Pub Date : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-b062
Connor Purcell, Anais Sidonia, Yumiko Imai, Audrey Su, Tyler Roady, Praveen R. Srinivasan, Maximilian Pinho-Schwermann, Benedito A. Carneiro, Wafik S. El-Deiry
Introduction: Androgen pathway inhibitors have transformed advanced prostate cancer (PCa) treatment yet remain susceptible to acquired resistance. Progression of PCa to androgen receptor (AR)-independent subtypes such as neuroendocrine prostate cancer (NEPC) confers poor prognosis. This lineage transformation is mediated by epigenetic mechanisms. NEPC frequently inactivates the tumor suppressor and cell cycle regulators RB1 and TP53, suggesting crosstalk between reprogramming factors and the cell cycle. While this bridge has been characterized in multiple cell types, it is understudied in NEPC. Salient examples include the pluripotency transcriptional factor (TF) SOX2, which regulates CCND1, and INSM1, which directly binds Cyclin D1 protein. Here, we investigate these interactions using isogenic inducible models and in-silico analysis of patient tumors, to identify therapeutic vulnerabilities exposed by neuroendocrine (NE) differentiation. Methods: Data were obtained from published datasets (Beltran et al, 2016; Labreque et al, 2019; DepMap) and the Caris CodeAI database. Patient and cell line data was analyzed for survival (where applicable) and differential mRNA expression between groups stratified by mRNA quartile. Inducible systems of TFs SOX2, ASCL1, FOXA2, and INSM1 were established in AR-positive LNCaP, and AR-negative DU145 and PC3 cell lines. RB1 and TP53 knockout (KO) LNCaP lines were generated by Cas9 electroporation, and Cyclin D1-HA (Addgene 174154) was stably overexpressed. TFs were induced with 200ng/mL doxycycline for 24h up to 28d, and protein expression was assessed via western blot. Cell viability and proliferation were surveyed by CellTiter-Glo® assay and nuclear counts, respectively. Results: NEPC patient data analysis revealed INSM1, ASCL1, FOXA2, and SOX2 expression to be negatively correlated with Cyclin D1 and positively correlated with Cyclin E1/2. High SOX2, ASCL1, FOXA2, or INSM1 correlated with worse prognosis in NEPC, while high SOX2 or INSM1 correlated with improved survival in prostate adenocarcinoma (PRAD). Elevated Cyclin D1 predicted improved outcomes in NEPC. INSM1 correlated with RB1 mutation and expression of E2F family members, CDK inhibitors, and E-/A-type cyclins in NEPC. Inducible INSM1, SOX2, ASCL1, and FOXA2 models showed robust induction 48h post-doxycycline addition, accompanied by expression of NE lineage markers and diminution of proliferation in the PRAD model LNCaP. Isogenic RB1 and TP53 KO LNCaP models were generated and validated, along with a CCND1 overexpression model. Ongoing work examines whether these models respond differently to TF induction. Conclusions: Our analyses reveal significant correlations between expression of NE-lineage TFs and cell cycle-regulators in clinical datasets. Novel in vitro studies suggest these TFs suppress proliferation. Future work will uncover whether RB1/TP53 loss and Cyclin D1 expression affect tolerance of NE programs, and uncover vulnerabilities such as G2/
导读：雄激素途径抑制剂已经改变了晚期前列腺癌（PCa）的治疗，但仍然容易获得性耐药。前列腺癌进展为雄激素受体（AR）非依赖性亚型，如神经内分泌前列腺癌（NEPC），预后较差。这种谱系转化是由表观遗传机制介导的。NEPC经常使肿瘤抑制因子和细胞周期调节因子RB1和TP53失活，提示重编程因子与细胞周期之间存在串扰。虽然这种桥在多种细胞类型中都有特征，但在NEPC中还没有得到充分的研究。突出的例子包括调控CCND1的多能转录因子SOX2和直接结合Cyclin D1蛋白的INSM1。在这里，我们使用等基因诱导模型和患者肿瘤的计算机分析来研究这些相互作用，以确定神经内分泌（NE）分化暴露的治疗脆弱性。方法：数据来自已发表的数据集（Beltran et al ., 2016; Labreque et al ., 2019; DepMap）和Caris CodeAI数据库。对患者和细胞系数据进行生存率（如适用）和按mRNA四分位数分层的组间mRNA表达差异分析。在ar阳性的LNCaP和ar阴性的DU145和PC3细胞系中建立了TFs SOX2、ASCL1、FOXA2和INSM1诱导体系。通过Cas9电穿孔生成RB1和TP53敲除（KO） LNCaP细胞系，Cyclin D1-HA （Addgene 174154）稳定过表达。用200ng/mL强力霉素诱导tf 24h至28d， western blot检测其蛋白表达。分别用CellTiter-Glo®法和核计数法检测细胞活力和增殖。结果：NEPC患者资料分析显示INSM1、ASCL1、FOXA2、SOX2的表达与Cyclin D1呈负相关，与Cyclin E1/2呈正相关。高SOX2、ASCL1、FOXA2或INSM1与NEPC患者预后差相关，而高SOX2或INSM1与前列腺腺癌（PRAD）患者生存率提高相关。Cyclin D1升高预示NEPC预后改善。INSM1与NEPC中RB1突变、E2F家族成员、CDK抑制剂和E-/ a型细胞周期蛋白的表达相关。添加强力霉素48小时后，诱导的INSM1、SOX2、ASCL1和FOXA2模型均表现出较强的诱导作用，同时PRAD模型LNCaP中NE谱系标记的表达和增殖减弱。生成并验证了等基因RB1和TP53 KO LNCaP模型，以及CCND1过表达模型。正在进行的研究将检验这些模型对TF诱导是否有不同的反应。结论：我们的分析揭示了临床数据集中ne -谱系tf的表达与细胞周期调节因子之间的显著相关性。新的体外研究表明，这些tf抑制增殖。未来的工作将揭示RB1/TP53缺失和Cyclin D1表达是否会影响NE程序的耐受性，并揭示G2/M检查点依赖、CDK抑制剂上调和代谢改变等脆弱性。引用格式：Connor Purcell， Anais Sidonia, Yumiko Imai, Audrey Su, Tyler Roady, Praveen R. Srinivasan, Maximilian Pinho-Schwermann, Benedito A. Carneiro, Wafik S. El-Deiry。前列腺癌谱系可塑性驱动因子与RB1/E2F轴在ar通路抑制剂获得性耐药性中的相互作用[摘要]。摘自：美国癌症研究协会癌症研究特别会议论文集：前列腺癌研究和治疗的创新；2026年1月20日至22日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86（增刊）：B062。
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Pub Date : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-a038
Chennan Li, Anna Baj, Clara C. Y. Seo, Nicholas T. Terrigino, John B. Bright, S. Thomas Hennigan, Isaiah M. King, Scott Wilkinson, Shana Y. Trostel, William D. Figg, William L. Dahut, Jung-Min Lee, David Y. Takeda, Fatima Karzai, Adam G. Sowalsky
Background: Metastatic castration-resistant prostate cancer (mCRPC) exhibits high mortality due to the emergence of therapy resistance phenotypes. We recently tested a novel combination therapy in patients with mCRPC who had progressed on androgen receptor (AR)-targeted therapies, targeting PD-L1 and PARP1 with durvalumab and olaparib, respectively. While a subset of patients exhibited partial responses, most patients experienced disease progression within a year. The goal of the current study is to perform comprehensive profiling of circulating tumor DNA (ctDNA) and buffy coat to assess the molecular characteristics of progressive vs. responsive prostate tumors. Methods: We obtained plasma cell-free DNA (cfDNA), a mixture of ctDNA and other tissue-derived DNA, from 38 individuals treated with the PD-L1/PARP1-targeted combination therapy (NCT02484404) at baseline, after two months of treatment, and upon disease progression. Whole-genome sequencing (WGS, median coverage: 139×) was performed using cfDNA and buffy coat DNA as germline control. Germline and somatic mutations including small mutations and structural rearrangements were individually curated to determine cfDNA tumor fraction. To infer epigenetic regulation, whole-genome 5-hydroxymethylcytosine and 5-methylcytosine (5hmC and 5mC, respectively) sequencing was performed using the Biomodal evoC platform. T/B cell receptor repertoire was inferred from buffy coat sequencing using MiXCR. Results: A negative association between baseline cfDNA tumor fraction and progression-free survival (PFS) was observed. BRCA2 alterations were associated with durable responses, whereas oncogenic mutations in TP53 and MAPK signaling pathway were associated with intrinsic resistance or rapid progression. Using cfDNA methylation sequencing, we identified disease-specific AR signaling genes depleted for promoter/early intronic 5mCs and enriched for 5hmCs in ctDNA-positive plasma. Similarly, AR-associated transcription factor binding sites were depleted for 5mCs and enriched for 5hmCs. Given the association between 5mC depletion and gene expression from matched tissues, we inferred gene expression and evaluated genes that correlate with drug response. Longer PFS was associated with greater activities of interferon signaling and inflammation at baseline, consistent with greater diversity of inferred T cell clonotypes. Comparing pre- and post-treatment plasma samples, distinct genetic programs were identified from patients with longer vs shorter PFS, suggesting different mechanisms of adaptive vs intrinsic treatment resistance. Conclusions: Baseline genomic deficiencies associated with DNA damage repair were differentially correlated with PD-L1/PARP1-targeted therapy response. Epigenetic alterations associated with inflammatory genes and baseline T lymphocyte clonal complexity inform better therapy outcomes. Time-course evaluation of global patterns of 5hmCs and 5mCs identified distinct epigenetic mechanisms associa
背景：转移性去势抵抗性前列腺癌（mCRPC）由于出现治疗耐药表型而表现出高死亡率。我们最近在雄激素受体（AR）靶向治疗进展的mCRPC患者中测试了一种新的联合疗法，分别使用durvalumab和olaparib靶向PD-L1和PARP1。虽然一小部分患者表现出部分反应，但大多数患者在一年内出现疾病进展。本研究的目的是对循环肿瘤DNA （ctDNA）和黄皮进行全面分析，以评估进行性和反应性前列腺肿瘤的分子特征。方法：我们从38名接受PD-L1/ parp1靶向联合治疗（NCT02484404）的患者中获得无浆细胞DNA (cfDNA)，这是一种ctDNA和其他组织来源DNA的混合物，这些患者在基线、治疗两个月后和疾病进展时均接受了PD-L1/ parp1靶向联合治疗。全基因组测序（WGS，中位数覆盖率：139x）以cfDNA和灰褐色被毛DNA作为种系对照。生殖系和体细胞突变（包括小突变和结构重排）被单独筛选以确定cfDNA肿瘤分数。为了推断表观遗传调控，使用biommodal evoC平台进行了全基因组5-羟甲基胞嘧啶和5-甲基胞嘧啶（分别为5hmC和5mC）测序。T/B细胞受体库是利用MiXCR从褐皮测序中推断出来的。结果：观察到基线cfDNA肿瘤分数与无进展生存期（PFS）呈负相关。BRCA2的改变与持久的反应有关，而TP53和MAPK信号通路的致癌突变与内在抗性或快速进展有关。通过cfDNA甲基化测序，我们发现了ctdna阳性血浆中启动子/早期内含子5mCs缺失和5hmCs富集的疾病特异性AR信号基因。同样，ar相关转录因子结合位点在5mCs中缺失，而在5hmCs中富集。考虑到5mC消耗与匹配组织的基因表达之间的关联，我们推断了基因表达并评估了与药物反应相关的基因。较长的PFS与基线时干扰素信号和炎症的活性较高相关，这与推断的T细胞克隆型的多样性较高一致。比较治疗前和治疗后的血浆样本，从PFS较长和较短的患者中发现了不同的遗传程序，这表明适应性和内在治疗耐药的机制不同。结论：与DNA损伤修复相关的基线基因组缺陷与PD-L1/ parp1靶向治疗反应存在差异相关。与炎症基因和基线T淋巴细胞克隆复杂性相关的表观遗传改变告知更好的治疗结果。对5hmc和5mCs整体模式的时间过程评估确定了与治疗反应或失败相关的不同表观遗传机制。引文格式：Chennan Li， Anna Baj, Clara C. Y. Seo, Nicholas T. Terrigino, John B. Bright， S. Thomas Hennigan, Isaiah M. King, Scott Wilkinson, Shana Y. Trostel, William D. Figg, William L. Dahut, Jung-Min Lee, David Y. Takeda, Fatima Karzai, Adam G. Sowalsky。液体活检推断转移性去势抵抗性前列腺癌对PD-L1/ parp1靶向治疗的耐药机制[摘要]。摘自：美国癌症研究协会癌症研究特别会议论文集：前列腺癌研究和治疗的创新；2026年1月20日至22日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86（2增刊）：no A038。
{"title":"Abstract A038: Mechanisms of resistance to PD-L1/PARP1-targeted therapy in metastatic castration-resistant prostate cancer inferred by liquid biopsy","authors":"Chennan Li, Anna Baj, Clara C. Y. Seo, Nicholas T. Terrigino, John B. Bright, S. Thomas Hennigan, Isaiah M. King, Scott Wilkinson, Shana Y. Trostel, William D. Figg, William L. Dahut, Jung-Min Lee, David Y. Takeda, Fatima Karzai, Adam G. Sowalsky","doi":"10.1158/1538-7445.prostateca26-a038","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-a038","url":null,"abstract":"Background: Metastatic castration-resistant prostate cancer (mCRPC) exhibits high mortality due to the emergence of therapy resistance phenotypes. We recently tested a novel combination therapy in patients with mCRPC who had progressed on androgen receptor (AR)-targeted therapies, targeting PD-L1 and PARP1 with durvalumab and olaparib, respectively. While a subset of patients exhibited partial responses, most patients experienced disease progression within a year. The goal of the current study is to perform comprehensive profiling of circulating tumor DNA (ctDNA) and buffy coat to assess the molecular characteristics of progressive vs. responsive prostate tumors. Methods: We obtained plasma cell-free DNA (cfDNA), a mixture of ctDNA and other tissue-derived DNA, from 38 individuals treated with the PD-L1/PARP1-targeted combination therapy (NCT02484404) at baseline, after two months of treatment, and upon disease progression. Whole-genome sequencing (WGS, median coverage: 139×) was performed using cfDNA and buffy coat DNA as germline control. Germline and somatic mutations including small mutations and structural rearrangements were individually curated to determine cfDNA tumor fraction. To infer epigenetic regulation, whole-genome 5-hydroxymethylcytosine and 5-methylcytosine (5hmC and 5mC, respectively) sequencing was performed using the Biomodal evoC platform. T/B cell receptor repertoire was inferred from buffy coat sequencing using MiXCR. Results: A negative association between baseline cfDNA tumor fraction and progression-free survival (PFS) was observed. BRCA2 alterations were associated with durable responses, whereas oncogenic mutations in TP53 and MAPK signaling pathway were associated with intrinsic resistance or rapid progression. Using cfDNA methylation sequencing, we identified disease-specific AR signaling genes depleted for promoter/early intronic 5mCs and enriched for 5hmCs in ctDNA-positive plasma. Similarly, AR-associated transcription factor binding sites were depleted for 5mCs and enriched for 5hmCs. Given the association between 5mC depletion and gene expression from matched tissues, we inferred gene expression and evaluated genes that correlate with drug response. Longer PFS was associated with greater activities of interferon signaling and inflammation at baseline, consistent with greater diversity of inferred T cell clonotypes. Comparing pre- and post-treatment plasma samples, distinct genetic programs were identified from patients with longer vs shorter PFS, suggesting different mechanisms of adaptive vs intrinsic treatment resistance. Conclusions: Baseline genomic deficiencies associated with DNA damage repair were differentially correlated with PD-L1/PARP1-targeted therapy response. Epigenetic alterations associated with inflammatory genes and baseline T lymphocyte clonal complexity inform better therapy outcomes. Time-course evaluation of global patterns of 5hmCs and 5mCs identified distinct epigenetic mechanisms associa","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":"146006227","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}
Pub Date : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-pr024
Amber W. Wang, Michal Pawlak, Eric Ariazi, Livia Ulicna, Anne Page, Rupal Patel, Edna Chow Maneval, Pratik S. Multani, Lori S. Friedman, Anneleen Daemen, Aleksandr Pankov
Androgen Receptor Pathway Inhibition (ARPI) is a cornerstone of prostate cancer treatment; however, therapeutic resistance often arises due to an AR-independent cell state emerging as a result of tumor plasticity. Dysregulation of epigenetic reprogramming factors, including Polycomb Repressive Complex 2 (PRC2), creates an environment conducive to lineage plasticity. Thus inhibiting PRC2 offers a promising strategy to overcome ARPI therapeutic resistance in prostate cancer. ORIC-944 is a potent, orally bioavailable, allosteric PRC2 inhibitor with potential best-in-class drug properties that is currently in Phase 1b clinical development. In preclinical studies, ORIC-944 in combination with ARPI demonstrated efficacy across various models including AR-mutant and -wildtype, ARPI-resistant and -sensitive, and castration-resistant and -sensitive prostate cancers. Despite the spectrum of resistance mechanisms in these AR positive models, ORIC-944 consistently enhanced signatures of luminal cell state and AR signaling. These preclinical observations reveal the potential for ORIC-944 to block prostate tumor adaptation and re-sensitize tumors to ARPI. In this study of clinical samples from the ORIC-944-01 Phase 1b clinical trial, we aimed to evaluate the mechanism of ORIC-944 in patients with prostate cancer. DNA methylation profiling from liquid biopsies was chosen as a non-invasive method for investigating the epigenetic landscape of circulating tumor DNA. We identified CpG-rich regions associated with prostate tumorigenesis and transcriptional subtypes based on publicly available DNA methylation data from 100 metastatic castration-resistant prostate cancer (mCRPC) tumors, 35 healthy blood samples, and 150+ normal tissues. These selected regions became the foundation of a custom panel utilized on liquid biopsies to profile the epigenetic states of tumors from mCRPC patients treated with single-agent ORIC-944. A new methodology for cell-free DNA methylation was established to detect and quantify changes in subtype-associated regions independently of tumor burden. This approach and the clinical DNA methylation data showed that following treatment with ORIC-944, tumors from most patients experienced a shift in methylation pattern that suggests an increase in AR signaling. Notably, this shift was detectable after one treatment cycle of single agent ORIC-944, consistent with preclinical studies. Conversely, no patients showed an increase in neuroendocrine-associated signals after one cycle of treatment. These findings suggest that a selected set of informative methylation regions evaluated in plasma can identify epigenetic-driven changes in transcriptional activity during the treatment of patients with advanced prostate cancer. This approach is a key step towards enabling non-invasive epigenomic profiling of transcriptional states of prostate cancer. Furthermore, this analysis confirms our preclinical mechanistic data and hypothesis that ORIC-944 treatment en
雄激素受体途径抑制（ARPI）是前列腺癌治疗的基石；然而，治疗耐药往往是由于肿瘤可塑性导致的与ar无关的细胞状态而产生的。表观遗传重编程因子的失调，包括多梳抑制复合体2 (PRC2)，创造了一个有利于谱系可塑性的环境。因此，抑制PRC2为克服前列腺癌ARPI治疗耐药提供了一个有希望的策略。ORIC-944是一种有效的口服变构PRC2抑制剂，具有潜在的同类最佳药物特性，目前处于1b期临床开发。在临床前研究中，ORIC-944联合ARPI在各种模型中显示出疗效，包括ar突变型和野生型，ARPI耐药和敏感，去势耐药和敏感前列腺癌。尽管在这些AR阳性模型中存在多种耐药机制，但ORIC-944始终增强了腔细胞状态和AR信号的特征。这些临床前观察揭示了ORIC-944阻断前列腺肿瘤适应和使肿瘤对ARPI再敏感的潜力。本研究以ORIC-944-01 1b期临床试验的临床样本为研究对象，旨在评估ORIC-944治疗前列腺癌的作用机制。选择液体活检的DNA甲基化谱作为研究循环肿瘤DNA表观遗传景观的非侵入性方法。基于100例转移性去势抵抗性前列腺癌（mCRPC）肿瘤、35例健康血液样本和150多个正常组织的公开DNA甲基化数据，我们确定了与前列腺肿瘤发生和转录亚型相关的富含cpg的区域。这些选定的区域成为液体活检中定制面板的基础，用于描述单药ORIC-944治疗的mCRPC患者肿瘤的表观遗传状态。建立了一种新的无细胞DNA甲基化方法，以检测和量化亚型相关区域的变化，而不依赖于肿瘤负荷。该方法和临床DNA甲基化数据显示，在ORIC-944治疗后，大多数患者的肿瘤经历了甲基化模式的转变，这表明AR信号的增加。值得注意的是，这种转变在单药ORIC-944的一个治疗周期后就可以检测到，与临床前研究一致。相反，在一个治疗周期后，没有患者表现出神经内分泌相关信号的增加。这些发现表明，在晚期前列腺癌患者治疗期间，血浆中评估的一组信息丰富的甲基化区域可以识别表观遗传驱动的转录活性变化。这种方法是实现前列腺癌转录状态的非侵入性表观基因组分析的关键一步。此外，该分析证实了我们的临床前机制数据和假设，即ORIC-944治疗可增强前列腺癌的AR信号传导。引文格式：Amber W. Wang, michael Pawlak, Eric Ariazi, Livia Ulicna, Anne Page, Rupal Patel, Edna Chow Maneval, Pratik S. Multani, Lori S. Friedman, Anneleen Daemen, Aleksandr Pankov。循环肿瘤DNA甲基化捕获PRC2抑制剂ORIC-944诱导的患者的表观遗传变化[摘要]。摘自：美国癌症研究协会癌症研究特别会议论文集：前列腺癌研究和治疗的创新；2026年1月20日至22日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(2_supl): nr PR024。
{"title":"Abstract PR024: Circulating tumor DNA methylation captures epigenetic changes in patients induced by the PRC2 inhibitor ORIC-944","authors":"Amber W. Wang, Michal Pawlak, Eric Ariazi, Livia Ulicna, Anne Page, Rupal Patel, Edna Chow Maneval, Pratik S. Multani, Lori S. Friedman, Anneleen Daemen, Aleksandr Pankov","doi":"10.1158/1538-7445.prostateca26-pr024","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-pr024","url":null,"abstract":"Androgen Receptor Pathway Inhibition (ARPI) is a cornerstone of prostate cancer treatment; however, therapeutic resistance often arises due to an AR-independent cell state emerging as a result of tumor plasticity. Dysregulation of epigenetic reprogramming factors, including Polycomb Repressive Complex 2 (PRC2), creates an environment conducive to lineage plasticity. Thus inhibiting PRC2 offers a promising strategy to overcome ARPI therapeutic resistance in prostate cancer. ORIC-944 is a potent, orally bioavailable, allosteric PRC2 inhibitor with potential best-in-class drug properties that is currently in Phase 1b clinical development. In preclinical studies, ORIC-944 in combination with ARPI demonstrated efficacy across various models including AR-mutant and -wildtype, ARPI-resistant and -sensitive, and castration-resistant and -sensitive prostate cancers. Despite the spectrum of resistance mechanisms in these AR positive models, ORIC-944 consistently enhanced signatures of luminal cell state and AR signaling. These preclinical observations reveal the potential for ORIC-944 to block prostate tumor adaptation and re-sensitize tumors to ARPI. In this study of clinical samples from the ORIC-944-01 Phase 1b clinical trial, we aimed to evaluate the mechanism of ORIC-944 in patients with prostate cancer. DNA methylation profiling from liquid biopsies was chosen as a non-invasive method for investigating the epigenetic landscape of circulating tumor DNA. We identified CpG-rich regions associated with prostate tumorigenesis and transcriptional subtypes based on publicly available DNA methylation data from 100 metastatic castration-resistant prostate cancer (mCRPC) tumors, 35 healthy blood samples, and 150+ normal tissues. These selected regions became the foundation of a custom panel utilized on liquid biopsies to profile the epigenetic states of tumors from mCRPC patients treated with single-agent ORIC-944. A new methodology for cell-free DNA methylation was established to detect and quantify changes in subtype-associated regions independently of tumor burden. This approach and the clinical DNA methylation data showed that following treatment with ORIC-944, tumors from most patients experienced a shift in methylation pattern that suggests an increase in AR signaling. Notably, this shift was detectable after one treatment cycle of single agent ORIC-944, consistent with preclinical studies. Conversely, no patients showed an increase in neuroendocrine-associated signals after one cycle of treatment. These findings suggest that a selected set of informative methylation regions evaluated in plasma can identify epigenetic-driven changes in transcriptional activity during the treatment of patients with advanced prostate cancer. This approach is a key step towards enabling non-invasive epigenomic profiling of transcriptional states of prostate cancer. Furthermore, this analysis confirms our preclinical mechanistic data and hypothesis that ORIC-944 treatment en","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":"146006229","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}
Pub Date : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-pr027
Martin K. Bakht, Jacob Egelberg, Yasutaka Yamada, Louise Clark, Xiao Wei, Varadha Balaji Venkadakrishnan, Anthony P. Belanger, Alice Bernard-Tessier, Sarah J. Hill, Francesca Khani, David J. Einstein, Mary-Ellen Taplin, Eliezer Van Allen, Heather A. Jacene, Himisha Beltran
Background: PSMA expression is heterogeneous across advanced prostate cancer, limiting the durability of PSMA-radioligand therapy (RLT). To characterize tumor heterogeneity and identify determinants of RLT resistance, we established the SHAPE cohort (Spatial Heterogeneity Atlas of Prostate Cancer Evolution). SHAPE is a multimodal resource integrating PET imaging, clinical treatment history, histopathology, immunohistochemistry, spatial transcriptomics, and genomic profiling across 46 patient tumor samples collected through rapid autopsy, biopsy, and surgical resection. The cohort spans adenocarcinoma, castration-resistant (CRPC), and neuroendocrine (NEPC) prostate cancer states and includes eight xenograft models. Methods: Twenty-five samples profiled using the 10x Genomics Visium spatial transcriptomics platform, comprising 195,905 spots, were integrated and analyzed using Seurat (v5) in R. Targeted genomic profiling was performed using the Dana-Farber Cancer Institute OncoPanel platform on 36 samples derived from 7 patients and 2 animal models. Among the cohort, seven cases had prior Lu-PSMA exposure, and ten cases were untreated. Eleven clinical and preclinical samples had PSMA PET/CT, including six with both pre- and post-treatment imaging. Data integration connected structural genomic events with spatial lineage programs and imaging features. Results: RLT–treated tumors exhibited a copy-number–dominant profile compared with untreated tumors. Recurrent alterations enriched in treated tumors included PTEN deletion (p<0.01), KLLN deletion (p<0.01), AURKA gain (p<0.01), and ZNF217 gain (p<0.01). Treated tumors also showed higher per-sample copy number loss (47.6 vs 37.5, p<0.05) and amplification burden (7.91 vs 2, p<0.05). In contrast, untreated tumors displayed more single nucleotide variants (14.9 vs 6.3, ns) and indels (4.7 vs 1.9, ns). Spatial transcriptomics provided complementary insights. Treated samples with PSMA SUV below the liver reference demonstrated higher copy-number loss burden (p<0.05) and contained unique transcriptomic clusters enriched for glucose metabolism. These clusters displayed variable expression of classical NEPC markers but consistently upregulated genes involved in glucose uptake and utilization. In preclinical studies, head-to-head FDG and Ga-PSMA imaging of WCM12 xenografts demonstrated that FDG, as a surrogate marker of glucose uptake, was significantly increased following relapse after PSMA-RLT (FC, p<0.05). Conclusions: The SHAPE cohort integrates genomic, spatial, and imaging data to characterize tumor heterogeneity in advanced prostate cancer. Genomic profiling identified PTEN/KLLN loss and AURKA/ZNF217 gain as recurrent alterations enriched in Lu-PSMA–exposed tumors, while spatial transcriptomics revealed PSMA-low metastases with distinct. clusters enriched for glucose metabolic programs. Together, SHAPE can inform rational strategies for combination o
背景：PSMA在晚期前列腺癌中的表达是不均匀的，这限制了PSMA放射配体治疗（RLT）的持久性。为了表征肿瘤异质性并确定RLT耐药的决定因素，我们建立了SHAPE队列（前列腺癌进化的空间异质性图谱）。SHAPE是一个多模式资源，整合了PET成像、临床治疗史、组织病理学、免疫组织化学、空间转录组学和基因组图谱，涵盖了通过快速尸检、活检和手术切除收集的46例患者肿瘤样本。该队列涵盖腺癌、去势抵抗（CRPC）和神经内分泌（NEPC）前列腺癌状态，包括8种异种移植模型。方法：利用10x Genomics Visium空间转录组学平台分析的25份样本，包括195,905个位点，使用Seurat (v5) in r进行整合和分析。使用Dana-Farber Cancer Institute OncoPanel平台对来自7名患者和2个动物模型的36份样本进行靶向基因组分析。在该队列中，7例既往有Lu-PSMA暴露，10例未接受治疗。11例临床和临床前样本进行了PSMA PET/CT检查，其中6例同时进行了治疗前和治疗后成像。数据集成将结构基因组事件与空间谱系程序和成像特征联系起来。结果：与未治疗的肿瘤相比，rlt治疗的肿瘤表现出拷贝数优势。治疗肿瘤中富集的复发性改变包括PTEN缺失（p<0.01）、KLLN缺失（p<0.01）、AURKA增益（p<0.01）和ZNF217增益（p<0.01）。治疗后的肿瘤也表现出更高的每样本拷贝数损失（47.6 vs 37.5, p<0.05）和扩增负担（7.91 vs 2, p<0.05）。相比之下，未经治疗的肿瘤显示更多的单核苷酸变异（14.9 vs 6.3, ns）和索引（4.7 vs 1.9, ns）。空间转录组学提供了互补的见解。PSMA SUV低于肝脏参考值处理的样品显示出更高的拷贝数损失负担（p<0.05），并且含有丰富葡萄糖代谢的独特转录组簇。这些集群表现出经典NEPC标记的可变表达，但一致上调参与葡萄糖摄取和利用的基因。在临床前研究中，WCM12异种移植物的头对头FDG和Ga-PSMA成像显示，FDG作为葡萄糖摄取的替代标志物，在PSMA-RLT后复发后显著增加（FC, p<0.05）。结论：SHAPE队列整合了基因组、空间和影像学数据来表征晚期前列腺癌的肿瘤异质性。基因组分析发现PTEN/KLLN缺失和AURKA/ZNF217增加在暴露于lupsma的肿瘤中是复发性改变，而空间转录组学显示psma低转移具有明显的特异性。富含葡萄糖代谢程序的簇。总之，SHAPE可以为联合或替代靶向治疗的合理策略提供信息。引用格式：Martin K. Bakht, Jacob Egelberg, Yasutaka Yamada, Louise Clark, Xiao Wei, Varadha Balaji Venkadakrishnan, Anthony P. Belanger, Alice Bernard-Tessier, Sarah J. Hill, Francesca Khani, David J. Einstein, Mary-Ellen Taplin, Eliezer Van Allen, Heather A. Jacene7, Himisha Beltran。前列腺癌进化的空间异质性图谱（SHAPE）：接受和不接受Lu-PSMA治疗的晚期前列腺癌的空间和基因组景观[摘要]。摘自：美国癌症研究协会癌症研究特别会议论文集：前列腺癌研究和治疗的创新；2026年1月20日至22日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(2_supl): nr PR027。
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Pub Date : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-b032
Juan M. Jiménez-Vacas, Jonathan Welti, Denisa Bogdan, Ines Figueiredo, Bora Gurel, Wanting Zeng, Tomas Goldsmith, Souvik Das, Joe Taylor, Nicholas Waldron, Claudia Bertan, Suzanne Carreira, Wei Yuan, Paul Workman, Steven P. Balk, Johann de Bono, Adam Sharp
Background: Despite recent therapeutic advances, advanced prostate cancer (PCa) remains lethal as tumors develop resistance to current treatments. Novel and more effective therapeutic strategies to induce cell death in these tumors are urgently needed. Our group recently reported that NXP800, a drug in clinical development, drives unfolded protein response (UPR) and targets AR and E2F, decreasing the growth of castration-resistant PCa (CRPC) models in vitro and in vivo. BH3 mimetics are small molecules that inhibit antiapoptotic BCL-2 family proteins, thereby promoting apoptosis, and have shown particular promise in hematological malignancies. However, their efficacy in CRPC has been limited, likely due to functional redundancies among antiapoptotic proteins such as MCL1, BCLXL, and BCL2. Objective: We investigated the potential of combining NXP800 with BH3 mimetics targeting MCL1 (S63845) or BCLXL (A-1331852) to drive cell death by inducing the intrinsic apoptosis pathway in CRPC models. Methods: Cell viability and caspase 3/7 activity were assessed by luminescence assays, while additional apoptosis markers were evaluated by western blot following treatment with NXP800, S63845, and A-1331852, as single agents or in combination. To identify key mediators of the synergistic effects, an siRNA screen targeting BH3-only proteins was performed in CRPC cells before treatment with the single agents or their combination. To assess the molecular consequences of NXP800 treatment in vivo, RNA-seq was performed on tumors from CRPC-bearing mice treated with NXP800 (35 mg/kg daily for 5 days), with particular focus on genes involved in the intrinsic apoptosis pathway. Results: NXP800 synergized with MCL1 and BCLXL inhibitors in CRPC cells, inducing apoptosis as evidenced by caspase 3/7 activation and PARP cleavage. Co-silencing of the mitochondrial pore–forming proteins BAX and BAK, as well as treatment with the pan-caspase inhibitor Q-VD-OPh, prevented cell death induced by NXP800 in combination with BH3 mimetics, indicating that the effect is caspase-dependent and involves activation of the intrinsic apoptosis pathway. Blocking NXP800-induced eIF2α phosphorylation using ISRIB abolished the synergistic effect observed with BH3 mimetics. Thapsigargin, which induces the unfolded protein response via SERCA inhibition, recapitulated the synergy and triggered apoptosis in combination with BH3 mimetics. RNA-seq analysis of LNCaP95 xenograft tumors treated with NXP800 revealed induction of specific BH3-only proteins whose silencing (in vitro) prevented caspase 3/7 activation and abolished the synergistic cell death observed with NXP800 in combination with MCL1 or BCLXL inhibition. Conclusion: NXP800 sensitizes CRPC cells to BH3 mimetics by inducing UPR and dysregulating BH3-only proteins. These findings highlight the potential of combining UPR-inducing agents with BH3 mimetics as a therapeutic strategy in CRPC. Citation Format: Juan M. Jiménez-Vacas, Jonathan Welti,
背景：尽管最近的治疗取得了进展，晚期前列腺癌（PCa）仍然是致命的，因为肿瘤对目前的治疗产生了耐药性。迫切需要新的和更有效的治疗策略来诱导这些肿瘤的细胞死亡。我们的团队最近报道了一种临床开发的药物NXP800，它可以驱动未折叠蛋白反应（UPR），靶向AR和E2F，在体外和体内降低去势抵抗性PCa （CRPC）模型的生长。BH3模拟物是抑制抗凋亡BCL-2家族蛋白的小分子，从而促进细胞凋亡，并在血液恶性肿瘤中显示出特别的希望。然而，它们在CRPC中的疗效有限，可能是由于抗凋亡蛋白如MCL1、BCLXL和BCL2之间的功能冗余。目的：探讨NXP800联合靶向MCL1 （S63845）或BCLXL （A-1331852）的BH3模拟物在CRPC模型中通过诱导内在凋亡途径驱动细胞死亡的潜力。方法：采用荧光法检测细胞活力和caspase 3/7活性，western blot检测NXP800、S63845和A-1331852单独或联合作用后细胞凋亡标志物。为了确定协同作用的关键介质，在使用单一药物或联合药物治疗前，在CRPC细胞中进行了针对BH3-only蛋白的siRNA筛选。为了评估NXP800在体内的分子效应，研究人员对携带crpc的小鼠的肿瘤进行了rna测序（每天35 mg/kg，持续5天），特别关注与内在凋亡途径相关的基因。结果：NXP800在CRPC细胞中与MCL1和BCLXL抑制剂协同作用，通过caspase 3/7活化和PARP切割诱导细胞凋亡。共沉默线粒体孔形成蛋白BAX和BAK，以及用泛caspase抑制剂Q-VD-OPh处理，可以防止NXP800联合BH3模拟物诱导的细胞死亡，表明这种作用依赖于caspase，涉及激活内在凋亡途径。使用ISRIB阻断nxp800诱导的eIF2α磷酸化，可以消除BH3模拟物的协同效应。Thapsigargin通过抑制SERCA诱导未折叠蛋白反应，再现了协同作用并与BH3模拟物联合引发细胞凋亡。NXP800对LNCaP95异种移植肿瘤的RNA-seq分析显示，特异性BH3-only蛋白的诱导，其沉默（体外）阻止了caspase 3/7的激活，并消除了NXP800与MCL1或BCLXL联合抑制时观察到的协同细胞死亡。结论：NXP800通过诱导UPR和BH3-only蛋白失调使CRPC细胞对BH3模拟物增敏。这些发现强调了将upr诱导剂与BH3模拟物结合作为CRPC治疗策略的潜力。引文格式：Juan M. jimsamunez - vacas, Jonathan Welti, Denisa Bogdan, Ines Figueiredo, Bora Gurel, wanging Zeng, Tomas Goldsmith, Souvik Das, Joe Taylor, Nicholas Waldron, Claudia Bertan, Suzanne Carreira, Wei Yuan, Paul Workman, Steven P. Balk, Johann de Bono, Adam Sharp。未折叠蛋白反应的诱导揭示了晚期前列腺癌细胞对BH3模拟物的脆弱性[摘要]。摘自：美国癌症研究协会癌症研究特别会议论文集：前列腺癌研究和治疗的创新；2026年1月20日至22日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86（增刊）：B032。
{"title":"Abstract B032: Induction of the unfolded protein response unveils a vulnerability of advanced prostate cancer cells to BH3 mimetics","authors":"Juan M. Jiménez-Vacas, Jonathan Welti, Denisa Bogdan, Ines Figueiredo, Bora Gurel, Wanting Zeng, Tomas Goldsmith, Souvik Das, Joe Taylor, Nicholas Waldron, Claudia Bertan, Suzanne Carreira, Wei Yuan, Paul Workman, Steven P. Balk, Johann de Bono, Adam Sharp","doi":"10.1158/1538-7445.prostateca26-b032","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b032","url":null,"abstract":"Background: Despite recent therapeutic advances, advanced prostate cancer (PCa) remains lethal as tumors develop resistance to current treatments. Novel and more effective therapeutic strategies to induce cell death in these tumors are urgently needed. Our group recently reported that NXP800, a drug in clinical development, drives unfolded protein response (UPR) and targets AR and E2F, decreasing the growth of castration-resistant PCa (CRPC) models in vitro and in vivo. BH3 mimetics are small molecules that inhibit antiapoptotic BCL-2 family proteins, thereby promoting apoptosis, and have shown particular promise in hematological malignancies. However, their efficacy in CRPC has been limited, likely due to functional redundancies among antiapoptotic proteins such as MCL1, BCLXL, and BCL2. Objective: We investigated the potential of combining NXP800 with BH3 mimetics targeting MCL1 (S63845) or BCLXL (A-1331852) to drive cell death by inducing the intrinsic apoptosis pathway in CRPC models. Methods: Cell viability and caspase 3/7 activity were assessed by luminescence assays, while additional apoptosis markers were evaluated by western blot following treatment with NXP800, S63845, and A-1331852, as single agents or in combination. To identify key mediators of the synergistic effects, an siRNA screen targeting BH3-only proteins was performed in CRPC cells before treatment with the single agents or their combination. To assess the molecular consequences of NXP800 treatment in vivo, RNA-seq was performed on tumors from CRPC-bearing mice treated with NXP800 (35 mg/kg daily for 5 days), with particular focus on genes involved in the intrinsic apoptosis pathway. Results: NXP800 synergized with MCL1 and BCLXL inhibitors in CRPC cells, inducing apoptosis as evidenced by caspase 3/7 activation and PARP cleavage. Co-silencing of the mitochondrial pore–forming proteins BAX and BAK, as well as treatment with the pan-caspase inhibitor Q-VD-OPh, prevented cell death induced by NXP800 in combination with BH3 mimetics, indicating that the effect is caspase-dependent and involves activation of the intrinsic apoptosis pathway. Blocking NXP800-induced eIF2α phosphorylation using ISRIB abolished the synergistic effect observed with BH3 mimetics. Thapsigargin, which induces the unfolded protein response via SERCA inhibition, recapitulated the synergy and triggered apoptosis in combination with BH3 mimetics. RNA-seq analysis of LNCaP95 xenograft tumors treated with NXP800 revealed induction of specific BH3-only proteins whose silencing (in vitro) prevented caspase 3/7 activation and abolished the synergistic cell death observed with NXP800 in combination with MCL1 or BCLXL inhibition. Conclusion: NXP800 sensitizes CRPC cells to BH3 mimetics by inducing UPR and dysregulating BH3-only proteins. These findings highlight the potential of combining UPR-inducing agents with BH3 mimetics as a therapeutic strategy in CRPC. Citation Format: Juan M. Jiménez-Vacas, Jonathan Welti,","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"45 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006159","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}
Pub Date : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-b028
Saskia Elena. Haarmann, Martin Eilers, Steffi Herold
The androgen receptor (AR) is a key driver of prostate cancer progression, making androgen deprivation therapy and AR signaling inhibitors the standard of care therapies for treating prostate cancer. Although these treatments are effective initially, they often lead to the development of resistance, limiting their long-term efficacy. This acquired resistance is frequently linked to the MYC oncogene family, which, together with reduced AR signaling, is associated with poor clinical prognosis. Among the resistant phenotypes, treatment-induced neuroendocrine prostate cancer (tNEPC) is a particularly aggressive AR-independent subtype characterized by loss of AR signaling and epigenetic reprogramming. These molecular changes promote cell lineage plasticity, creating a permissive environment for MYCN activation, which further drives tumor progression and neuroendocrine differentiation. In summary, MYC proteins pose a major biological challenge, but also offer opportunities to develop new therapeutic approaches. To address these, we generated LNCaP-derived prostate cancer cell lines that constitutively express c-MYC or MYCN. Their sustained proliferation under enzalutamide treatment confirmed the development of a resistant phenotype. In addition, RNA sequencing of MYCN-overexpressing cells revealed transcriptional reprogramming, including the activation of neural lineage markers and epithelial-mesenchymal transition programs consistent with a neuroendocrine-like phenotype. To identify dependency factors, we performed a genome-wide shRNA screen to uncover genes whose knockdown selectively impaired growth of LNCaP cells expressing c-MYC or MYCN under enzalutamide. In c-MYC-expressing cells approximately 80 significantly downregulated genes were identified, many of which had previously been associated with therapeutic resistance. Interestingly, a substantial proportion of these factors were also significantly enriched in RNA processing and metabolic pathways. Both c-MYC and MYCN bind directly to DNA as well as RNA, and recent studies have revealed that MYC proteins play distinct mechanistic roles in transcriptional regulation and RNA metabolism. The newly described RNA-related functions of MYC highlight the importance of RNA regulatory mechanisms as key drivers of MYC-dependent oncogenesis in prostate cancer. Approximately 20 genes were significantly downregulated in MYCN-expressing cells, most of which are involved in RNA splicing. This is an intriguing observation given that MYCN is a well-characterized transcription factor that orchestrates transcriptional reprogramming. The data suggest that MYCN can influence oncogenic processes by modulating RNA splicing mechanisms, revealing an additional level of regulatory complexity in tNEPC. Ongoing validation and integrative analyses, including bulk mRNA-sequencing of patient data, aim to define the roles of these genes, delineate pathways, and identify novel therapeutic targets to overcome MYC-mediated and AR-
{"title":"Abstract B028: Global shRNA screen to identify factors that are involved in MYC/MYCN-dependent growth of prostate cancer","authors":"Saskia Elena. Haarmann, Martin Eilers, Steffi Herold","doi":"10.1158/1538-7445.prostateca26-b028","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b028","url":null,"abstract":"The androgen receptor (AR) is a key driver of prostate cancer progression, making androgen deprivation therapy and AR signaling inhibitors the standard of care therapies for treating prostate cancer. Although these treatments are effective initially, they often lead to the development of resistance, limiting their long-term efficacy. This acquired resistance is frequently linked to the MYC oncogene family, which, together with reduced AR signaling, is associated with poor clinical prognosis. Among the resistant phenotypes, treatment-induced neuroendocrine prostate cancer (tNEPC) is a particularly aggressive AR-independent subtype characterized by loss of AR signaling and epigenetic reprogramming. These molecular changes promote cell lineage plasticity, creating a permissive environment for MYCN activation, which further drives tumor progression and neuroendocrine differentiation. In summary, MYC proteins pose a major biological challenge, but also offer opportunities to develop new therapeutic approaches. To address these, we generated LNCaP-derived prostate cancer cell lines that constitutively express c-MYC or MYCN. Their sustained proliferation under enzalutamide treatment confirmed the development of a resistant phenotype. In addition, RNA sequencing of MYCN-overexpressing cells revealed transcriptional reprogramming, including the activation of neural lineage markers and epithelial-mesenchymal transition programs consistent with a neuroendocrine-like phenotype. To identify dependency factors, we performed a genome-wide shRNA screen to uncover genes whose knockdown selectively impaired growth of LNCaP cells expressing c-MYC or MYCN under enzalutamide. In c-MYC-expressing cells approximately 80 significantly downregulated genes were identified, many of which had previously been associated with therapeutic resistance. Interestingly, a substantial proportion of these factors were also significantly enriched in RNA processing and metabolic pathways. Both c-MYC and MYCN bind directly to DNA as well as RNA, and recent studies have revealed that MYC proteins play distinct mechanistic roles in transcriptional regulation and RNA metabolism. The newly described RNA-related functions of MYC highlight the importance of RNA regulatory mechanisms as key drivers of MYC-dependent oncogenesis in prostate cancer. Approximately 20 genes were significantly downregulated in MYCN-expressing cells, most of which are involved in RNA splicing. This is an intriguing observation given that MYCN is a well-characterized transcription factor that orchestrates transcriptional reprogramming. The data suggest that MYCN can influence oncogenic processes by modulating RNA splicing mechanisms, revealing an additional level of regulatory complexity in tNEPC. Ongoing validation and integrative analyses, including bulk mRNA-sequencing of patient data, aim to define the roles of these genes, delineate pathways, and identify novel therapeutic targets to overcome MYC-mediated and AR-","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":"146006189","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}
Pub Date : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-a008
Ruhollah Moussavi-Baygi, Matthew Ryan, Woogwang Sim, Samuel Hoelscher, Valbona Luga, Arun Chandrakumar, Lore Hoes, Junghwa Cha, Young Sun Lee, Katelyn Herm, Ben Doron, Danika Bakke, C.K. Cornelia Ding, Bradley Stohr, Peng Jin, Tejasveeta Nadkarni, Xiangyi Fang, Melita Haryono, An Nguyen, Wouter Karthaus, Charles Sawyers, Felix Feng, Hani Goodarzi, Rohit Bose
Rising incidence of early-onset prostate and other solid tumors underscores the need for experimental systems that model how normal tissues traverse premalignant states, acquire mutations, and become therapy-responsive malignancies under authentic immune and stromal pressures. A major barrier has been the lack of tractable in vivo platforms that enable genome-wide discovery while preserving continuous tumor evolution without catastrophic chromosomal instability. To address this, the Bose Lab developed Stochastically Emergent Tumors (SETs), an organoid-derived in vivo evolution engine that redefines discovery for early-onset and understudied patient groups. In this system, mismatch-repair deficiency is induced in non-malignant human organoids, which are passaged to accumulate stochastic point mutations and transplanted into mice to permit malignancy to emerge under physiologic selection. SETs evolve primarily through high-resolution point mutations rather than broad copy-number changes, yielding bioinformatically tractable clonal dynamics ideally suited for whole-genome driver discovery and machine learning. Compared with conventional xenografts, SETs display greater intertumoral heterogeneity and reproducible recovery of sensitizing and resistance alleles under therapeutic pressure. As proof of principle in prostate cancer, endocrine therapy applied to SET pools recovered known determinants of androgen-pathway sensitivity and uncovered new drivers. Loss of ZFHX3, typically obscured within a multigene suppressor locus in bulk cohorts, promoted luminal histology and sensitized tumors to androgen-receptor inhibition in vivo, whereas KMT2D or CIC alterations mediated resistance. Consistent with model predictions, ZFHX3 loss in patients correlated with significantly improved survival, a finding comparable in magnitude to the most favorable molecular subtypes of advanced prostate cancer. SETs also quantify evolutionary thresholds: in a Pten-null background, approximately 900 coding mutations accumulated over 208 days were sufficient for malignant transformation in half of grafts. This defines a measurable axis linking mutation burden, genotype, and tumor incidence. Because SETs generate neoantigen-rich point-mutation landscapes, they can be extended to immunocompetent hosts to study tumor–immune coevolution, early T-cell surveillance, macrophage-mediated immune exclusion, and myeloid checkpoints that enable immune escape. In summary, SETs provide a scalable, evolution-aware platform that connects mutational dynamics to therapeutic vulnerability, enabling identification of lineage- and ancestry-associated drivers, immunopreventive targets, and biomarkers of early-onset prostate cancer. Citation Format: Ruhollah Moussavi-Baygi, Matthew Ryan, Woogwang Sim, Samuel Hoelscher, Valbona Luga, Arun Chandrakumar, Lore Hoes, Junghwa Cha, Young Sun Lee, Katelyn Herm, Ben Doron, Danika Bakke, C.K. Cornelia Ding, Bradley Stohr, Peng Jin, Tejasveeta Nadkarni, Xiangyi
早发性前列腺瘤和其他实体瘤的发病率不断上升，这强调了对实验系统的需求，这些实验系统可以模拟正常组织如何在真实的免疫和基质压力下穿越癌前状态、获得突变并成为治疗反应性恶性肿瘤。一个主要的障碍是缺乏可处理的体内平台，使全基因组的发现，同时保持连续的肿瘤进化没有灾难性的染色体不稳定性。为了解决这个问题，Bose实验室开发了随机发生肿瘤（SETs），这是一种源自类器官的体内进化引擎，重新定义了早发和未充分研究的患者群体的发现。在这个系统中，在非恶性的人类类器官中诱导错配修复缺陷，通过传代积累随机点突变并移植到小鼠体内，使恶性肿瘤在生理选择下出现。set的进化主要是通过高分辨率的点突变，而不是广泛的拷贝数变化，产生生物信息上可处理的克隆动力学，非常适合全基因组驱动发现和机器学习。与传统的异种移植物相比，set在治疗压力下表现出更大的肿瘤间异质性和可重复的致敏和抗性等位基因恢复。作为前列腺癌的原理证明，应用于SET池的内分泌治疗恢复了雄激素通路敏感性的已知决定因素，并发现了新的驱动因素。ZFHX3的缺失，通常隐藏在一个多基因抑制位点中，在体内促进了腔内组织学和使肿瘤对雄激素受体抑制敏感，而KMT2D或CIC的改变介导了耐药性。与模型预测一致，患者的ZFHX3缺失与生存率显著提高相关，这一发现与晚期前列腺癌最有利的分子亚型相当。set还量化了进化阈值：在pten缺失的背景下，在208天内积累的大约900个编码突变足以使一半的移植物发生恶性转化。这定义了一个可测量的轴，将突变负担、基因型和肿瘤发生率联系起来。由于set产生富含新抗原的点突变景观，它们可以扩展到免疫能力强的宿主，以研究肿瘤免疫协同进化、早期t细胞监视、巨噬细胞介导的免疫排斥和使免疫逃逸的骨髓检查点。总之，set提供了一个可扩展的、进化感知的平台，将突变动力学与治疗易感性联系起来，能够识别谱系和祖先相关的驱动因素、免疫预防靶点和早发性前列腺癌的生物标志物。引用格式：Ruhollah Moussavi-Baygi， Matthew Ryan, Woogwang Sim, Samuel Hoelscher, Valbona Luga, Arun Chandrakumar, Lore Hoes, junhwa Cha, Young Sun Lee, Katelyn Herm, Ben Doron, Danika Bakke， C.K. Cornelia Ding, Bradley Stohr, Peng Jin, Tejasveeta Nadkarni, Xiangyi Fang, Melita Haryono, An Nguyen, Wouter Karthaus, Charles Sawyers, Felix Feng, Hani Goodarzi, Rohit Bose。随机突发性肿瘤（set）重建前列腺进化揭示了体内治疗脆弱性[摘要]。摘自：美国癌症研究协会癌症研究特别会议论文集：前列腺癌研究和治疗的创新；2026年1月20日至22日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86（增刊）：no A008。
{"title":"Abstract A008: Reconstructing prostate evolution with Stochastically Emergent Tumors (SETs) reveals in vivo therapeutic vulnerabilities","authors":"Ruhollah Moussavi-Baygi, Matthew Ryan, Woogwang Sim, Samuel Hoelscher, Valbona Luga, Arun Chandrakumar, Lore Hoes, Junghwa Cha, Young Sun Lee, Katelyn Herm, Ben Doron, Danika Bakke, C.K. Cornelia Ding, Bradley Stohr, Peng Jin, Tejasveeta Nadkarni, Xiangyi Fang, Melita Haryono, An Nguyen, Wouter Karthaus, Charles Sawyers, Felix Feng, Hani Goodarzi, Rohit Bose","doi":"10.1158/1538-7445.prostateca26-a008","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-a008","url":null,"abstract":"Rising incidence of early-onset prostate and other solid tumors underscores the need for experimental systems that model how normal tissues traverse premalignant states, acquire mutations, and become therapy-responsive malignancies under authentic immune and stromal pressures. A major barrier has been the lack of tractable in vivo platforms that enable genome-wide discovery while preserving continuous tumor evolution without catastrophic chromosomal instability. To address this, the Bose Lab developed Stochastically Emergent Tumors (SETs), an organoid-derived in vivo evolution engine that redefines discovery for early-onset and understudied patient groups. In this system, mismatch-repair deficiency is induced in non-malignant human organoids, which are passaged to accumulate stochastic point mutations and transplanted into mice to permit malignancy to emerge under physiologic selection. SETs evolve primarily through high-resolution point mutations rather than broad copy-number changes, yielding bioinformatically tractable clonal dynamics ideally suited for whole-genome driver discovery and machine learning. Compared with conventional xenografts, SETs display greater intertumoral heterogeneity and reproducible recovery of sensitizing and resistance alleles under therapeutic pressure. As proof of principle in prostate cancer, endocrine therapy applied to SET pools recovered known determinants of androgen-pathway sensitivity and uncovered new drivers. Loss of ZFHX3, typically obscured within a multigene suppressor locus in bulk cohorts, promoted luminal histology and sensitized tumors to androgen-receptor inhibition in vivo, whereas KMT2D or CIC alterations mediated resistance. Consistent with model predictions, ZFHX3 loss in patients correlated with significantly improved survival, a finding comparable in magnitude to the most favorable molecular subtypes of advanced prostate cancer. SETs also quantify evolutionary thresholds: in a Pten-null background, approximately 900 coding mutations accumulated over 208 days were sufficient for malignant transformation in half of grafts. This defines a measurable axis linking mutation burden, genotype, and tumor incidence. Because SETs generate neoantigen-rich point-mutation landscapes, they can be extended to immunocompetent hosts to study tumor–immune coevolution, early T-cell surveillance, macrophage-mediated immune exclusion, and myeloid checkpoints that enable immune escape. In summary, SETs provide a scalable, evolution-aware platform that connects mutational dynamics to therapeutic vulnerability, enabling identification of lineage- and ancestry-associated drivers, immunopreventive targets, and biomarkers of early-onset prostate cancer. Citation Format: Ruhollah Moussavi-Baygi, Matthew Ryan, Woogwang Sim, Samuel Hoelscher, Valbona Luga, Arun Chandrakumar, Lore Hoes, Junghwa Cha, Young Sun Lee, Katelyn Herm, Ben Doron, Danika Bakke, C.K. Cornelia Ding, Bradley Stohr, Peng Jin, Tejasveeta Nadkarni, Xiangyi","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":"146006221","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}
Pub Date : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-b049
Niamh Murphy, Emma Allott, Declan McKenna, Suneil Jain, Ross Murphy
Background: Prostate cancer is among the most common causes of cancer-related mortality for males globally. A major challenge lies in distinguishing indolent from potentially fatal disease at the time of diagnosis. Hypertension is associated with an increased risk of developing prostate cancer. However, evidence suggests that antihypertensive medication usage could be associated with better outcomes for patients with prostate cancer. Despite this, the underlying tumour biology of hypertension in patients with prostate cancer has not been characterised. Materials and Methods: We analysed 466 patients with intermediate-to-high risk prostate cancer receiving radiotherapy and androgen deprivation therapy, of whom 248 patients had tumour gene expression profiling. High-risk prostate cancer was defined as Cambridge Prognostic Group (CPG) 4 or 5, or having a Gleason score ≥ 8. Multivariate survival analysis, including age and initial prostate specific antigen levels as covariates, was used to determine the relationship between hypertension status at diagnosis with prostate cancer, prostate cancer risk groups, and metastatic disease. Differential gene expression was performed for hypertension status at diagnosis with prostate cancer and metastatic disease. Immune and stromal cell estimation scores, and Hallmark gene sets, were inferred using patient tumour gene expression profiles. Results and Discussion: Hypertension status at diagnosis with prostate cancer was not associated with metastatic disease. When classifying by Gleason score risk, hypertension had significantly better outcomes for metastatic disease in high-risk patients (HR = 0.43, p-value = 0.009), but not in low- and intermediate-risk patients (HR = 1.86, p-value = 0.18; p-interaction = 0.022). However, when classifying by CPG risk, hypertension was not associated with metastatic disease in high-risk patients or low- and intermediate-risk patients. 142 genes were differentially expressed for hypertension status at diagnosis of prostate cancer (p-value < 0.01), of which 4 were also differentially expressed in relation to metastatic disease (p-value < 0.01). Immune and stromal cell type estimation scores and Hallmark gene sets were not differentially expressed for hypertension status at diagnosis of prostate cancer. Conclusion: Hypertension was protective of metastatic disease in patients diagnosed with high-risk prostate cancer, but not in patients diagnosed with low- and intermediate-risk prostate cancer. Our ongoing analysis will aim to validate these findings in separate independent prostate cancer cohorts and to assess whether the observed associations are influenced by antihypertensive medication use prior to diagnosis. Using hypertension as a surrogate for antihypertensive medication usage, our analysis could potentially suggest antihypertensive medication as repurposed, preventative therapeutics for high-risk prostate cancer. Citation Format: Niamh Murphy, Emma Allott, De
{"title":"Abstract B049: Hypertension is significantly associated with better outcomes in high-risk patients with prostate cancer","authors":"Niamh Murphy, Emma Allott, Declan McKenna, Suneil Jain, Ross Murphy","doi":"10.1158/1538-7445.prostateca26-b049","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b049","url":null,"abstract":"Background: Prostate cancer is among the most common causes of cancer-related mortality for males globally. A major challenge lies in distinguishing indolent from potentially fatal disease at the time of diagnosis. Hypertension is associated with an increased risk of developing prostate cancer. However, evidence suggests that antihypertensive medication usage could be associated with better outcomes for patients with prostate cancer. Despite this, the underlying tumour biology of hypertension in patients with prostate cancer has not been characterised. Materials and Methods: We analysed 466 patients with intermediate-to-high risk prostate cancer receiving radiotherapy and androgen deprivation therapy, of whom 248 patients had tumour gene expression profiling. High-risk prostate cancer was defined as Cambridge Prognostic Group (CPG) 4 or 5, or having a Gleason score ≥ 8. Multivariate survival analysis, including age and initial prostate specific antigen levels as covariates, was used to determine the relationship between hypertension status at diagnosis with prostate cancer, prostate cancer risk groups, and metastatic disease. Differential gene expression was performed for hypertension status at diagnosis with prostate cancer and metastatic disease. Immune and stromal cell estimation scores, and Hallmark gene sets, were inferred using patient tumour gene expression profiles. Results and Discussion: Hypertension status at diagnosis with prostate cancer was not associated with metastatic disease. When classifying by Gleason score risk, hypertension had significantly better outcomes for metastatic disease in high-risk patients (HR = 0.43, p-value = 0.009), but not in low- and intermediate-risk patients (HR = 1.86, p-value = 0.18; p-interaction = 0.022). However, when classifying by CPG risk, hypertension was not associated with metastatic disease in high-risk patients or low- and intermediate-risk patients. 142 genes were differentially expressed for hypertension status at diagnosis of prostate cancer (p-value &lt; 0.01), of which 4 were also differentially expressed in relation to metastatic disease (p-value &lt; 0.01). Immune and stromal cell type estimation scores and Hallmark gene sets were not differentially expressed for hypertension status at diagnosis of prostate cancer. Conclusion: Hypertension was protective of metastatic disease in patients diagnosed with high-risk prostate cancer, but not in patients diagnosed with low- and intermediate-risk prostate cancer. Our ongoing analysis will aim to validate these findings in separate independent prostate cancer cohorts and to assess whether the observed associations are influenced by antihypertensive medication use prior to diagnosis. Using hypertension as a surrogate for antihypertensive medication usage, our analysis could potentially suggest antihypertensive medication as repurposed, preventative therapeutics for high-risk prostate cancer. Citation Format: Niamh Murphy, Emma Allott, De","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"213 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006156","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}
Pub Date : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-b082
Fang Xie
Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer (PC), but clinically meaningful mechanisms of resistance remain to be established. We generated an in vivo model of docetaxel resistance using castration resistant patient-derived xenografts and found increased expression of genes that drive development of multiciliated cells, including FOXJ1 and its effector genes, many of which regulate ciliary microtubules (MTs). Mechanistically, FOXJ1 overexpression conferred docetaxel resistance in vitro and in vivo, which was associated with decreased docetaxel-mediated MT bundling. Overexpression of a MT-associated FOXJ1-regulated gene (TPPP3) had similar effects. Conversely, FOXJ1 knockdown impaired basal MT function, enhanced taxane binding to MTs, and increased docetaxel sensitivity. These results establish mechanistic causality between the FOXJ1 signaling axis, MT biology, and taxane resistance. Clinically, FOXJ1 gene amplification was increased in taxane-treated PC patients. Moreover, in the CHAARTED clinical trial of docetaxel combined with androgen deprivation for metastatic PC, higher baseline FOXJ1 was predictive of decreased survival in PC patients treated with docetaxel, further supporting clinical relevance. Together these findings identify a previously unrecognized clinically impactful mechanism of taxane resistance whose exploitation could stratify patients that will not benefit from taxane treatment. Citation Format: Fang Xie. FOXJ1 mediates taxane resistance through regulation of microtubule dynamics [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 B082.
{"title":"Abstract B082: FOXJ1 mediates taxane resistance through regulation of microtubule dynamics","authors":"Fang Xie","doi":"10.1158/1538-7445.prostateca26-b082","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b082","url":null,"abstract":"Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer (PC), but clinically meaningful mechanisms of resistance remain to be established. We generated an in vivo model of docetaxel resistance using castration resistant patient-derived xenografts and found increased expression of genes that drive development of multiciliated cells, including FOXJ1 and its effector genes, many of which regulate ciliary microtubules (MTs). Mechanistically, FOXJ1 overexpression conferred docetaxel resistance in vitro and in vivo, which was associated with decreased docetaxel-mediated MT bundling. Overexpression of a MT-associated FOXJ1-regulated gene (TPPP3) had similar effects. Conversely, FOXJ1 knockdown impaired basal MT function, enhanced taxane binding to MTs, and increased docetaxel sensitivity. These results establish mechanistic causality between the FOXJ1 signaling axis, MT biology, and taxane resistance. Clinically, FOXJ1 gene amplification was increased in taxane-treated PC patients. Moreover, in the CHAARTED clinical trial of docetaxel combined with androgen deprivation for metastatic PC, higher baseline FOXJ1 was predictive of decreased survival in PC patients treated with docetaxel, further supporting clinical relevance. Together these findings identify a previously unrecognized clinically impactful mechanism of taxane resistance whose exploitation could stratify patients that will not benefit from taxane treatment. Citation Format: Fang Xie. FOXJ1 mediates taxane resistance through regulation of microtubule dynamics [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 B082.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"45 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006196","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}
Pub Date : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-b024
Shu Ning, Zachary Schaaf, Masuda Sharifi, Pui-Kai Li, Allen Gao
Background Resistance to current therapies is a significant challenge in advanced prostate cancer. The bromodomain and extra-terminal (BET) subclass of proteins are known to contribute to cancer progression and resistance to standard therapies. To date, intervention strategies for targeting BET proteins on bromodomains using small-molecule inhibitors, specifically acetylated lysine mimics, have been developed to block the binding of BET protein bromodomains to acetylated lysine. Unfortunately, clinical trials have yielded disappointing results characterized by limited efficacy and significant dose-limiting toxicities. Methods: We use docking, surface plasmon resonance (SPR), and affinity precipitation assays to discover the sequence of amino acids for the critical binding moieties on extra-terminal (ET) of BET domain. High-throughput virtual screening is utilized to identify ET-BET binding inhibitors. SPR were used to evaluate the binding affinity and anti-tumor effects in enzalutamide-(MDVR) and darolutamide-resistant (DaroR) cells. Mechanism of action (MOA) of the selected compound BETi-10 was evaluated by transcriptomic sequencing, qRT-PCR, western blotting, and luciferase reporter assay. Alteration of chromatin accessibility by BETi-10 in MDVR cells was determined via ATAC sequencing. Ex vivo and in vivo anti-tumor effects of BETi-10 in LuCaP35CR PDX were evaluated. Results Based on the structure of ET-BET protein interface, ten compounds have been identified through computational screening to effectively inhibit the ET-domain binding. Biological screening on enzalutamide- and darolutamide-resistant cell lines revealed that BETi-10 as the most potent inhibitory compound. RNAseq analysis showed that the top downregulated pathways by BETi-10 include Myc and E2F pathways. ATAC-seq and ChIP-seq analysis has shown that BETi-10 decreases the genome-wide chromatin accessibility in MDVR cells. Ex vivo and in vivo study in LuCaP35CR PDX model demonstrated that BETi-10 effectively inhibits the growth of organoids and tumor, synergizes with enzalutamide and has better safety profile than current BET inhibitor. Conclusions In this study, we have developed BETi-10, a first-in-class small-molecule inhibitor targeting the ET domain of BET proteins. Our findings show that targeting BET/BRD4 by BETi-10 suppresses resistant tumor viability in vitro and in vivo, providing a novel therapeutic strategy for advanced prostate cancer patients. Citation Format: Shu Ning, Zachary Schaaf, Masuda Sharifi, Pui-Kai Li, Allen Gao. Novel therapeutics targeting BET-mediated oncogenesis in lethal 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 B024.
{"title":"Abstract B024: Novel therapeutics targeting BET-mediated oncogenesis in lethal prostate cancer","authors":"Shu Ning, Zachary Schaaf, Masuda Sharifi, Pui-Kai Li, Allen Gao","doi":"10.1158/1538-7445.prostateca26-b024","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b024","url":null,"abstract":"Background Resistance to current therapies is a significant challenge in advanced prostate cancer. The bromodomain and extra-terminal (BET) subclass of proteins are known to contribute to cancer progression and resistance to standard therapies. To date, intervention strategies for targeting BET proteins on bromodomains using small-molecule inhibitors, specifically acetylated lysine mimics, have been developed to block the binding of BET protein bromodomains to acetylated lysine. Unfortunately, clinical trials have yielded disappointing results characterized by limited efficacy and significant dose-limiting toxicities. Methods: We use docking, surface plasmon resonance (SPR), and affinity precipitation assays to discover the sequence of amino acids for the critical binding moieties on extra-terminal (ET) of BET domain. High-throughput virtual screening is utilized to identify ET-BET binding inhibitors. SPR were used to evaluate the binding affinity and anti-tumor effects in enzalutamide-(MDVR) and darolutamide-resistant (DaroR) cells. Mechanism of action (MOA) of the selected compound BETi-10 was evaluated by transcriptomic sequencing, qRT-PCR, western blotting, and luciferase reporter assay. Alteration of chromatin accessibility by BETi-10 in MDVR cells was determined via ATAC sequencing. Ex vivo and in vivo anti-tumor effects of BETi-10 in LuCaP35CR PDX were evaluated. Results Based on the structure of ET-BET protein interface, ten compounds have been identified through computational screening to effectively inhibit the ET-domain binding. Biological screening on enzalutamide- and darolutamide-resistant cell lines revealed that BETi-10 as the most potent inhibitory compound. RNAseq analysis showed that the top downregulated pathways by BETi-10 include Myc and E2F pathways. ATAC-seq and ChIP-seq analysis has shown that BETi-10 decreases the genome-wide chromatin accessibility in MDVR cells. Ex vivo and in vivo study in LuCaP35CR PDX model demonstrated that BETi-10 effectively inhibits the growth of organoids and tumor, synergizes with enzalutamide and has better safety profile than current BET inhibitor. Conclusions In this study, we have developed BETi-10, a first-in-class small-molecule inhibitor targeting the ET domain of BET proteins. Our findings show that targeting BET/BRD4 by BETi-10 suppresses resistant tumor viability in vitro and in vivo, providing a novel therapeutic strategy for advanced prostate cancer patients. Citation Format: Shu Ning, Zachary Schaaf, Masuda Sharifi, Pui-Kai Li, Allen Gao. Novel therapeutics targeting BET-mediated oncogenesis in lethal 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 B024.","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":"146006249","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}
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