Cancer research最新文献

{"title":"Abstract B042: Enhancing ferroptosis in supraphysiologic androgen–treated prostate cancer through GPX4 inhibition","authors":"Rajendra Kumar, Sheila Jonnatan, Shivani Kumar, Nihar Mehta, David E. Sanin, Laura A . Sena, Samuel R. Denmeade, Sushant K . Kachhap","doi":"10.1158/1538-7445.prostateca26-b042","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b042","url":null,"abstract":"Background: While androgen-signaling–directed strategies and other chemotherapies extend survival, at large, outcomes in metastatic castration-resistant PCa (mCRPC) remain poor. Treatment with Supraphysiological Androgen (SPA), which is clinically known as Bipolar Androgen Therapy (BAT), has been shown to inhibit the growth of certain prostate cancer types while also inducing oxidative stress. Ferroptosis, a regulated and iron-dependent form of cell death, has emerged as a promising vulnerability in androgen receptor-positive prostate cancer, especially in the context of the metabolic changes induced by SPA treatment. Methods: AR-positive CRPC cell lines (LNCaP, VCaP, LAPC4, 22Rv1) were treated with SPA to assess changes in ferroptosis sensitivity. Transcriptomic profiling, lipid peroxidation assays, and cellular ultrastructural analyses were used to evaluate ferroptosis hallmarks. Pharmacologic inhibition of GPX4 using RSL3 was employed to induce ferroptosis, and synergy with SPA was quantified through cell viability, ROS accumulation, and other related assays. Results: SPA treatment downregulated key ferroptosis defense proteins, including GPX4 and xCt, increased labile iron pools, and promoted mitochondrial ROS, lipid peroxidation, and mitochondrial changes consistent with ferroptosis. These changes sensitized CRPC cells to ferroptotic death. Combined treatment with SPA and RSL3 produced synergistic suppression of cell viability, elevated mitochondrial ROS, and growth suppression. Conclusion: SPA primes AR-positive prostate cancer cells for ferroptosis by disrupting redox homeostasis and suppressing protective antioxidant pathways. GPX4 inhibition synergizes with SPA to induce ferroptotic cell death, offering a mechanistically focused strategy to enhance therapeutic efficacy in CRPC. This combination warrants further investigation as a potential approach to overcome treatment resistance. Funding Acknowledgments: The research was supported by the PCF Young Investigator Award 21YOUN22, as well as DoD grants W81XWH2210118 and HT94252310029, which supported RK. Citation Format: Rajendra Kumar, Sheila Jonnatan, Shivani Kumar, Nihar Mehta, David E. Sanin, Laura A . Sena, Samuel R. Denmeade, Sushant K . Kachhap. Enhancing ferroptosis in supraphysiologic androgen–treated prostate cancer through GPX4 inhibition [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 B042.","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":"146006163","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 B001: Genetic and clinical profiles of early-onset prostate cancer in Puerto Rican men: A preliminary characterization","authors":"Gustavo Alayón-Rosario, Sebastián Bernaschina-Rivera, Natalia Yordán-Fernández, Juliana Meléndez-Ojeda, Gabriela Castro-Morales, Lenin Godoy-Muñoz, Fabiola A. Benitez-Ríos, Laura F. Rodríguez-Fernández, Carmen Ortiz-Sánchez, Gilberto Ruiz-Deyá","doi":"10.1158/1538-7445.prostateca26-b001","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b001","url":null,"abstract":"BACKGROUND: Prostate cancer (PCA) is the second leading cause of cancer-related death among men in the US. Early-onset prostate cancer (EOPCa) accounts for ∼10% of all PCA diagnoses, with an ∼58,694 new cases reported worldwide in 2021. Although EOPCa accounts for a growing proportion of cases, it remains underexplored. Younger patients often present with distinct clinical features, hereditary predispositions, and long-term survivorship challenges. Hispanic/Latino men, particularly those from Puerto Rico, experience disparities in incidence and outcomes, yet remain underrepresented in PCA research. A better understanding of the epidemiological, clinical, and germline genetic profile of Puerto Rican men with EOPCa is essential to guide risk stratification and inform precision medicine strategies. METHODS: This study retrospectively identified 80 cases of EOPCa of 9,393 patients treated for PCA between 2020–2025 in a tertiary hospital in southern PR. Demographic, clinicopathological variables were collected, including age, PSA, BMI, Gleason score (GS), tumor stage, family history, lifestyle factors, and treatments. Germline genetic testing results were analyzed and variants classified as pathogenic, variants of uncertain significance (VUS), or benign. Frequencies of recurrent alterations were calculated. RESULTS: Eighty patients were identified; 39 met the inclusion criteria. Age ranged 37–49 years (mean 45.7). PSA at diagnosis ranged 1.7–25.4 ng/mL (mean 6.2). Nearly half (48.7%) were obese (BMI ≥30). At biopsy, GS 6 was most frequent (56.4%); following prostatectomy (87.2% of cases), GS 6 remained most common (50.0%), followed by GS 8 (23.5%). Stage T2 (55.9%) and T3 (23.5%) predominated. Family history of PCA was reported by 38.0%. Most patients consumed alcohol (76.9%) but denied smoking (71.8%). Germline testing identified 10.3% pathogenic variants, 35.9% VUS, and 5.1% carriers, with the remainder negative. In total, 21 alterations were detected: 15 VUS, 5 pathogenic, and 1 benign. Alterations were distributed across 15 genes, with recurrent findings in RECQL4 (n=3), POLD1 (n=3), ATM (n=2), and TMEM127 (n=2). CONCLUSIONS: This study provides the first characterization of the epidemiological, clinical, and germline genetic profile of EOPCa in Puerto Rico. Findings highlight a notable burden of germline alterations and underscore the importance of incorporating genetic testing into clinical management. Expanding research among underrepresented populations is critical to guide early detection, refine prognostication, and reduce PCA disparities. Citation Format: Gustavo Alayón-Rosario, Sebastián Bernaschina-Rivera, Natalia Yordán-Fernández, Juliana Meléndez-Ojeda, Gabriela Castro-Morales, Lenin Godoy-Muñoz, Fabiola A. Benitez-Ríos, Laura F. Rodríguez-Fernández, Carmen Ortiz-Sánchez, Gilberto Ruiz-Deyá. Genetic and clinical profiles of early-onset prostate cancer in Puerto Rican men: A preliminary characterization [abstract]. In: Proceedings of the","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":"146006197","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 B075: Transcriptional reprogramming mediates ARSi resistance in Rb-deficient CRPC","authors":"HyeonYeong Sun, Yaozong Su, Changmeng Cai, Jill Macoska, Songqi Zhang, Jaeweon Jeong, Mingyu Liu","doi":"10.1158/1538-7445.prostateca26-b075","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b075","url":null,"abstract":"Background: Prostate Cancer (PCa) is initially treated with Androgen Deprivation Therapy (ADT), but it eventually progresses to Castration-Resistance Prostate Cancer (CRPC) due to acquired treatment resistance. Enzalutamide, a second-generation androgen receptor signaling inhibitor (ARSi), is a current standard treatment for CRPC. However, its long-term efficacy is limited by resistance development. A subset of CRPCs harbor biallelic RB1 deletions, yet the mechanisms through which RB1-loss tumors progress under ARSi treatment remain poorly defined. In this study, we established an RB1-loss CRPC model that acquires resistance through long-term enzalutamide exposure and aimed to elucidate the associated molecular alterations. Hypothesis: We hypothesize that RB1-loss prostate cancer cells undergo distinct transcriptional and metabolic reprogramming during long-term ARSi exposure. Our goal is to characterize these molecular changes and identify key pathways driving enzalutamide resistance. Methods: RB1 was knocked out in C4-2 cells (an AR-positive/PTEN-negative CRPC line) using CRISPR/Cas9-mediated silencing, followed by prolonged high-dose enzalutamide treatment for approximately six months to generate a fully resistant line (called ER6 cells). Intermediate lines were collected at 1.5 (ER1.5) and 3 (ER3) months. Functional assays were performed to validate therapeutic resistance, and integrated RNA-seq and ChIP-seq analyses were conducted to define transcriptional and epigenetic alterations associated with resistance. Results: The ER6 cells exhibited cross-resistance to multiple ARSi agents, including apalutamide. Protein analyses revealed further loss of expression of the Rb-like protein, RBL2, resulting in complete depletion of the Rb repressive program. Notably, ER6 cells retained AR expression but lacked expression of neuroendocrine markers, instead displaying reduced expression of luminal drivers (FOXA1, HOXB13) and increased expression of AP-1 components (JUN) and EMT markers, suggesting a transition toward an EMT-like phenotype. JUN silencing restored FOXA1 expression and reduced EMT markers, suggesting an important role for AP-1 in this reprogramming process. Furthermore, ER6 cells displayed enhanced MAPK pathway activation, shown by increased phospho-ERK levels. RNA-seq analysis was consistent with these findings, revealing enrichment of EMT, Ras-MAPK, and inflammatory pathways in resistant cells. Conclusion: This study demonstrates that RB1-loss CRPC tumors can acquire ARSi resistance through alternative mechanisms independent of neuroendocrine differentiation. Our findings suggest that AP-1–mediated transcriptional reprogramming and MAPK pathway activation may be key drivers of this adaptive resistance. These data uncover potential therapeutic vulnerabilities and highlight the AP-1 and MAPK pathways as potential targets for treating ARSi-resistant, Rb-deficient prostate cancer. Citation Format: HyeonYeong Sun, Yaozong Su, Changmeng Cai, J","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"6 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006223","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 B010: Targeting SSTR1 to overcome resistance to androgen receptor signaling inhibition in prostate cancer","authors":"Shu Chen, Tianyi Liu, Jun Zhu, Haolong Li, David Quigley, Alan Ashworth, Rahul Aggarwal, Eric Small, Felix Feng, Xiaolin Zhu","doi":"10.1158/1538-7445.prostateca26-b010","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b010","url":null,"abstract":"Background: Resistance to androgen receptor signaling inhibitors (ARSIs), such as abiraterone or enzalutamide (ENZ), is a major obstacle to improving outcomes for patients with prostate cancer. We previously identified SSTR1 to be transcriptionally downregulated in ARSI-resistant prostate cancer. SSTR1 encodes somatostatin receptor type 1, which mediates anti-proliferative, anti-invasive, and anti-angiogenic effects when binding to somatostatin or somatostatin analogues. Here, we studied the biology of SSTR1 in prostate cancer, focusing on its relationship with ARSI resistance and its potential as a therapeutic target. Methods: To examine the impact of ARSI on SSTR1 expression, we treated C42B and 22Rv1 cells and LTL484 and LTL331 patient-derived organoids (PDOs) with enzalutamide and determined SSTR1 expression after the treatment. To investigate the function of SSTR1, we generated stable knockdown (using CRISPR interference), CRISPR knockout, and stable lentiviral over-expression cell lines of C42B and 22Rv1. Using such cells, we assessed live cell number with and without enzalutamide treatment. To evaluate the therapeutic potential of targeting SSTR1, we tested CH275, a SSTR1-specific agonist, and pasireotide, the only FDA-approved SSTR1 agonist with a pan-SSTR activity. The effects of these SSTR1 agonists, alone or in combination with enzalutamide, were evaluated in C42B and 22Rv1 cells by live cell number, and in LTL484 and LTL331 PDOs by cell viability and apoptosis. Results: SSTR1 protein levels decreased after enzalutamide treatment in both cell lines and PDOs, consistent with decreased mRNA levels in tumor biopsies. CH275 and pasireotide decreased the live cell number of C42B and 22Rv1 cells. SSTR1 knockdown and knockout increased live cell number and attenuated the effect of CH275, whereas SSTR1 overexpression decreased live cancer cell number and enhanced the CH275 effect. Moreover, both SSTR1 agonists (CH275 and pasireotide) synergized with ARSIs (enzalutamide and apalutamide) in eliminating live cells. Similar trends were observed in LTL484 and LTL331 PDOs treated with pasireotide, enzalutamide, or their combination. SSTR1 knockdown and knockout attenuated the synergistic effects of combination treatment in both cell lines. Conclusions: ARSI treatment in CRPC models decreased SSTR1 expression. SSTR1 agonists enhanced the efficacy of ARSI in suppressing prostate cancer growth. These findings motivate the testing of SSTR1 agonists in preclinical models in vivo as a potential therapeutic approach to improve treatment response and outcomes for patients with prostate cancer. Citation Format: Shu Chen, Tianyi Liu, Jun Zhu, Haolong Li, David Quigley, Alan Ashworth, Rahul Aggarwal, Eric Small, Felix Feng, Xiaolin Zhu. Targeting SSTR1 to overcome resistance to androgen receptor signaling inhibition in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Trea","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":"146006226","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 PR009: A dependency map of androgen receptor activity identifies drivers of prostate cancer growth","authors":"Arnab Bose, Ilsa Coleman, Dapei Li, Rabeya Bilkis, Brian Hanratty, Michael Nyquist, Jared Lucas, Sander Frank, Peter Nelson","doi":"10.1158/1538-7445.prostateca26-pr009","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-pr009","url":null,"abstract":"Background. The Androgen Receptor (AR) is an important therapeutic target in patients with advanced prostate cancer (PC). Androgen deprivation therapy and drugs designed to inhibit AR signaling (ARSI) cause tumor regression and extend survival. However, disease progression is nearly universal and is usually accompanied by reactivation of AR signaling. To date, the specific mechanisms by which the AR maintains cell survival or promotes cell proliferation have not been defined and thus downstream programs cannot be exploited for treatment benefit. In this study, we sought to define the transcriptional program regulated by the AR in PC and identify AR target genes/proteins capable of promoting cell survival and growth. Methods. The transcriptional programs of established and novel PC cell line models with AR activity (ARPC) were characterized upon androgen treatment. Comparative analyses defined a cohort of 1144 common and unique AR-upregulated genes (ARGs) across the models. A CRISPR-Cas9 knockout library targeting these ARGs and AR-V7 associated genes was generated and viability screens were performed across six ARPC lines. Gene dependencies were identified by MAGeCK analysis. Open reading frames (ORFs) of essential ARGs were used for establishing stable cell lines in LNCaP_FGC cells and the influence of ARG overexpression on proliferation determined by Incucyte live-cell Imaging and Cell-titer-glo assays. Results. Phenotypic effects of escalating androgen doses and ARSI co-treatment suggested involvement of transcriptional function of AR in promoting PC cell growth. CRISPR-Cas9 knockout screens identified ARG dependencies encompassing a wide range of cellular networks. Collectively, 29 ARGs were commonly essential across all models tested (core essential genes; CEG). Individual lines displayed additional private dependencies. Several CEGs namely PAK1IP1, CENPN, NKX3-1, SPDEF and POTEM displayed high expression in normal human prostate tissue. Notably, deletion of the tumor suppressor gene NKX3-1 resulted in complete cell growth arrest across 4 different ARPC models. To determine phenotypic functionalities, we overexpressed CEG ORFs in LNCaP_FGC cells. While majority of the CEGs had neutral or modestly enhanced proliferative fitness in the basal state, SPDEF, POTEM and GMPPB repressed LNCaP_FGC growth. Conclusions. The AR transcriptionally regulates a cell autonomous genetic program that promotes PC survival and proliferation. A component of this program appears to function via a hierarchical network involving other transcription factors such as NKX3-1 that may exert survival and growth activity in addition to its known tumor suppressor functions. Current efforts are being directed toward developing a mechanistic understanding of cell-type context for the individual CEGs; identifying minimal and sufficient CEG combinations which can drive AR-mediated survival program; and identifying epistatic relationships between growth sustaining and repressing","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":"146006248","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 B018: Impact of 13q.14 loss in prostate cancer progression and sensitivity to targeted agents","authors":"Victor Esquefa, Pablo Cresta Morgado, Richard Norris, Lara de Llobet, Julian Brandariz, Sara Arce-Gallego, Teresa Casals, Manuel Ramos, Daniel Aguilar, Gisela Mir, Irene Casanova-Salas, Francisco M. Barriga, Joaquin Mateo","doi":"10.1158/1538-7445.prostateca26-b018","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b018","url":null,"abstract":"Purpose of the study: Chromosomal aberrations are frequent in cancer and play a pivotal role in disease initiation and progression. In prostate cancer (PCa), deletions at chromosome 13q14 are common and enriched in advanced disease, suggesting selective advantage in tumor progression. Beyond BRCA2, this region harbors other tumor suppressor genes, including RB1 and RNASEH2B, which impact sensitivity to androgen receptor inhibitors (ARi) and PARP inhibitors (PARPi). This study aims to elucidate the effect of individual vs concomitant loss of RB1 and RNASEH2B in response to dual AR and PARP inhibition. Methods: To explore the prevalence of deletions in 13q we interrogated copy number alterations in the Hartwig Medical Foundation (HMF) PCa WGS dataset (n=486). In vitro, we generated CRISPR-Cas9-mediated knock-outs (KO) of RB1, RNASEH2B, or both genes in PCa cell lines (LNCaP, C4-2, 22Rv1, DU145). Gene editing was confirmed by Sanger, and western blot analysis validated protein loss. Antitumor activity of enzalutamide (ARi), and olaparib or saruparib (PARPi) was determined using CCK8 kit and colony formation assays. Results: RB1 deletions were present in 42% of HMF PCa samples (205/486), being mostly heterozygous deletions (200/205). RB1 deletions co-occurred with RNASEH2B loss in 94% of cases (192/205) and with BRCA2 deletions in 42% of cases (87/205). In vitro, RB1-KO increased resistance to ARi and PARPi in hormone-sensitive lines LNCaP and C4-2, while no change in sensitivity was detected in AR-independent models 22Rv1 and DU145. Loss of RNASEH2B increased sensitivity to PARPi in all models. Next, we generated RB1 and RNASEH2B double KO models in LNCaP and C4-2 by sequentially editing single KO populations. After single-cell seeding, we obtained: (1) RB1-KO (homozygous) clones with complete protein loss; (2) RNASEH2B-heterozygous (RNASEH2B-Het) models with partial protein expression; and (3) RB1-KO/RNASEH2B-Het models. No clones with complete RNASEH2B loss were obtained, suggesting that RNASEH2B-loss population is transient and that clones with complete loss do not proliferate. RB1-KO models maintained resistance to both treatments. RNASEH2B-Het cells showed increased sensitivity to PARPi, although to lower extent than the population with complete RNASEH2B loss. Importantly, introducing RB1-loss in RNASEH2B-Het cells restored PARPi resistance, and combined AR/PARP inhibition did not overcome resistance in RB1-KO or RB1-KO/RNASEH2B-Het cells. Conclusions: Our findings indicate that 13q14 deletions in PCa predominantly occur as heterozygous events encompassing key genes influencing ARi and PARPi responses. Heterozygous loss of RNASEH2B confers sensitivity to PARPi, although to a lesser extent than in models with complete RNASEH2B loss. RB1-loss confers higher resistance to ARi and PARPi, restoring resistance to PARPi in RNASEH2B heterozygous models. These results highlight the need for models that better mirror the heterozygous nature of 13q14 dele","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":"146006117","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 B071: Monitoring the evolution of treatment resistance by transcriptional profiling of circulating tumor cells with RNAseq","authors":"Jamie M. Sperger, Marina N. Sharifi, Amy K. Taylor, Krisitin L. Rosche, David Gallo, Viridiana Carreno, Alex H. Chang, Emily Abella, Kaitlin Durnen, Muhammad Dar, Charlotte Linebarger, William M. Stump, Kendra Marr, Kyle T. Helzer, Grace C. Blitzer, John Floberg, David Kosoff, Rana R. McKay, Xiao X. Wei, Shuang G. Zhao, Joshua M. Lang","doi":"10.1158/1538-7445.prostateca26-b071","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b071","url":null,"abstract":"Background: Treatment with androgen receptor (AR)-targeted therapy, chemotherapy and 177Lu-PSMA-617 radioligand therapy have improved patient outcomes for patients with metastatic prostate cancer (PCa). However, development of treatment resistance remains universal, occurring through AR dependent mechanisms driving constitutive AR signaling, or lineage state transitions that bypass AR signaling and culminate in highly proliferative tumors, including those with luminal B (LumB) and neuroendocrine phenotypes. We recently described two distinct luminal phenotypes with high luminal and AR signaling gene expression but distinguished by high (LumB) or low (luminal A (LumA)) proliferation signature scores, with the LumB phenotype associated with shorter survival compared to the LumA phenotype. We also identified a low proliferation phenotype characterized by low AR/luminal signature and low proliferation, and a neuroendocrine phenotype characterized by high neuroendocrine and proliferation signature scores. Evolution of tumor biology has been difficult to monitor due to challenges in collecting serial tissue biopsies. Blood-based liquid biopsy is non-invasive and well suited for repeat sampling. RNA sequencing of circulating tumor cells (CTCs) provides an accessible means to perform longitudinal transcriptional profiling to track mechanisms of resistance over time. Methods: CTCs were isolated from patients with PCa during standard of care treatments including baseline and progression timepoints with automated microfluidic technology integrating negative and positive selection. CTCs and RNA were captured immunomagnetically. RNAseq data was assessed for CTC RNAseq phenotype, signature scores including CCP-31, signatures of tumor suppressor loss (p53, RB1, PTEN) and MYC signatures and genes previously identified as expressed in AR+ PCa or NEPC. Results: We analyzed longitudinal samples including 27 sets of matched baseline and post-treatment samples from 22 patients with metastatic PCa during treatment with AR targeted therapies, chemotherapy and 177Lu-PSMA-617. In 30% (8/27) of these patients, we observed a switch of CTC phenotype at treatment progression from pretreatment baseline sample. The most common switch (n=5) was from the LumA phenotype to LumB phenotype, which was associated with increased RB1 loss signature score (p=0.016). We observed a patient transitioning from a LumB phenotype to neuroendocrine at progression on 177Lu-PSMA-617 radioligand therapy. In this patient, coinciding with the phenotype shift, we detected decreased expression of KLK3 and FOLH1 (PSMA)and increased expression of ASCL1, INSM1 and SYP consistent with a shift from a luminal adenocarcinoma to a neuroendocrine phenotype. Conclusions: To better understand tumor evolution, it is essential to monitor molecular changes during treatment. RNAseq of CTCs enables longitudinal tracking of lineage phenotype transitions. Ongoing studies are investigating mechanisms that drive resistan","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"2 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006157","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 B048: Tolinapant sensitizes PTEN-deficient prostate cancer to radiotherapy by targeting anti-apoptotic pathways","authors":"Letitia Mohamed-Smith, Dimitra Kalamida, Suneil Jain, David J. Waugh, Melissa J. LaBonte-Wilson","doi":"10.1158/1538-7445.prostateca26-b048","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b048","url":null,"abstract":"Introduction High-risk prostate cancer (PCa) with loss of the tumour suppressor gene phosphatase and tensin homolog (PTEN) remains clinically challenging, often progressing despite radiotherapy (RT) and androgen receptor (AR) pathway inhibition. PTEN loss contributes to immune-mediated radioresistance, in part through pro-inflammatory cytokine tumour necrosis alpha (TNF-α)–induced upregulation of cellular inhibitor of apoptosis proteins (cIAP1/2 and XIAP), promoting survival and treatment resistance. This study investigated the efficacy of inhibition of IAPs using tolinapant as a radiosensitiser in PTEN-deficient PCa models and explored its potential synergy with AR inhibition using enzalutamide. We hypothesised that pharmacological inhibition of IAPs would overcome RT resistance in PTEN-deficient PCa and augment apoptotic signalling. Methods Quantitative cell-based assays, immunofluorescence and Western blotting were used to evaluate tolinapant-mediated inhibition of IAP related proteins in PTEN-deficient and wildtype (WT) PCa cell lines both alone and in combination with radiation and enzalutamide, and the impact of these treatments on cell viability, survival and apoptosis. Xenograft mouse models of PTEN-deficient PCa were employed to assess tolinapant’s radio-sensitizing effects in vivo both as a single agent and in combination with RT, whilst ex vivo mechanistic studies focused on apoptotic signalling pathways. Results Tolinapant significantly enhanced the radiosensitivity of PTEN-deficient PCa cells, reducing cell viability and colony formation, with minimal impact in PTEN-WT cells. In xenograft models, tolinapant significantly delayed tumour progression, reduced proliferation (Ki67) expression and increased apoptosis (cleaved caspase-3) compared to RT alone. Ex vivo analyses confirmed on-target IAP suppression and activation of apoptosis pathway. Preliminary in vitro data suggest that adding enzalutamide further enhances radiosensitivity in PCa models, warranting further evaluation. Conclusion Our findings support tolinapant as a radiosensitiser in PTEN-deficient PCa, offering a promising therapeutic pathway for patients with high-risk or castration-resistant disease. By targeting anti-apoptotic signalling, tolinapant may enhance standard-of-care RT and delay disease progression. Ongoing studies aim to define optimal combinatorial strategies for clinical translation. Citation Format: Letitia Mohamed-Smith, Dimitra Kalamida, Suneil Jain, David J. Waugh, Melissa J. LaBonte-Wilson. Tolinapant sensitizes PTEN-deficient prostate cancer to radiotherapy by targeting anti-apoptotic pathways [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 B048.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"3 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006192","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 PR029: Monitoring tumor evolution and phenotypic diversity in metastatic prostate cancer using liquid biopsy profiling","authors":"Irene Casanova-Salas, Laura Martínez, Daniel Aguilar, Haitham Alatoom, Manuel J. Ramos, Pablo Cresta, Gisela Mir, Anna Oliveira, Mar Moré, Lara De Llobet, Joaquin Mateo","doi":"10.1158/1538-7445.prostateca26-pr029","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-pr029","url":null,"abstract":"Background Tumor heterogeneity and lineage plasticity pose major challenges in the management of metastatic prostate cancer (mPC), particularly as the disease evolves under therapeutic pressure. While resistance is often driven by genomic mutations, transcriptomic adaptations also play a critical role. Liquid biopsy offers a minimally invasive strategy to longitudinally monitor both genomics (via circulating tumor DNA, ctDNA) and transcriptomics (via extracellular vesicle RNA, EV-RNA) in real time, providing insights into disease evolution and treatment response. Methods Longitudinal blood samples were collected from a prospective cohort of 145 mPC patients treated at Vall d’Hebron Hospital, spanning hormone-sensitive (HSPC), castration-resistant (CRPC), and neuroendocrine (NEPC) states, and across treatment lines (ARSI, taxanes, others). Plasma was processed to isolate ctDNA and EV-RNA. Mutational profiling of ctDNA (n=262) was performed using Guardant Infinity. Whole-transcriptome profiling of EV-RNA (n=126) was conducted using a custom RExCuE-based library preparation enabling simultaneous gene expression analysis. Exome-capture RNA-seq was performed in matched tumor and blood samples from a collection of patient-derived xenografts (PDXs) representing HSPC (n=12), CRPC (n=4), and NEPC (n=2). Results CtDNA profiling recapitulated the mutational landscape and phenotypic diversity of mPC. In CRPC, AR alterations were most frequent (51%), whereas NEPC showed enrichment of MYC (70%), RB1 (60%), and PI3K pathway mutations (30–70%). Although no variants were detected in 3/262 samples, tumor fraction (TF) was identifiable through methylation-based scoring, underscoring the platform’s sensitivity for both genomic and epigenetic alterations. Baseline ctDNA TF, estimated from variant allele frequency (SNV-TF) or methylation score (methylation-TF), was significantly associated with shorter progression-free survival, discriminating patients’ outcome even at very low TF (<2% SNV-TF; <1% methylation-TF). SNV and methylation-TF were strongly correlated (r=0.8, p<0.0001), though less so in NEPC. Matched EV-RNA revealed concordant gene expression shifts across ctDNA genotypes with prognostic relevance. Both ctDNA and EV-RNA captured inter- and intrapatient heterogeneity, with ctDNA clonality reflecting therapeutic trajectories. CtDNA also captured homologous recombination deficiency (HRD) status, consistent with RAD51 foci assay. Transcriptomic profiling of EV-RNA identified CRPC-related and NEPC-associated gene signatures in both PDXs and patient samples. Furthermore, longitudinal profiling enabled real-time monitoring of lineage transitions, capturing early transcriptomic adaptations to therapy, including emergence of castration resistance and neuroendocrine features. Conclusions Combined analysis of ctDNA and EV-RNA provides complementary insights into tumor evolution and phenotypic diversity, enabling minimally invasive longitudinal mon","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"94 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006193","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 PR035: Cooperativity between DNA methylation and EZH2 activity drives neuroendocrine phenotype in advanced prostate cancer","authors":"Richa Singh, Varadha Balaji. Venkadakrishnan, Eddie Imada, Yasutaka Yamada, Nicholas J. Brady, Kate Dunmore, Richard Garner, Brian D. Robinson, David S. Rickman, Himisha Beltran","doi":"10.1158/1538-7445.prostateca26-pr035","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-pr035","url":null,"abstract":"Introduction: Upon prolonged anti-androgen treatment, 15-20% of castration resistant prostate cancer (CRPC) progresses to poorly differentiated, androgen-independent neuroendocrine prostate cancer (NEPC) that express neural markers through a mechanism of lineage plasticity. Data from patient tumors have revealed a distinct DNA methylome profile between NEPC and CRPC, suggesting the relevance of DNA methylation during lineage plasticity in advanced CRPC. EZH2, a catalyzer of repressive H3K27me3 deposition is overexpressed in NEPC. EZH2 inhibition is being studied as a therapeutic strategy for advanced prostate cancer in clinical trials. Although evidence from embryonic stem cell studies suggest a possible interplay between DNA methylation and EZH2 activity, their cooperativity in driving lineage plasticity in advanced CRPC is unknown. Methods: DNA methylome and H3K27me3 deposition in patient-derived xenografts/organoids and murine model engineered with MYCN induction and Pten/Rb1 co-loss were analyzed following EZH2 or DNMT1 depletion, respectively. We also assessed the impact of EZH2/DNMT1 depletion on gene transcription. Results: Both DNA methylome and H3K27me3 profile shifted during progression of CRPC to NEPC. H3K27me3 was enriched at hypomethylated regions in NEPC compared to CRPC tumors. EZH2 loss resulted in changes at clinically relevant NEPC-associated differentially methylated regions. Neuron-related genes were hypomethylated and upregulated while, morphogenesis-related and bivalent genes were hypermethylated and downregulated upon EZH2 deletion. Conversely, DNMT1 deletion altered H3K27me3 landscape in NEPC. Neuron-related genes and bivalent genes were downregulated and enriched with H3K27me3 but were upregulated and depleted in H3K27me3 in CRPC upon DNMT1 deletion. H3K4me3 was also decreased upon DNMT1 depletion in NEPC at these regions suggesting loss of bivalency. Short-term DNMT inhibition using decitabine in NEPC xenografts resulted in similarly altered H3K27me3 deposition as noted upon DNMT deletion. Conclusions: DNMT1 and EZH2 activity overlaps and together reprograms the epigenome during lineage plasticity of advanced CRPCs. EZH2 loss was partially compensated by DNMT activity leading to further neuroendocrine differentiation while DNMT1 loss shifted H3K27me3 leading to suppression of neuron-related genes. Citation Format: Richa Singh, Varadha Balaji. Venkadakrishnan, Eddie Imada, Yasutaka Yamada, Nicholas J. Brady, Kate Dunmore, Richard Garner, Brian D. Robinson, David S. Rickman, Himisha Beltran. Cooperativity between DNA methylation and EZH2 activity drives neuroendocrine phenotype in advanced 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 PR035.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"86 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005958","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}