Cancer research最新文献

{"title":"Abstract B025: Integrated proteomic and molecular profiling reveals race-associated RNA splicing and metabolic reprogramming in prostate cancer","authors":"Praveen Kumar Guttula, Ganesan Muthusamy, Kirti Agrawal, Sanjit Roy, Shang Su, Nrusingh C Biswal, Hem D Shukla, Manas Ranjan Gartia","doi":"10.1158/1538-7445.prostateca26-b025","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b025","url":null,"abstract":"Background: Prostate cancer (PCa) disproportionately affects African American (AA) men, who experience higher incidence, earlier onset, and poorer outcomes than Caucasian (CA) men. The molecular mechanisms underlying these disparities remain poorly understood. This study uniquely integrates proteomic, molecular, and bioinformatics analyses to uncover race-specific protein expression patterns and biological pathways driving aggressive and therapy-resistant PCa. Methods: Clinical samples (n = 28) were collected from AA (n = 10) and CA (n = 10) PCa patients. For each group, four healthy control prostate tissues were also collected. We conducted an integrated LC-MS-based proteomic analysis of patient tissues to investigate race-specific differential protein expression. Multivariate statistical modeling (OPLS-DA, hierarchical clustering) was used to identify race-distinct protein signatures. Key targets were validated by Western blotting and qPCR in AA-derived MDA-PCa-2B, CA-derived PC-3 cell lines, C4-2B cells, and VCaP cells. Functional annotation and pathway enrichment analyses were performed to assess biological significance. Tissue immunohistochemistry (IHC) and Raman lipid mapping further evaluated the expression of key protein markers (AR, PSA, PSMA, CAV1) and lipid species, including ω-3, ω-6 fatty acids and cholesterol. Results: Distinct molecular profiles emerged between AA and CA tumors. AA tissues and MDA-PCa-2B cells exhibited marked upregulation of the splicing regulators SRSF9 and HNRNPH3, metabolic enzyme MCCC2, surface antigen FOLH1 (PSMA), and ferritin subunits (FTH1/FTL). Gene ontology and pathway analyses highlighted enrichment in RNA splicing (notably AR-V7 variant production), mTOR/PI3K-AKT signaling, amino acid and folate metabolism, and iron homeostasis. The recently established role of SRSF9 in promoting AR-V7 formation suggests a splicing-based mechanism of androgen receptor (AR) reactivation and antiandrogen resistance in AA PCa. Raman lipid mapping further revealed enrichment of pro-tumorigenic lipid species (DHA, ALA, ω-6) and elevated cholesterol in AA tumors, aligning with IHC findings of increased AR and PSMA expression. Together, these alterations reflect a convergent network of metabolic and signaling adaptations underlying a therapy-resistant phenotype in AA PCa. Conclusion: This first integrated proteomic and lipidomic study in a race-stratified PCa cohort reveals molecular drivers of aggressive, therapy-resistant AA PCa. Upregulation of SRSF9, MCCC2, FOLH1, and ferritin, along with AR-V7–associated pathways and lipid remodeling, identifies novel targets for precision therapy. These findings provide critical insight into the biological basis of racial disparities in PCa outcomes. Citation Format: Praveen Kumar Guttula, Ganesan Muthusamy, Kirti Agrawal, Sanjit Roy, Shang Su, Nrusingh C Biswal, Hem D Shukla, Manas Ranjan Gartia. Integrated proteomic and molecular profiling reveals race-associated RNA splicing and meta","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"142 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006230","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 A081: FOXA1 Lysine methylation remodels its chromatin binding and restrains oncogenic reprogramming in prostate cancer","authors":"Songqi Zhang, Mingyu Liu, Yaozong Su, Jaeweon Jeong, HyeonYeong Sun, Mannan Nouri, Dong Han, Shuai Gao, Jill A. Macoska, Steven P. Balk, Changmeng Cai","doi":"10.1158/1538-7445.prostateca26-a081","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-a081","url":null,"abstract":"Background: FOXA1 acts as a pioneer transcription factor that enhances chromatin accessibility and facilitates androgen receptor (AR) binding in prostate cancer (PCa). In the stage of castration-resistant prostate cancer (CRPC), FOXA1 undergoes chromatin remodeling that promotes tumor progression and therapy resistance. Our recent findings revealed that the chromatin binding of FOXA1 is destabilized by SETD7-mediated lysine 270 methylation and stabilized by LSD1-mediated demethylation. However, how FOXA1 methylation status influences global FOXA1 binding landscape, AR signaling, and other transcriptional programs in CRPC remain unclear. Methods: We firstly used AlphaFold structural modeling tool to predict the direct interaction between LSD1/SETD7 and FOXA1. To further define the functional role of FOXA1 K270 methylation, we generated stable cell lines expressing either inducible wildtype FOXA1 or the methylation-defective K270R mutant with knockdown of endogenous FOXA1. Integrated ChIP-seq and RNA-seq analyses were performed to evaluate changes in global FOXA1 chromatin occupancy, AR binding dynamics in response to AR-targeted therapies, super-enhancer landscape, and downstream transcriptional programs. We then determined effects of a clinical relevant LSD1 inhibitor bomedemstat, on FOXA1 chromatin binding and oncogenic reprogramming in cell lines and xenograft models. Results: AlphaFold modeling revealed that the amine oxidase domain of LSD1 interacts closely with the wing2 loop region of FOXA1. The K270R mutant exhibited expanded FOXA1 chromatin occupancy and altered AR chromatin binding in response to enzalutamide. Transcriptomic profiling showed upregulation of E2F, MYC, and other cell cycle-associated pathways in K270R mutant cells. Pharmacologic inhibition of LSD1 with bomedemstat globally reduced FOXA1 chromatin binding, suppressed E2F signaling, and decreased xenograft tumor growth in FOXA1-high CRPC models. Conclusions: Our study identifies FOXA1 K270 methylation as a critical molecular brake that restricts FOXA1 chromatin binding and its oncogenic transcriptional activities. LSD1 inhibition that restores FOXA1 methylation can restrict FOXA1 chromatin binding, repress FOXA1-activated E2F signaling, and reduce tumor growth. These findings provide a strong rationale for targeting the LSD1-FOXA1 axis as a therapeutic strategy in the AR/FOXA1-high CRPC tumors. Citation Format: Songqi Zhang, Mingyu Liu, Yaozong Su, Jaeweon Jeong, HyeonYeong Sun, Mannan Nouri, Dong Han, Shuai Gao, Jill A. Macoska, Steven P. Balk, Changmeng Cai. FOXA1 Lysine methylation remodels its chromatin binding and restrains oncogenic reprogramming 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 A081.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"128 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A033: Plasma cell-free DNA methylation-based prognosis in metastatic castrate-resistant prostate cancer","authors":"Manish Kohli, Jodie Wong, Yijun Tian, ManishKumar S. Patel, Kapil Avasthi, Claire Hanson, Enos Ampaw, Rebekah Gutowski, Muhammad Zaki H. Fadlullah, Joseph Finklestein, Aik C. Tan, Jong Park, Brandon J. Manley, Chiang-Ching Huang, Liang Wang","doi":"10.1158/1538-7445.prostateca26-a033","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-a033","url":null,"abstract":"Background: Prognostication in metastatic castration-resistant prostate cancer (mCRPC) is based largely on non-specific proteins and clinical factors which cannot be targeted therapeutically for delaying cancer progression in lethal mCRPC. DNA methylation, which can capture tumor-specific epigenetic changes, shows promise as a platform for identifying biology-based prognostic markers. This study investigates plasma cell-free DNA (cfDNA) methylation to identify mCRPC prognostic markers and develops an integrated clinical-molecular nomogram model for risk stratification and potentially personalized treatment strategies. Methods: Plasma was prospectively collected from localized prostate cancer (PC) (n=19), metastatic hormone-sensitive PC (mHSPC) (n=28), and metastatic castration resistant PC (mCRPC) (n=48) patients (pts). Extracted cfDNA underwent enzymatic methylation sequencing (EM-seq) targeting 366 genomic regions implicated in PC biology. Whole genome sequencing libraries were captured with a Twist targeted methylome panel. Bismark was used for methylation calling. mHapSuite was used to identify methylation haplotype blocks (MHBs) and subsequently calculate methylation haplotype load (MHL), the successive methylation at each fragment length. Differentially methylated regions (DMRs) unique to mCRPC were identified with Welch’s t-tests by comparing PC to mHSPC and mCRPC states. mCRPC survival analysis was performed with Cox proportional hazards models, Kaplan-Meier analysis, and nomograms. Results: From 366 target genomic regions, we identified 316 MHBs (linkage disequilibrium r2>0.5, CpG sites≥5) across the 96 PC patients. Comparing PC to mHSPC, 29 DMRs were identified (p-value<0.05). Comparing mHPSC to mCRPC, 271 DMRs were identified, of which 28 were shared with the localized PC vs. mHSPC analysis (p-value<0.05). A MHB-based composite risk score of the top 22 MHBs was generated for DMRs restricted to mCRPC state which showed worse mCRPC survival in high-risk patients (median survival time=15.5 months) than in low-risk patients (median survival time=36.5 months) (log-rank p-value=0.00052). Combining the top significant clinical markers with the MHB-based composite risk score also demonstrated decreased survival probability in high-risk patients (median survival time=15.5 months) as compared to low-risk patients (median survival time=42.8 months) (log-rank p-value=0.00025). Incorporation of the MHB-based score with predicted ctDNA fraction and clinical biomarkers into a multi-modal nomogram model improved the prognostic performance (6-month AUC=0.99, 1-year AUC=0.90, 2-year AUC=0.87) over clinical biomarkers alone (6-month AUC=0.98, 1-year AUC=0.87, 2-year AUC=0.84). Conclusions: Our findings demonstrate that cfDNA methylation signatures can complement existing prognostic models, offering a tumor-biology based personalized approach to mCRPC prognostication, which also identify therapeutic targets in pts with short survival.","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":"146006118","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 B005: RSAD2-CMPK2 signaling mediates PVT1 exon 9 action in an AR-independent manner in PVT1 exon 9 overexpressing neuroendocrine prostate cancers","authors":"Rachel E . Bonacci, Seidu Adams, Chinedum C. Udekwu, Siti Khaula Nurazizah, Luke Washington, Olorunseun O. Ogunwobi","doi":"10.1158/1538-7445.prostateca26-b005","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b005","url":null,"abstract":"Neuroendocrine prostate cancer (NEPC) is a deadly disease with limited treatment options, a predicted increase in incidence, and poor response to conventional therapeutics. NEPC is characterized by muscle-invasive disease and frequent rates of distant metastasis1. There is no FDA-approved molecular targeted treatment for NEPC, and the lack of therapeutics is reflected in the overall survival rate, which remains around 9 months1-2. We have previously reported that PVT1 exon 9 overexpression induces the development of in vivo tumors with the NEPC phenotype, and inhibition of PVT1 exon 9 is an effective therapeutic target in these tumors. Understanding the underlying molecular mechanisms that drive aggressive prostate cancer subtypes is desperately needed. Here, we report findings from the characterization of the novel PVT1 exon 9 overexpressing NEPC subtype. PVT1 exon 9 transcript is found within both the nuclear and cytosolic compartments. Upregulation of PVT1 exon 9 leads to the overexpression of the innate immune surveillance proteins RSAD2 and CMPK2. In PVT1 exon 9 overexpressing NEPC, RSAD2 is localized mainly to the nucleus, a novel observation, via an interaction between the nuclear import complex KPNB1/KPNA2 and its newly identified nuclear localization sequence. We have observed a significantly enhanced expression of the nuclear import complex proteins as well as a direct interaction with PVT1 exon 9 and KPNB1. The function of the RSAD2 nuclear localization is unclear, but PVT1 exon 9 mediated-RSAD2 overexpression does lead to increased interferon gamma secretion. PVT1 exon 9 directly binds to RSAD2 protein as well as the CMPK2 protein. We have observed that CMPK2 overexpression is caused by the overexpression of RSAD2. CMPK2 is localized within the nucleus and cytosolic compartments. Both RSAD2 and CMPK2 proteins do not directly interact, but the RSAD2 protein does bind to the CMPK2 transcript within the nucleus, leading to changes in CMPK2 RNA stability. CMPK2 overexpression is not involved in mediating interferon gamma signaling and is downstream of this signaling network. PVT1 exon 9 overexpression leads to androgen receptor (AR) suppression via an unknown mechanism independent of RSAD2 or CMPK2 activity. Targeting PVT1 exon 9 with antisense oligonucleotides at its 5’ end leads to loss of PVT1 exon 9 expression, decoupling of PVT1 exon 9 from RSAD2 and CMPK2 proteins, re-expression of AR, and loss of cell viability, migration, invasion, and colony formation. Co-treatment with PVT1 exon 9 antisense oligonucleotides and the AR inhibitor enzalutamide leads to significant inhibition of NEPC cell proliferation/viability, invasion and migration. This novel signaling mechanism present in a subset of neuroendocrine prostate cancer is a clinically relevant and targetable molecular aberration. Further investigation is warranted to understand the best treatment strategy for this subtype, as well as identify other aggressive prostate cancer subtyp","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"39 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006120","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 B078: MYCL drives lineage plasticity and resistance to androgen receptor inhibition in castration-resistant prostate cancer","authors":"Nicole A. Traphagen, Alok K. Tewari, Esmé Wheeler, Christian Alfieri, Sajin Patel, Rong Li, Michael Nyquist, Arnab Bose, Michael Haffner, Peter S. Nelson, Henry Long, Himisha Beltran, Myles Brown","doi":"10.1158/1538-7445.prostateca26-b078","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b078","url":null,"abstract":"Lineage plasticity and transition from prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC) is an increasingly common mechanism of resistance to androgen receptor (AR) inhibition in castration-resistant prostate cancer. Transition to NEPC is associated with loss of AR expression, activation of neuroendocrine transcriptional programs, and an aggressive phenotype with poor outcomes. Currently, the mechanisms underlying this lineage transition remain unclear, which has hindered drug discovery efforts. Nearly all NEPC tumors exhibit dual loss of p53 and Rb, however, this is insufficient to drive lineage transition from PRAD to NEPC. Using patient samples, patient cohorts and patient-derived xenograft models, we identified the transcription factor MYCL as highly expressed in a subset of NEPC tumors, with little expression in PRAD. MYCL is an essential gene in preclinical MYCL+ NEPC models, and expression of MYCL in PRAD models is sufficient to downregulate AR expression and induce complete resistance to AR inhibition only in the context of dual p53/Rb loss of function. In contrast, expression of the other Myc family members MYC and MYCN do not regulate AR expression and result in partial resistance to AR inhibition regardless of p53/Rb status. RNA-sequencing in p53/Rb-null models indicated that MYC and MYCN regulate similar transcriptional programs, corresponding primarily with the interferon and inflammatory responses. However, MYCL expression promotes a unique transcriptional program associated with neuroendocrine and neuronal development gene sets and strongly represses the AR transcriptional program. Similarly, ATAC-sequencing of p53/Rb-null models expressing MYC, MYCN, or MYCL indicates that while all three MYC family members regulate chromatin accessibility at a common core set of genomic sites, each MYC family member also regulates chromatin accessibility at unique sites. Concordant with RNA-sequencing results, MYCL unique sites correspond with neuronal and neuroendocrine gene sets. MYCL expression also results in decreased accessibility of the AR distal enhancer, providing a mechanistic basis for the decreased AR expression and repressed AR transcriptional program observed upon MYCL expression. In accordance with this data, we also find that MYCL expression induces morphological changes consistent with transition to a small-cell neuroendocrine phenotype. Using publicly available RNA interference and CRISPR screen data, we also find that models that express MYCL are differentially dependent upon Myc interacting proteins such as MNT and MAX. Ongoing work is focused on identifying the interactome and unique genetic dependencies of MYC, MYCN, and MYCL to gain a better understanding of the divergent functions and unique co-dependencies of each Myc family member. Collectively, this work implicates MYCL as a novel driver of lineage plasticity and provides insights into the unique and convergent functions of the three Myc family mem","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"30 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006154","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":"KRASG12R-Mutant Pancreatic Cancer Features Limited ERK/MAPK Transcriptional Activity and a Distinctive Tumor Microenvironment.","authors":"Rachel A Burge,Ozgun Le Roux,Olesja Popow,Victoria K Spadafora,Christabelle Rajesh,Sara J Adair,Lucas Bialousow,Cailey Murphy,Samaneh Saberi,Silvia G Vaena,Margaret C Taquey,Sarah Allen,Lu Han,Kristi L Helke,Sudarshana Sharma,Michael C Ostrowski,Denis C Guttridge,Toros A Dincman,Todd W Bauer,David F Kashatus,Thomas McFall,Kevin M Haigis,Michael A Hollingsworth,Christopher M Counter,Channing J Der,G Aaron Hobbs","doi":"10.1158/0008-5472.can-25-2630","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2630","url":null,"abstract":"Patients with pancreatic ductal adenocarcinoma (PDAC) harboring KRASG12R mutations have increased overall survival relative to patients with KRASG12D/V mutations. To investigate the mechanisms underlying this differential outcome, we developed a genetically engineered mouse model (GEMM) harboring KRASG12R and p53R172H mutations (KrasLSL-G12R/+;Trp53LSL-R172H/+;p48Cre-ERTM). Unlike KRASG12D models, KRASG12R-GEMMs exhibited limited tumorigenesis, with only 10% developing pancreatic tumors after one year. Additionally, mice harboring whole-body expression of KRASG12R remained healthy for over one year, whereas KRASG12D mice developed rapid multifocal disease. Comparison of KRAS mutant-selective transcription and signaling in murine and human PDAC cell lines, GEMMs, and patient-derived xenograft mouse models revealed that direct KRAS-mediated PI3K activation is necessary for robust tumor initiation in GEMMs. Unexpectedly, KRAS was not the primary driver of PI3K activity in human PDAC cell lines and patient-derived xenograft models regardless of KRAS mutation. KRASG12R and KRASG12D activated a similar pancreas-specific transcriptional network, but KRASG12R promoted these pathways less robustly due to limited ERK/MAPK nuclear translocation. Finally, KRASG12R human pancreatic tumors had an altered tumor microenvironment (TME) with reduced collagen deposition and metastatic liver invasion. Together, this study demonstrated that KRASG12R is capable of driving tumorigenesis despite the reduced ERK/MAPK nuclear translocation and transcriptional output. Although human KRASG12D and KRASG12R-mutant tumors display unexpected similarities in PI3K activity, the differential ERK/MAPK signaling activity and the extrinsic consequences on the TME provide support for using KRASG12R mutation status as a prognostic biomarker for therapeutic strategies.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"63 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005383","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 A051: Spontaneous Remission & Abscopal Responses in Prostate Cancer, a marker of “coldness”?","authors":"Tim Oliver","doi":"10.1158/1538-7445.prostateca26-a051","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-a051","url":null,"abstract":"Introduction: In 1957 spontaneous regression(SR) was established as most frequently in lymphomas, renal and melanoma and in 1968 used by MacFarlain Burnet, to suggest immune surveillance against cancer was a function of the immune system, and that the frequency was greater in earlier stages of cancer. In 1988 Renal cell cancer reported frequency was 6.6% in 73 cases. Despite SR reports increasing since the success of modern immunotherapeuty, a recent review found only 1 case of metastatic prostate cancer (PC) and there was no PC in a series of 58 cases of Radiation Abscopal response(RAR). Though fitting with PC’s reputation as a “cold” cancer, ie having a low response to modern immunotherapy (<5%), this abstract used alternative words in Urology literature to investigate further. Materials and Method: Three terms, evanescent, “vanished” and T0 were used in PUB med searches against second word Prostate.Active surveillance(AC) PC series with post entry biopsy data were also reviewed for incident of T0. Given the high incidence of obesity in series of PC, as additional evidence, we searched for GLP-1RA and PC. Results: The initial search revealed 16 cohorts of prostatectomy and found to have T0. The largest, Knipper, S. et al 2019, found 358/160,352(0.2%) were T0. Most had low volume disease but pT0 was identified in 13/358 (3.6%) with PSA ≥20 ng/ml, in 69 (19.3%) with biopsy GS ≥7 and in 78 (21.8%) with ≥cT2. In a subset, pT0 was identified in 34 (33.3%) patients with ≥2 positive biopsy cores. Eight series of AC with repeat biopsy revealed 952 T0/2862(33.3%), ranging from 41.45% in series with lowest relapse risk to 11.06% with highest relapse risk . Searching for association of GLP-1RA and Prostate cancer revealed a meta-analysis of 5 series of RR 0.72 (95% CI: 0.610 to 0.832). Conclusion: The Knipper et el series demonstrated SR in advanced Primary PC. The nem series in AS is the same as SR HPV positive pre-cancer of the Cervix and as reports of early Prostate cancer with HPV positive from Australia and Canada, investigation is need to see if T0 patients had HPV present. Autopsy series shows that earliest stages of PC precursors occur between 35 and 45 yrs of age , data on GLP-1RA suggests that could be benefit from exploring their use of in low grade PC patients on AS. Citation Format: Tim Oliver. Spontaneous Remission & Abscopal Responses in Prostate Cancer, a marker of “coldness”? [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 A051.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"276 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006161","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 B043: The role of GATA2 and TWIST1 in disrupted differentiation during prostate cancer tumorigenesis","authors":"Carina Magdaleno, Kasturi Banerjee, Cindy Miranti","doi":"10.1158/1538-7445.prostateca26-b043","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b043","url":null,"abstract":"A healthy prostate gland consists of a bilayer of epithelial luminal and basal cells. Each cell type express unique cell-specific markers that allow us to identify them. In prostate development, we observe basal cells able to differentiate to luminal cells which forms the bilayer of epithelial cells we observe in prostate glands. However, in a prostate tumor the bilayer is lost and the cells instead form a monolayer of tumor cells that express both luminal and basal markers. This suggests a defect in the differentiation process. Previous research in our laboratory demonstrates that the transcription factor, CREB1, is aberrantly activated in prostate cancer cells and blocks differentiation. RNA sequencing results identified GATA2 and TWIST1 as possible CREB1 target genes in prostate cancer. ChIP assay results demonstrate the CREB1 could possibly regulate GATA2 and TWIST1 by binding to the CREB1 binding sites, CREs, within their respective promoters. Both genes have been shown to be elevated in human prostate cancers, but their role in preventing differentiation or driving prostate cancer oncogenesis is unclear. To determine how GATA2 and TWIST1 affect differentiation in prostate cancer, we are knocking them down in prostate cancer cells or overexpressing them in normal prostate cells and performing our differentiation protocol. We were able to knockdown GATA2 as validated by immunoblotting. We demonstrate that knocking down GATA2 allows prostate cancer cells to form a second layer of cells. Immunofluorescence results show prostate cancer cells colocalize both basal and luminal markers whereas prostate cancer cells with GATA2 knocked down have a separation of basal and luminal cells indicative of the bilayer. We demonstrate that the loss of GATA2 in prostate cancer cells decreases the migratory ability of these cells. Together this data suggest GATA2 is responsible for promoting oncogenesis. Previous research in our laboratory demonstrates the requirement of NOTCH3 in promoting prostate epithelial differentiation. To elucidate the mechanism that might be responsible for our findings we investigated if there is a GATA2-NOTCH3 interaction. Thus far, we have determined that prostate cancer cells with GATA2 knocked down have less NOTCH3 than prostate cancer cells. Citation Format: Carina Magdaleno, Kasturi Banerjee, Cindy Miranti. The role of GATA2 and TWIST1 in disrupted differentiation during prostate cancer tumorigenesis [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 B043.","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":"146006232","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 A064: Identification and phenotypical evaluation of androgen receptor indifferent phenotype in treatment-naïve primary prostate cancer cases","authors":"Tessa B. Tolson, Beatrice Knudsen, Yi Qiao, Wei Zhang, Mason Hovinga, Chance Walker, Erika Egal, Michael Freeman, Yosep Chong, Qian Yang","doi":"10.1158/1538-7445.prostateca26-a064","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-a064","url":null,"abstract":"INTRODUCTION: High-grade, locally advanced primary prostate cancer (PC) carries an increased risk of metastatic progression. The Androgen Receptor indifferent (ARi) phenotype is characterized by low PSA expression despite high expression of AR and has been noted in CRPC where it is considered to be induced by treatment. We sought to examine primary, treatment-naïve PC cases for evidence of ARi. METHODS: We applied digital pathology and multiplexed, single-cell resolution tissue staining techniques to a locally advanced PC patient cohort with 27 patients, and computational RNA expression analysis to the TCGA prostate cancer dataset (TCGA-PRAD). Thus, we first quantify AR and PSA protein expression levels in cells and then identify tissue regions with >30% AR+ cells and <30% PSA+ cells as ARi cases. The PC regions we analyzed include seminal vesicle invasion (SV), lymph node metastasis (LN), extracapsular extension (ECE), perineural invasion (PNI), cribriform (CRIB), and non-cribriform (HGNC). For computational analysis of the TCGA bulk RNA sequencing data, we stratify patients according to high AR / low PSA (ARi-cohort) and high AR / high PSA (AR responsive, or ARr-cohort) and perform differential expression and gene set enrichment analysis accordingly. RESULTS: Pathologically, we identified ARi phenotype in one or more tissue samples from 5 out of 27 patients. ARi is more frequent in LN compared to SV; and within the prostate, HGNC exhibited more ARi than CRIB. Computational analysis of the TCGA-PRAD cohort (n=500) revealed that ARi patients, compared to AR-responsive patients, are enriched in epithelial-mesenchymal transition (EMT), stem-like, and ONECUT2-induced gene signatures. Moreover, we demonstrate that ARi phenotype is strongly associated with the Prostate Cancer Subtype 1 (PCS1) and PAM50 Basal subtype, consistent with the aggressiveness of the disease. CONCLUSION: We identified the ARi phenotype in two cohorts of primary PC patients using both tissue staining with single cell resolution and computational analysis of bulk RNA expression. We further characterized this phenotype using published gene signatures and determined its relationship to PC cancer subtypes. Furthermore, we propose that the presence of the ARi phenotype can be assessed quickly by clinical immunohistochemistry with AR and PSA antibodies followed by quantification of positive ARi cells (as defined by a high AR:PSA ratio). Moving forward, we will perform single cell RNA expression analysis on the cohort we performed tissue staining to further validate the presence and behavior of ARi phenotype in primary PC, expand into other cohorts, as well as evaluate treatment strategies likely to elicit a response in these cells according to their transcriptomic phenotypes. Citation Format: Tessa B. Tolson, Beatrice Knudsen, Yi Qiao, Wei Zhang, Mason Hovinga, Chance Walker, Erika Egal, Michael Freeman, Yosep Chong, Qian Yang. Identification and phenotypical evaluation","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":"146006153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B080: A patient-derived metastasis model with spontaneous neuroendocrine transformation","authors":"Dana S. Vargas Solivan, JuanJuan (Ivy) Yin, Tri Truong, Joseph Twohig, Ross Lake, Adam G. Sowalsky","doi":"10.1158/1538-7445.prostateca26-b080","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b080","url":null,"abstract":"Background: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease, in which patients each carry distinct molecular features that drive metastatic progression. However, the lack of clinically representative models that recapitulate this disease have limited our understanding in the heterogeneity between patients. LuCaP 147, established from a liver metastasis biopsy, is a prostate cancer transplantable xenograft carrying AR and SPOP mutations with a further hypermutated phenotype, as well as loss of MSH2 and MSH6 expression. Methods: Using LuCaP 147, we developed a novel patient-derived metastasis (PDM) model in NSG mice via intracardiac injection. The development of metastasis was monitored through weekly bioluminescent imaging. We analyzed the tumor burden and survival rate of the PDM147 models. At the endpoint, long bones, spines and soft tissues were collected. To evaluate the histologic phenotype of PDM147, tissue sections were stained by immunohistochemistry (IHC) for adenocarcinoma markers including AR and neuroendocrine markers (which include SOX2, ASCL1, and SYP). Results: After intracardiac injection, tumor burden (BLI) was detected after 5 weeks, and mice developed morbidity after 7-8 weeks. H&E stains showed that PDM147 developed bone metastases in spines, long bones, as well as visceral metastases in liver, brain, spinal cord, kidney and adrenal glands. IHC indicated that metastases were heterogeneous with both AR+/NE- and AR-/NE+ cells. AR+ and SYP+ cells were intermingled in the tumor, but the stains themselves were mutually exclusive between cels. Interestingly, no androgen-deprivation therapy was needed to promote NE differentiation, showcasing the biological novelty [SA([1] of this model. Conclusion: PDM147 is a hypermutated tumor with mutually exclusively expressing AR+ and NE+ markers in metastatic sites, including soft tissues and nervous tissues. Future work to define distinct pathways and molecular markers that lead to de novo vs. treatment-induced NE phenotype may offer a better understanding of the biology driving metastatic spread in these similar yet distinct NE subtypes and the role a hypermutator tumor can have in prostate cancer progression. These findings underscore the value of patient-derived models to study mCRPC progression and heterogeneity. Further use of these models for high-throughput drug screens may uncover targeted therapies for advanced prostate cancer. Citation Format: Dana S. Vargas Solivan, JuanJuan (Ivy) Yin, Tri Truong, Joseph Twohig, Ross Lake, Adam G. Sowalsky. A patient-derived metastasis model with spontaneous neuroendocrine transformation [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 B080.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"17 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006155","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}