responders from non-responders (defined as those with second biochemical failure after salvage). We hypothesized that somatic mutations in primary PC are correlated with response to salvage RT+ADT. Materials/Methods: We retrospectively identified 718 consecutive PC patients treated with post-operative RT at a single institution from 1992-2013, of whom 40 were treated with salvage RT+ADT and had formalin-fixed, paraffin-embedded prostatectomy and matched normal tissues available for DNA extraction. The indication for salvage therapy was biochemical failure after an undetectable post-operative PSA in 72%, gross local recurrence in 17%, and persistently elevated PSA after surgery in 11%. Median RT dose was 64.8 Gy, and all patients received concurrent ADT. Whole exome sequencing (WES) was performed to an average depth of 162X (r, 70.7-219). We tested for association between somatic mutations and clinical outcomes using the log-rank test and Cox proportional hazards model. Results: Median age at salvage was 64.5 yrs. High-quality WES data were available in 39 patients. With a median follow-up of 122 months (range, 29-248), 21 experienced second biochemical failure after salvage, while 18 did not. Median time to second biochemical failure was 82.3 months (range, 1.2-140). Overall tumor mutational burden (TMB) was 2.72 mutations/Mb (range, 1.4-12.8). TMB among those with second biochemical failure was 3.9 vs. 3.1 among those without (p=0.29). The most common mutations detected in the overall cohort were PLEC and TTN (n=7). The presence of mutations in BRCA2 (n = 1, p < 0.01, HR = 37 (95% CI: 2.3-600)), CASZ1 (n = 3, p < 0.01, HR = 10 (95% CI: 2.4-44)), XRCC4 (n = 1, p = 0.017, HR = 9.0 (95% CI: 1.0-8.)), ATR (n = 2, p < 0.01, HR = 7.8 (95% CI: 1.6-39)), WDR26 (n = 3, p < 0.01, HR = 6.5 (95% CI: 1.7-24)) and MYT1 (n = 3, p < 0.01, HR = 6.4 (95% CI: 1.5-20)) was significantly correlated with second biochemical failure after salvage RT+ADT. In contrast, none of the patients with mutations in FOXA1 (n=4, p = 0.046, HR: not calculable) experienced second biochemical failure during follow-up. Conclusions: In this cohort of PC patients with >10 years median follow-up after post-prostatectomy salvage RT+ADT, WES revealed that mutations in BRCA2, CASZ1, XRCC4, and ATR were associated with second biochemical failure after salvage therapy, while FOXA1 mutation was associated with favorable outcomes. These findings require validation in larger cohorts, but suggest that somatic mutations may serve as biomarkers to identify patients at greatest risk for recurrence after post-prostatectomy salvage therapy. Citation Format: Keisuke Otani, David J. Konieczkowski, Y","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"64 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006191","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 B034: Association of Neighborhood-Level Food Environment with Prostate Cancer-Specific Mortality Among Men in Georgia","authors":"Divya Lagisetti, Samuel Kennedy, Katherine J. Kim, R. Seth. Rozelle, Phillipe Gaillard, Avirup Guha, Zachary Klaassen, Martha K. Terris, Justin X. Moore, Malcolm S. Bevel, Ashanda R. Esdaille","doi":"10.1158/1538-7445.prostateca26-b034","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b034","url":null,"abstract":"Introduction and Objectives Food swamps (FS) –areas with a high density of ultra-processed food outlets relative to grocery stores and supermarkets –have emerged as contextual determinants of cancer risk and survival. We hypothesized that greater FS exposure would be associated with higher prostate cancer-specific mortality (PCSM) and that this association would differ by race in Georgia, a state marked by persistent prostate cancer (PCa) disparities. Methods We conducted a retrospective analysis of men diagnosed with PCa in Georgia (2000–2022) using Georgia Cancer Registry data. Census tract–level Federal Information Processing Series (FIPS) codes linked neighborhood-level food data from the National Neighborhood Data Archive (NaNDA; 1990–2021) and the Modified Retail Food Environment Index (RFEI) with patient-level cancer registry data. The RFEI, defined as the ratio of ultra-processed food outlets to grocery stores, farmers markets, and supermarkets, was categorized into low, moderate, and high FS exposure. Chi-square tests and ANOVA assessed group differences, and Cox proportional hazards models estimated associations between FS exposure and PCSM, stratified by race. Fully adjusted models controlled for age, race, insurance status, Gleason grade, PSA, stage at diagnosis, and primary treatment. Results Among 154,480 men (95,517 non-Hispanic [NH] White; 55,288 NH Black), 70% (N=108,146) lived in moderate/high FS tracts. Men in high FS areas (N = 33,330) were more likely to have public insurance, localized disease, and undergo surgery (p<0.05). Median follow up time was 8 years (IQR 4-13). There were 14,656 (9.5%) PCa-deaths. After age adjustment, each 1-unit increase in FS score corresponded to a 1% higher risk of PCSM (aHR 1.01 [95% CI 1.00–1.02], p = 0.005). The FS score ranged from 0-17 (median 1.16, mean 1.77; IQR 0.50–2.33). The association was attenuated after full adjustment (aHR 1.01 [95% CI 0.99-1.03], p=0.23). NHB men in moderate (aHR 1.14 [95% CI 1.01 – 1.28], p=0.04) or high (aHR 1.18 [95% CI 1.01 – 1.37], p=0.04) FS tracts had a higher risk of PCSM versus NHW men in low FS census tracts. No difference was observed among NHW men in high (aHR 1.09 [95% CI 0.96 – 1.24], p=0.20) FS census tracts. Conclusions The neighborhood food environment represents a potentially modifiable, contextual determinant of cancer outcomes and potential target for intervention. The higher mortality risk among NHB men across FS levels underscores the enduring effects of systemic inequities on PCa outcomes. Source of Funding: None Citation Format: Divya Lagisetti, Samuel Kennedy, Katherine J. Kim, R. Seth. Rozelle, Phillipe Gaillard, Avirup Guha, Zachary Klaassen, Martha K. Terris, Justin X. Moore, Malcolm S. Bevel, Ashanda R. Esdaille. Association of Neighborhood-Level Food Environment with Prostate Cancer-Specific Mortality Among Men in Georgia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Can","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"88 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006195","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 A074: Defining and targeting drivers of lineage plasticity in stem cell-like prostate cancer","authors":"Chen Khuan Wong, Dan Li, Hongsu Wang, Marjorie Roskes, Weiling Li, Shipra Shukla, Dana Schoeps, Ekta Khurana, Yu Chen","doi":"10.1158/1538-7445.prostateca26-a074","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-a074","url":null,"abstract":"Prostate cancer depends on androgen receptor (AR) signaling for growth, which is why androgen deprivation (castration) therapy is effective at early stages. However, many tumors eventually progress to a lethal form known as castration-resistant prostate cancer (CRPC). A subset of CRPC tumors bypass dependency on AR signaling by acquiring lineage plasticity, where prostate cancer cells transdifferentiate into alternate cellular states through epigenetic reprogramming. Neuroendocrine (NE) prostate cancer represents one well-known lineage plasticity phenotype. Nevertheless, most AR-independent tumors do not exhibit NE features and are defined as AR-negative/NE-negative or “double-negative prostate cancer” (DNPC). In a collaboration with Dr. Ekta Khurana’s computational genomics lab at Weill Cornell Medicine, we recently classified CRPC into four epigenetic subtypes, including the well-established 1) AR and 2) NE, as well as the novel DNPC subgroups 3) WNT and 4) stem cell-like (SCL) (PMID: 35617398). We focused on the SCL subtype as it is the second most common group in CRPC patients and lacks therapeutic targets. Using functional genomic approaches, we found that YAP/TAZ/TEAD cooperates with FOSL1 to drive the SCL lineage and growth of SCL models. We therefore hypothesize that the heightened dependency on the YAP/TAZ/TEAD/FOSL1 transcriptional program represents a therapeutic vulnerability in CRPC-SCL. To test this, we exposed CRPC models to TEAD inhibitors and found robust growth suppression in SCL cells compared to non-SCL cells in vitro. To evaluate whether the TEAD inhibitors are on-target, we performed transcriptomic profiling in SCL models and observed downregulation of YAP/TAZ gene signature as well as FOSL1 expression, which phenocopies the effects of YAP/TAZ double knockdown. To define the cistromes of these factors upon TEAD inhibition, we performed ChIP-seq and observed reduced co-occupancy at consensus sites, suggesting the disruption of the YAP/TAZ/TEAD/FOSL1 transcriptional circuit by the small molecule compound. To determine whether these phenotypes are recapitulated in vivo, we will treat mice harboring CRPC-SCL xenografts with TEAD inhibitors to assess growth response and evaluate epigenetic and transcriptional response using single-nucleus Multiome (ATAC+RNA). These studies will establish whether small molecule inhibition of TEAD is a promising strategy for the treatment of CRPC-SCL and allow high-resolution analysis of cell state transitions, with a focus on loss of SCL-specific signatures and potential emergence of AR/NE programs as adaptive resistance mechanisms. Citation Format: Chen Khuan Wong, Dan Li, Hongsu Wang, Marjorie Roskes, Weiling Li, Shipra Shukla, Dana Schoeps, Ekta Khurana, Yu Chen. Defining and targeting drivers of lineage plasticity in stem cell-like prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"88 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006228","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 B067: Investigating the implications of AGE-RAGE overexpression in cancer-associated fibroblasts","authors":"Krithika A. Senthil, Tuong Vi V. Nguyen, David P. Turner","doi":"10.1158/1538-7445.prostateca26-b067","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b067","url":null,"abstract":"Background: Prostate cancer is the second leading cause of cancer-related mortality in men. Recent investigations by the Turner group have implicated advanced glycation end products (AGEs) in prostate tumor progression through their interaction with the receptor for AGEs (RAGE). AGE-RAGE signaling promotes inflammation, cell proliferation, migration, and activation of cancer-associated fibroblasts (CAFs) within the tumor microenvironment, thereby supporting tumor growth. Additionally, our lab has shown that African American prostate cancer serum and tissue exhibit higher AGE levels than Caucasian serum and tissue samples. This disparity may stem from diets high in sugars, fats, and processed foods - key sources of AGEs. These findings link AGE biology to social drivers of health and disparities in prostate cancer outcomes. Aims: This study examines how AGE-RAGE signaling influences CAF activation and tumor cell behavior, specifically whether AGE treatment of fibroblasts enhances the migration of tumor epithelial cells. We hypothesize that AGE treatment increases fibroblast-driven migration via RAGE, supporting the connection between AGE accumulation and cancer aggressiveness. Methods: Prostate cancer tissue samples (DPT18) were enzymatically processed to establish matched epithelial and fibroblast cell lines. These lines were characterized through histopathological analysis via H&E staining and sulforhodamine B proliferation assays. Functional CAF activation was evaluated via transwell migration assays with matched primary fibroblast and epithelial cell lines, with or without AGE treatment. Statistical analysis was conducted using two-way ANOVA in GraphPad Prism. Results: Histopathology confirmed a Gleason grade 3 for DPT 18. The patient-matched fibroblasts proliferated faster than epithelial cells (doubling times: 1.39–1.42 vs. 2.20–2.57 days at seeding cell densities of 3125 and 6250). AGE treatment of fibroblasts significantly increased epithelial cell migration compared to untreated fibroblasts. Conversely, direct AGE treatment on epithelial cells did not produce a significant change in migration. These results suggest that AGE exposure enhances the pro-migratory capacity of CAFs, likely via AGE-RAGE signaling pathways. Conclusions: Our findings show that AGEs promote prostate cancer tumorigenicity by activating CAFs. The pro-migratory effect observed in fibroblasts, rather than epithelial cells, may be driven by AGE-RAGE signaling. Considering that elevated AGE levels are increased when social drivers are compromised, these results could explain, at least in part, observed disparities in prostate cancer outcomes. Therefore, targeting AGE-RAGE signaling warrants further research as a strategy to reduce cancer aggressiveness and address health disparities. Citation Format: Krithika A. Senthil, Tuong Vi V. Nguyen, David P. Turner. Investigating the implications of AGE-RAGE overexpression in cancer-associated fibroblasts [abstract]. In: Proc","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"56 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006119","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 A046: Integrated scRNAseq and spatial RNAseq analysis of aggressive prostatic adenocarcinoma identifies TIGIT-NECTIN 2/3 and TIGIT/PVR immunosuppressive interactions","authors":"Jerry A. Ombor, Anurendra Kumar, Jatin Gandhi, Rakesh Shiradkar, Tilak Pathak, Cynthia L. Winham, Ismaheel O. Lawal, Olayinka A. Abiodun-Ojo, Lara Harik, Saurabh Sinha, Martin G. Sanda, David M. Schuster, Adeboye O. Osunkoya, Carlos S. Moreno","doi":"10.1158/1538-7445.prostateca26-a046","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-a046","url":null,"abstract":"Background: Our understanding of the mechanisms of tumor immunosuppression in the tumor microenvironment (TME) of aggressive prostatic adenocarcinoma (PCa) at the single-cell level is limited. Integrated Visium-HD Spatial RNAseq analysis and 10X Flex sequencing of formalin-fixed paraffin-embedded (FFPE) tissue can provide unique insights into the mechanisms of immunosuppression in the ‘immune cold’ TME of PCa. Design: Visium-HD Spatial RNAseq analysis was performed on FFPE blocks from radical prostatectomy specimens of 12 patients of which six had lymph node metastases (LNM) and six did not. All specimens were also analyzed by 10X Flex sequencing, and data from each scRNAseq dataset were integrated with spatial RNAseq data. VisiumHD bins were processed with H&E images to generate cell-level expression data using the bin2cell package, and cell types were annotated. Ligand-receptor interactions were identified using the CellWhisper algorithm. Results: Mean patient age was 63 years (range: 50-77 years). Gleason scores ranged from 7-10 (Grade group 3-5). Patients with LNM had more significant enrichment for gene signatures associated with inflammation and immune responses and high numbers of naïve regulatory T cells (Naïve Treg) near the invasive front of the aggressive tumor foci. The inflamed stroma adjacent to PCa in patients with LNM was enriched in expression of antigen-presenting genes, but also in immunosuppressive gene signatures. In addition, there was significant enrichment for spatial co-expression of the immunosuppressive receptor TIGIT and the NECTIN2, NECTIN3, and PVR ligands. TIGIT was expressed in CD4 and CD8 expressing cells and CD14+ monocytes, while NECTIN2, NECTIN3, and PVR were expressed in tumor cells, suggesting that this is one of the mechanisms of immunosuppression in aggressive PCa. Conclusions: High-definition spatial RNAseq analysis with integrated 10X Flex scRNAseq enabled identification of mechanisms of immunosuppression in the TME of PCa. Targeting TIGIT-NECTIN2/3 and/or TIGIT/PVR interactions may be a potential immunotherapeutic strategy for the management of patients with aggressive PCa. Citation Format: Jerry A. Ombor, Anurendra Kumar, Jatin Gandhi, Rakesh Shiradkar, Tilak Pathak, Cynthia L. Winham, Ismaheel O. Lawal, Olayinka A. Abiodun-Ojo, Lara Harik, Saurabh Sinha, Martin G. Sanda, David M. Schuster, Adeboye O. Osunkoya, Carlos S. Moreno. Integrated scRNAseq and spatial RNAseq analysis of aggressive prostatic adenocarcinoma identifies TIGIT-NECTIN 2/3 and TIGIT/PVR immunosuppressive interactions [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl): nr A046.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"31 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006158","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 A030: Lossless altered histone modification analysis system to investigate patient derived cancer organoids and circulating tumor cells from patients with prostate cancer","authors":"Zachary J. Kauffman, Kevin Koesser, Kyle T. Helzer, Marina N. Sharifi, Erika Heninger, Emma E. Recchia, David Kosoff, David F. Jarrard, Shuang G. Zhao, Jamie M. Sperger, David J. Beebe, Joshua M. Lang","doi":"10.1158/1538-7445.prostateca26-a030","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-a030","url":null,"abstract":"Introduction Aberrant histone modifications and chromatin structure alter gene expression that drive phenotypic and functional behavior of aggressive prostate cancer. Technological limitations have constrained comprehensive analyses of epigenomic alterations to less relevant immortalized cell lines and pre-clinical models, as many current epigenomic assay techniques require hundreds of thousands of cells, thus limiting interrogation of clinical samples. To facilitate rare cell epigenetic analysis in patient derived cancer organoids (PDCOs) and circulating tumor cells (CTCs) from patients with prostate cancer, we miniaturized the Cleavage Under Targets and Tagmentation (CUT&Tag) assay with an Exclusive Liquid Repellency (ELR)-enabled “Lossless Altered Histone Modification Analysis System” (LAHMAS) device. CUT&Tag was developed to investigate protein-DNA interactions with high resolution, lower background and decreased cellular input requirements relative to ChIP but performance is less reliable for low inputs, making analysis of rare cell samples difficult for cell number <5000. Methods: Organoids were grown from primary tumor samples from 3 patient undergoing prostatectomy. There were a total of 5 loci collected. These samples were digested to single cells prior to assessment in the Cut&Tag assay with an antibody to H3K27Me3 or control IgG. Each sample was paired with RNAseq to assess gene expression. Results: Performing CUT&Tag on the LAHMAS device increases the signal to for very low input samples, enabling the investigation of chromatin dynamics in rare cell sample types, including PDCOs and CTCs. We observed significantly higher FRiP scores using the microscale method compared to macroscale method (average 30.3% vs 18.2%, p<0.0001) facilitating accurate chromatin profiling of low input and rare cell samples. H3K27Me3 peaks are conserved from 3000 down to 50 nuclei in cell line models on the LAHMAS device. We are evaluated H3K27Me3 histone modifications from PDCOs grown from prostatectomy samples from 3 patiens using the LAHMAS device. We obtained high quality results from these samples, obtaining yields (LNCaP: 0.147-5.15 [median: 1.13] vs. PDCO: 0.144-5.36 [0.445]), and MACS2 FRiP scores (LNCaP: 1.79-29.91 [median: 4.91] vs. PDCO: 0.73-10.21 [5.76]) similar to cell line sample. We have also leveraged the LAHMAS device to evaluate circulating tumor cells from a patient with prostate adenocarcinoma progressing on chemotherapy. This patient demonstrated high expression of ASCL1 (0 tpm) and low expression KLK3 (16237.6 tpm) by RNAseq. Concordantly, we detected H3K27Me3 peaks at the promoter of ASCL1, consistent with the repression of transcription. Conclusions: The pairing of this LAHMAS microfluidic device with a highly sensitive CUT&Tag assay has enabled the investigation of chromatin dynamics in rare cells such as PDCOs and CTCs to evaluate the contribution of these molecular alterations in tumorigenesis and ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"88 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006160","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 B057: Pathway-Level Molecular Evolution and Composite Molecular Genomic Risk following Lu-177-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer","authors":"Ruth A. Pe Benito, Sahil KM. Mohammed, Brandon Nathasingh, Jiemin Liao, Yekaterina Khotskaya, Sowmya Jairam, Sheenu Chandwani","doi":"10.1158/1538-7445.prostateca26-b057","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b057","url":null,"abstract":"As PSMA-targeted radioligand therapy (RLT) becomes an established option in patients with metastatic castration-resistant prostate cancer (mCRPC), a major clinical challenge is understanding why resistance emerges, so clinicians can optimally sequence the growing range of post-RLT treatments, including antibody-drug conjugates, next-generation RLTs and T-cell-redirecting agents. To explore molecular drivers of resistance, we analyzed real-world clinico-genomic data from 305 men treated with Lu-177-PSMA-617. Each patient had Guardant Health (GH) liquid-biopsy profiling integrated within ConcertAI’s Prostate Translational360™ dataset, linking longitudinal electronic health records, claims, and molecular results. We examined associations between disease patterns, genomic profiles, and timing of molecular testing before therapy, and evaluated post-treatment ctDNA evolution in a serially tested subset. Baseline genomic profiles from samples drawn prior to Lu-177-PSMA-617 initiation, showed that AR amplification (24%), PTEN loss (6%), and HRR alterations (18%, defined as HRR genes consistently reported across GH assays) were the most frequent molecular events (Muniz et. al., J Clin Oncol, 2024). Patients with AR or PTEN alterations had shorter median progression-free survival (PFS, HR 1.85, 95% CI 1.39-2.45, p < 0.0001) and overall survival (OS, HR 2.06, 95% CI 1.49-2.85, p < 0.00001) compared with patients without alterations. When stratified by composite molecular risk, outcomes declined stepwise with increasing pathway alterations (median PFS 8.5, 6.5, and 4.8 months for patients with 0, 1 or >=2 pathway alterations [AR, PTEN, HRR, FGFR/EGFR/CTNNB1, respectively]). Timing of pre-treatment molecular testing relative to RLT initiation did not meaningfully change baseline TMB values or the proportion of patients with HRR alterations, suggesting molecular stability before therapy. Among 53 patients with serial ctDNA testing, post-treatment evolution revealed post-treatment molecular changes were detected despite temporary clinical benefit. Maximum variant allele fraction (mVAF) increased modestly after RLT, and new or expanded AR (21%), PTEN (24%), TP53 (41%), and FGFR/EGFR (11%) alterations emerged. These findings indicate convergent activation of AR, PTEN, HRR, and alternative signaling pathways as mechanisms of acquired resistance under RLT pressure. Together, these observations show that molecular complexity and pathway co-alterations at baseline and post-therapy are strongly associated with worse outcomes to PSMA-RLT. Incorporating serial ctDNA profiling and pathway based composite risk models could refine patient selection and guide development of combination strategies as RLT moves into earlier treatment settings. Citation Format: Ruth A. Pe Benito, Sahil KM. Mohammed, Brandon Nathasingh, Jiemin Liao, Yekaterina Khotskaya, Sowmya Jairam, Sheenu Chandwani. Pathway-Level Molecular Evolution and Composite Molecular Genomic Risk ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"21 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006194","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}