Pub Date : 2026-01-22DOI: 10.1158/0008-5472.can-24-4388
Giselle Sek Suan Nah,Yuk Kien Chong,Fatin Nasha Sulaimi,Kian Leong Lee,See Wee Lim,Qing You Pang,Mengge Yu,Zhen Wei Neo,Jabed Iqbal,Kassoum Nacro,Jeffrey Hill,Alex Matter,Henry Yang,Beng Ti Ang,Carol Tang,S Tiong Ong
Glioblastoma (GBM) is the deadliest primary brain tumor in adults, with a median survival of only 15 months and fewer than 10% of patients surviving beyond 5 years. Despite aggressive multimodal therapies, including surgical resection, radiation, and temozolomide (TMZ) chemotherapy, recurrence is almost inevitable. The MNK-eIF4E axis plays a significant role in cancer cell survival, and MNK1 and MNK2 are upregulated in gliomas. In this study, we discovered that elevated MNK1/2 expression correlates with poor prognosis and aggressive GBM phenotypes. Development of ETC-501, a selective brain-penetrant MNK kinase inhibitor, enabled modulation of key oncogenic pathways, including MYC signaling, DNA replication, cell cycle regulation, and inflammation. ETC-501 effectively inhibited GBM proliferation, impaired DNA damage repair, delayed cell cycle progression, and suppressed ribosome biogenesis. Notably, in combination with TMZ, ETC-501 not only enhanced senescence but also attenuated the senescence-associated secretory phenotype in GBM cells. The augmented senescence increased the vulnerability of GBM cells to the senolytic agent navitoclax, facilitating targeted elimination of residual senescent cells. These findings underscore the therapeutic potential of MNK inhibition in GBM, offering a promising strategy to advance GBM treatment paradigms and improve patient outcomes.
{"title":"ETC-501 is a Brain Penetrant MNK Kinase Inhibitor that Potentiates TMZ-Induced Senescence and Sensitizes Glioblastoma Cells to Senolytic Therapy.","authors":"Giselle Sek Suan Nah,Yuk Kien Chong,Fatin Nasha Sulaimi,Kian Leong Lee,See Wee Lim,Qing You Pang,Mengge Yu,Zhen Wei Neo,Jabed Iqbal,Kassoum Nacro,Jeffrey Hill,Alex Matter,Henry Yang,Beng Ti Ang,Carol Tang,S Tiong Ong","doi":"10.1158/0008-5472.can-24-4388","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-4388","url":null,"abstract":"Glioblastoma (GBM) is the deadliest primary brain tumor in adults, with a median survival of only 15 months and fewer than 10% of patients surviving beyond 5 years. Despite aggressive multimodal therapies, including surgical resection, radiation, and temozolomide (TMZ) chemotherapy, recurrence is almost inevitable. The MNK-eIF4E axis plays a significant role in cancer cell survival, and MNK1 and MNK2 are upregulated in gliomas. In this study, we discovered that elevated MNK1/2 expression correlates with poor prognosis and aggressive GBM phenotypes. Development of ETC-501, a selective brain-penetrant MNK kinase inhibitor, enabled modulation of key oncogenic pathways, including MYC signaling, DNA replication, cell cycle regulation, and inflammation. ETC-501 effectively inhibited GBM proliferation, impaired DNA damage repair, delayed cell cycle progression, and suppressed ribosome biogenesis. Notably, in combination with TMZ, ETC-501 not only enhanced senescence but also attenuated the senescence-associated secretory phenotype in GBM cells. The augmented senescence increased the vulnerability of GBM cells to the senolytic agent navitoclax, facilitating targeted elimination of residual senescent cells. These findings underscore the therapeutic potential of MNK inhibition in GBM, offering a promising strategy to advance GBM treatment paradigms and improve patient outcomes.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"35 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021722","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 : 2026-01-22DOI: 10.1158/0008-5472.CAN-24-3718
Mathew Bloomfield, Sydney M Huth, Daniella S McCausland, Ron Saad, Nazia Bano, Tran N Chau, Megan L Sweet, Nicolaas C Baudoin, Andrew McCaffrey, Kai Fluet, Eva M Schmelz, Uri Ben-David, Daniela Cimini
Whole genome doubling (WGD) is a frequent event in cancer evolution associated with chromosomal instability, metastasis, and poor prognosis. While the genomic consequences of WGD are well documented, non-genetic alterations that accompany WGD, such as changes to cell and nuclear size, may also play an important role in tetraploid (4N) cancer cell physiology. Here, we showed that cell and nuclear volume do not always scale with DNA content after WGD in cancer cells, resulting in 4N cells that differ in size. Small size was associated with enhanced cell fitness, mitotic fidelity, and tumorigenicity in 4N cancer cells and with poor patient survival in WGD-positive human cancers. Overall, these results suggest that cell and nuclear size may contribute to the tumorigenic potential of 4N cancer cells and could be an important prognostic marker in human tumors that undergo WGD.
{"title":"Cell and Nuclear Size are Associated with Chromosomal Instability and Tumorigenicity in Cancer Cells that Undergo Whole Genome Doubling.","authors":"Mathew Bloomfield, Sydney M Huth, Daniella S McCausland, Ron Saad, Nazia Bano, Tran N Chau, Megan L Sweet, Nicolaas C Baudoin, Andrew McCaffrey, Kai Fluet, Eva M Schmelz, Uri Ben-David, Daniela Cimini","doi":"10.1158/0008-5472.CAN-24-3718","DOIUrl":"10.1158/0008-5472.CAN-24-3718","url":null,"abstract":"<p><p>Whole genome doubling (WGD) is a frequent event in cancer evolution associated with chromosomal instability, metastasis, and poor prognosis. While the genomic consequences of WGD are well documented, non-genetic alterations that accompany WGD, such as changes to cell and nuclear size, may also play an important role in tetraploid (4N) cancer cell physiology. Here, we showed that cell and nuclear volume do not always scale with DNA content after WGD in cancer cells, resulting in 4N cells that differ in size. Small size was associated with enhanced cell fitness, mitotic fidelity, and tumorigenicity in 4N cancer cells and with poor patient survival in WGD-positive human cancers. Overall, these results suggest that cell and nuclear size may contribute to the tumorigenic potential of 4N cancer cells and could be an important prognostic marker in human tumors that undergo WGD.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028315","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}
While surgical resection is an effective intervention for early-stage hepatocellular carcinoma (HCC), postoperative recurrence remains a major clinical hurdle. Delving into the mechanisms underlying relapse and pinpointing potential therapeutic targets are imperative for improving HCC patient outcomes. By comparing the microbiota composition in patients with early-relapsing and non-relapsing HCC, we identified that Lactobacillus was enriched in relapse-free HCC patients, serving as an independent prognostic predictor of disease-free survival. Higher levels of intratumoral Lactobacillus johnsonii (L. johnsonii) correlated with an increased abundance of IFN-γ+PD-1+CD8+ T cells. Single-cell RNA sequencing, transcriptomic profiling of intratumoral CD45+ immune cells, and in vitro functional assays demonstrated that L. johnsonii preferentially enhanced this cytotoxic-exhausted T cell population. Nicotinic acid (NA) served as a key metabolite derived from L. johnsonii that expanded IFN-γ+PD-1+CD8+ T cells and upregulated effector (GZMB) and exhaustion (CTLA-4) markers. Mechanistically, both L. johnsonii and NA activated the NF-κB pathway, leading to increased IFN-γ production and upregulation of the transcription factor NR4A2, which in turn sustained PD-1 expression on CD8+ T cells. Combining L. johnsonii or NA with anti-PD-1 therapy synergistically inhibited tumor relapse and tumor growth in immunocompetent or humanized mice. Crucially, the anti-tumor efficacy of L. johnsonii was CD8+ T cell-dependent, as depletion abolished its activity. This work unveils a mechanism by which L. johnsonii and its metabolite NA enrich intratumoral IFN-γ+PD-1+CD8+ T cells, thereby reshaping the immune microenvironment to potentiate immunotherapy efficacy and suppress HCC recurrence.
{"title":"Intratumoral Lactobacillus johnsonii Enhances Sensitivity to PD-1 Blockade by Inducing CD8+ T Cell Expansion in Hepatocellular Carcinoma.","authors":"Qianshi Liu,Yiqiang Liu,Yue Zhou,Liang Liang,Yejian Wan,Ying Wang,Ting Huang,Ling Zhong,Zhaoshen Li,Tao Luo,Ming Zhao,Zhe-Xuan Li,Yu-Cong Li,Hai-Tao Lan,Hong Wu,Chuan Xu,Jie Chen","doi":"10.1158/0008-5472.can-25-0346","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0346","url":null,"abstract":"While surgical resection is an effective intervention for early-stage hepatocellular carcinoma (HCC), postoperative recurrence remains a major clinical hurdle. Delving into the mechanisms underlying relapse and pinpointing potential therapeutic targets are imperative for improving HCC patient outcomes. By comparing the microbiota composition in patients with early-relapsing and non-relapsing HCC, we identified that Lactobacillus was enriched in relapse-free HCC patients, serving as an independent prognostic predictor of disease-free survival. Higher levels of intratumoral Lactobacillus johnsonii (L. johnsonii) correlated with an increased abundance of IFN-γ+PD-1+CD8+ T cells. Single-cell RNA sequencing, transcriptomic profiling of intratumoral CD45+ immune cells, and in vitro functional assays demonstrated that L. johnsonii preferentially enhanced this cytotoxic-exhausted T cell population. Nicotinic acid (NA) served as a key metabolite derived from L. johnsonii that expanded IFN-γ+PD-1+CD8+ T cells and upregulated effector (GZMB) and exhaustion (CTLA-4) markers. Mechanistically, both L. johnsonii and NA activated the NF-κB pathway, leading to increased IFN-γ production and upregulation of the transcription factor NR4A2, which in turn sustained PD-1 expression on CD8+ T cells. Combining L. johnsonii or NA with anti-PD-1 therapy synergistically inhibited tumor relapse and tumor growth in immunocompetent or humanized mice. Crucially, the anti-tumor efficacy of L. johnsonii was CD8+ T cell-dependent, as depletion abolished its activity. This work unveils a mechanism by which L. johnsonii and its metabolite NA enrich intratumoral IFN-γ+PD-1+CD8+ T cells, thereby reshaping the immune microenvironment to potentiate immunotherapy efficacy and suppress HCC recurrence.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"86 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021619","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-b077
Gobi Thillainadesan, Yutaka Amemiya, Robert Nam, Arun Seth
Background: Prostate cancer presents significant clinical heterogeneity, making it difficult to predict tumor aggressiveness and guide therapy using tissue biopsies alone. Circulating microRNAs (miRNAs) in plasma represent promising, minimally invasive biomarkers that may reflect the molecular phenotype of the primary tumor. Methods: Using NanoString technology, we analyzed paired plasma and primary tumor samples from 24 patients with diverse prostate cancer subtypes to evaluate whether plasma miRNA expression patterns could stratify tumor phenotypes. Absolute global normalization and z-score transformation were applied to the miRNA sequencing data to minimize technical and biological variability. Dimensionality reduction using principal component analysis (PCA) was employed to uncover intrinsic structure and identify pattern-defining miRNAs. A unique pattern-based identity was generated for each primary and corresponding plasma sample, allowing comparison between their spatial distributions in reduced-dimension space. Results: Optimized PCA revealed distinct clustering of plasma miRNA profiles that mirrored the groupings observed for the corresponding primary tumors. These shared expression patterns enabled discrimination between tumor subtypes using circulating miRNAs alone, despite minimal overlap in specific miRNA identities between plasma and tissue. This indicates that the relative expression relationships among miRNAs, rather than the presence of identical miRNAs, carry information reflective of the underlying tumor phenotype. The approach leverages plasma miRNA expression as a surrogate signature for tumor characterization without requiring matched expression concordance between compartments. Conclusions: Our findings demonstrate that dimensionality-reduction analysis of plasma miRNA expression can stratify prostate cancer phenotypes and reflect tissue-level molecular diversity. This unsupervised, pattern-based framework provides a foundation for non-invasive tumor profiling and may enable future precision diagnostics using circulating miRNA signatures. Citation Format: Gobi Thillainadesan, Yutaka Amemiya, Robert Nam, Arun Seth. Unsupervised computational characterization of circulating microRNA networks defines plasma-based tumor phenotypes [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 B077.
{"title":"Abstract B077: Unsupervised computational characterization of circulating microRNA networks defines plasma-based tumor phenotypes","authors":"Gobi Thillainadesan, Yutaka Amemiya, Robert Nam, Arun Seth","doi":"10.1158/1538-7445.prostateca26-b077","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b077","url":null,"abstract":"Background: Prostate cancer presents significant clinical heterogeneity, making it difficult to predict tumor aggressiveness and guide therapy using tissue biopsies alone. Circulating microRNAs (miRNAs) in plasma represent promising, minimally invasive biomarkers that may reflect the molecular phenotype of the primary tumor. Methods: Using NanoString technology, we analyzed paired plasma and primary tumor samples from 24 patients with diverse prostate cancer subtypes to evaluate whether plasma miRNA expression patterns could stratify tumor phenotypes. Absolute global normalization and z-score transformation were applied to the miRNA sequencing data to minimize technical and biological variability. Dimensionality reduction using principal component analysis (PCA) was employed to uncover intrinsic structure and identify pattern-defining miRNAs. A unique pattern-based identity was generated for each primary and corresponding plasma sample, allowing comparison between their spatial distributions in reduced-dimension space. Results: Optimized PCA revealed distinct clustering of plasma miRNA profiles that mirrored the groupings observed for the corresponding primary tumors. These shared expression patterns enabled discrimination between tumor subtypes using circulating miRNAs alone, despite minimal overlap in specific miRNA identities between plasma and tissue. This indicates that the relative expression relationships among miRNAs, rather than the presence of identical miRNAs, carry information reflective of the underlying tumor phenotype. The approach leverages plasma miRNA expression as a surrogate signature for tumor characterization without requiring matched expression concordance between compartments. Conclusions: Our findings demonstrate that dimensionality-reduction analysis of plasma miRNA expression can stratify prostate cancer phenotypes and reflect tissue-level molecular diversity. This unsupervised, pattern-based framework provides a foundation for non-invasive tumor profiling and may enable future precision diagnostics using circulating miRNA signatures. Citation Format: Gobi Thillainadesan, Yutaka Amemiya, Robert Nam, Arun Seth. Unsupervised computational characterization of circulating microRNA networks defines plasma-based tumor phenotypes [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 B077.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"52 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005961","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-b007
Agata Carreira, Marianna Ciuffreda, Nathakan Thongon, Elena Cerri, Sharon Eddie, Rebecca Steele, Charles Haughey, Beatrice Ghezzi, Irene Fiorilla, Valentina Audrito, Andrea Lunardi, Toma Tebaldi, Wouter Karthaus, Alessandro Provenzani, Ian Mills
Cellular plasticity enables cancer cells to acquire new biological properties and become resistant to therapy. Late-stage castration resistant prostate cancer (CRPC) present heterogenous phenotypes in response to antiandrogen therapy, which likely arise from widely plastic adenocarcinomas, but invariably renders hormonal therapy ineffective. As a consequence, CRPCs lacks effective treatment options. Although immunotherapy has shown promising results in several cancers, CRPC is largely refractory to immunotherapeutic interventions mainly due to its tumour-immune microenvironment (TIME) with low infiltration of activated anti-tumour immune cells. Understanding how cellular plasticity modulates the TIME in the context of CRPC could provide insights on how to activate anti-cancer immunity. Using immortalized human PC cell lines, we showed that the metabolic enzyme nicotinamide N-methyltransferase (NNMT), which catalyses the transfer of methyl groups from S-adenosylmethionine to nicotinamide, is upregulated in the CRPC subtypes presenting “stem cell-like features” (CRPC-SCL). As a consequence, CRPC-SCL are more sensitivity to small molecules targeting the nicotinamide-dependent enzyme nicotinamide phospho-ribosyl transferase (NAMPT). NNMT upregulation and sensitivity to NAMPT inhibition was also validated in murine prostate cancer cells isolated from prostate lobes of a Pten−/−/trp53−/− Pb-Cre4 mouse and grown in low mitogen and low hormone, stem cell-like conditions (DVL-SCM). DVL3-SCM cells generate more aggressive tumours in vivo, though the mechanistic basis of this aggressiveness is unclear. Transcriptomic analysis revealed that DVL3-SCM cells exhibit a pronounced immunological signature with enrichment of terms linked with the innate and adaptative systems, interferon and cytokine signalling and immunoregulatory interactions between lymphoid and non-lymphoid cells. Such terms may indicate a chronically inflamed, immunosuppressive tumour niche, with altered T cell activation, that favours tumour growth. Interestingly, we have demonstrated that NNMT can be secreted by cancer cells (extracellular NNMT – eNNMT) and activate TLR4-dependent NF-kB signalling in macrophages. eNNMT is secreted by immortalized human PC cells with SCL-phenotypes (PC3) and by DVL3-SCM cells, compared with their non stem cell-like counterparts (DVL3-PAR). The increased secretion of eNNMT by PC models with stem-cell like phenotypes and NNMT intracellular upregulation, suggests eNNMT as a potential novel immunomodulatory cytokine in the context of CRPC-SCL. Targeting intra and extracellular NNMT may provide a therapeutic strategy to treat CRPC patients with SCL phenotypes. Citation Format: Agata Carreira, Marianna Ciuffreda, Nathakan Thongon, Elena Cerri, Sharon Eddie, Rebecca Steele, Charles Haughey, Beatrice Ghezzi, Irene Fiorilla, Valentina Audrito, Andrea Lunardi, Toma Tebaldi, Wouter Karthaus, Alessandro Provenzani, Ian Mills. Unravel the role of extracellular NNMT (eNNMT
细胞的可塑性使癌细胞获得新的生物学特性，并对治疗产生抗药性。晚期去势抵抗性前列腺癌（CRPC）在抗雄激素治疗中表现出异质表型，这可能源于广泛的可塑性腺癌，但总是使激素治疗无效。因此，CRPCs缺乏有效的治疗选择。尽管免疫治疗在几种癌症中显示出有希望的结果，但CRPC对免疫治疗干预在很大程度上是难治性的，这主要是由于其肿瘤免疫微环境（TIME）具有低浸润的活化抗肿瘤免疫细胞。了解细胞可塑性如何在CRPC的背景下调节时间可以为如何激活抗癌免疫提供见解。利用永生化的人PC细胞系，我们发现代谢酶烟酰胺n -甲基转移酶（NNMT）在CRPC亚型中上调，表现出“干细胞样特征”（CRPC- scl）。NNMT催化甲基从s -腺苷蛋氨酸转移到烟酰胺。因此，CRPC-SCL对靶向烟酰胺依赖酶烟酰胺磷酸核糖基转移酶（NAMPT）的小分子更敏感。从Pten - / - /trp53 - / - Pb-Cre4小鼠前列腺叶中分离的小鼠前列腺癌细胞，并在低丝裂原和低激素、干细胞样条件（DVL-SCM）下生长，也证实了NNMT上调和对NAMPT抑制的敏感性。DVL3-SCM细胞在体内产生更具侵袭性的肿瘤，尽管这种侵袭性的机制基础尚不清楚。转录组学分析显示，DVL3-SCM细胞表现出明显的免疫特征，富集了与先天和适应性系统、干扰素和细胞因子信号传导以及淋巴细胞和非淋巴细胞之间的免疫调节相互作用相关的术语。这些术语可能表明慢性炎症、免疫抑制的肿瘤生态位，具有改变的T细胞激活，有利于肿瘤生长。有趣的是，我们已经证明NNMT可以由癌细胞分泌（细胞外NNMT - eNNMT）并激活巨噬细胞中tlr4依赖性NF-kB信号。与非干细胞样细胞（DVL3-PAR）相比，enmt由具有scl表型的永生化人PC细胞（PC3）和DVL3-SCM细胞分泌。具有干细胞样表型和细胞内NNMT上调的PC模型分泌的enmt增加，表明在CRPC-SCL背景下，enmt可能是一种新的免疫调节细胞因子。靶向细胞内和细胞外的NNMT可能为治疗伴有SCL表型的CRPC患者提供一种治疗策略。引文格式：Agata Carreira， Marianna Ciuffreda, nathan akan Thongon, Elena Cerri, Sharon Eddie, Rebecca Steele, Charles Haughey, Beatrice Ghezzi, Irene Fiorilla, Valentina Audrito, Andrea Lunardi, Toma Tebaldi, Wouter Karthaus, Alessandro Provenzani, Ian Mills。揭示细胞外NNMT （eNNMT）在前列腺癌（PC）肿瘤免疫微环境（TIME）调节中的作用[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）：no B007。
{"title":"Abstract B007: Unravel the role of extracellular NNMT (eNNMT) in the modulation of prostate cancer (PC) tumour immune microenvironment (TIME)","authors":"Agata Carreira, Marianna Ciuffreda, Nathakan Thongon, Elena Cerri, Sharon Eddie, Rebecca Steele, Charles Haughey, Beatrice Ghezzi, Irene Fiorilla, Valentina Audrito, Andrea Lunardi, Toma Tebaldi, Wouter Karthaus, Alessandro Provenzani, Ian Mills","doi":"10.1158/1538-7445.prostateca26-b007","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-b007","url":null,"abstract":"Cellular plasticity enables cancer cells to acquire new biological properties and become resistant to therapy. Late-stage castration resistant prostate cancer (CRPC) present heterogenous phenotypes in response to antiandrogen therapy, which likely arise from widely plastic adenocarcinomas, but invariably renders hormonal therapy ineffective. As a consequence, CRPCs lacks effective treatment options. Although immunotherapy has shown promising results in several cancers, CRPC is largely refractory to immunotherapeutic interventions mainly due to its tumour-immune microenvironment (TIME) with low infiltration of activated anti-tumour immune cells. Understanding how cellular plasticity modulates the TIME in the context of CRPC could provide insights on how to activate anti-cancer immunity. Using immortalized human PC cell lines, we showed that the metabolic enzyme nicotinamide N-methyltransferase (NNMT), which catalyses the transfer of methyl groups from S-adenosylmethionine to nicotinamide, is upregulated in the CRPC subtypes presenting “stem cell-like features” (CRPC-SCL). As a consequence, CRPC-SCL are more sensitivity to small molecules targeting the nicotinamide-dependent enzyme nicotinamide phospho-ribosyl transferase (NAMPT). NNMT upregulation and sensitivity to NAMPT inhibition was also validated in murine prostate cancer cells isolated from prostate lobes of a Pten−/−/trp53−/− Pb-Cre4 mouse and grown in low mitogen and low hormone, stem cell-like conditions (DVL-SCM). DVL3-SCM cells generate more aggressive tumours in vivo, though the mechanistic basis of this aggressiveness is unclear. Transcriptomic analysis revealed that DVL3-SCM cells exhibit a pronounced immunological signature with enrichment of terms linked with the innate and adaptative systems, interferon and cytokine signalling and immunoregulatory interactions between lymphoid and non-lymphoid cells. Such terms may indicate a chronically inflamed, immunosuppressive tumour niche, with altered T cell activation, that favours tumour growth. Interestingly, we have demonstrated that NNMT can be secreted by cancer cells (extracellular NNMT – eNNMT) and activate TLR4-dependent NF-kB signalling in macrophages. eNNMT is secreted by immortalized human PC cells with SCL-phenotypes (PC3) and by DVL3-SCM cells, compared with their non stem cell-like counterparts (DVL3-PAR). The increased secretion of eNNMT by PC models with stem-cell like phenotypes and NNMT intracellular upregulation, suggests eNNMT as a potential novel immunomodulatory cytokine in the context of CRPC-SCL. Targeting intra and extracellular NNMT may provide a therapeutic strategy to treat CRPC patients with SCL phenotypes. Citation Format: Agata Carreira, Marianna Ciuffreda, Nathakan Thongon, Elena Cerri, Sharon Eddie, Rebecca Steele, Charles Haughey, Beatrice Ghezzi, Irene Fiorilla, Valentina Audrito, Andrea Lunardi, Toma Tebaldi, Wouter Karthaus, Alessandro Provenzani, Ian Mills. Unravel the role of extracellular NNMT (eNNMT","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":"146005964","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-pr008
Melissa Lauren. Abel, Aanika Warner, Renee Donahue, Yo-ting Tsai, Jennifer Marte, Ruchi Patel, Lisa Cordes, Megan Hausler, Amy Hankin, Nikki Williams, Philip Arlen, William D. Figg, James Hodge, Jeffrey Schlom, James Gulley, Fatima Karzai, Ravi Madan
Background: Although immune checkpoint inhibitors have not demonstrated clinical efficacy in unselected prostate cancer patients, there is a rationale to explore other immunotherapy strategies, including those that can activate natural killer (NK) cells. PDS01ADC is a tumor-targeting IL-12 that recognizes DNA-histone epitopes exposed on necrotic regions of tumors Preliminary clinical data have demonstrated the ability to activate NK and associated cytokines in prostate cancer patients (pts). Furthermore, in a small cohort, PDS01ADC treatment was associated with PSA declines. (Meininger, ASCO GU 2022) Preclinical modeling suggested therapeutic synergy between PDS01ADC and docetaxel. (Franks, Cancer Immunol Immunother 2023) These data provided the rationale for clinical trial NCT04633252. Phase 1 data at 3 doses of PDS01ADC demonstrated preliminary evidence of immune synergy, regardless of dose level. Herein, we present preliminary data from all mCRPC pts enrolled on the phase 1 and 2 portions of NCT04633252. (Madan, Cytokines 2023) Methods: NCT04633252 is an ongoing Phase I/II study enrolling up to 24 pts with mCRPC with progressive disease following prior therapy including androgen deprivation and an androgen pathway inhibitor. Participants in the phase 2 portion are treated with standard-of-care docetaxel (75 mg/m2 every 3 weeks) with the addition of PDS01ADC at a dose of 12 mcg/kg, given as a subcutaneous injection with each cycle of chemotherapy starting with cycle 2. The primary endpoint of the single arm, phase 2 study is to increase expected median progression free survival (PFS) on docetaxel from 4.5 months (mo) to 9 mo with the addition of PDS01ADC. Results: Thus far, 16 mCRPC pts have enrolled on both the phase 1 and 2 portions of the study with a median age of 68 (range: 45-82) and a median baseline PSA of 150 ng/dL (range:14.2-2251 ng/dL). All pts were previously treated with enzalutamide and/or abiraterone acetate, and 6/16 pts had previous docetaxel in the castrate-sensitive setting. The median PFS of these mCPRC pts is 9.6 mo (range: 4.3 to 32.2 mo). The median PSA response was a 40% decrease from pre-treatment baseline, with 13/16 pts experiencing a PSA decline and 6/16 pts with a >50% PSA decline. Treatment has been well-tolerated with expected adverse events consistent with phase 1 results, without new safety signals. The most common treatment-related adverse event, beyond known docetaxel side effects, is transient fever/flu-like symptoms following PDS01ADC. Discussion: The preliminary data from the NCT04633252 study suggest that the combination of docetaxel and PDS01ADC is tolerable with emerging evidence of activity in mCRPC. This trial continues to enroll at the National Cancer Institute (NCI), Bethesda, MD. Additional NCI studies are also exploring cytokine-based strategies that can impact the pleiotropic tumor immune microenvironment in prostate cancer. Citation Format: Melissa Lauren. Abel, Aanika Warner, Renee Donah
{"title":"Abstract PR008: Docetaxel and the Tumor Targeting Interleukin-12 (IL-12) PDS01ADC in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)","authors":"Melissa Lauren. Abel, Aanika Warner, Renee Donahue, Yo-ting Tsai, Jennifer Marte, Ruchi Patel, Lisa Cordes, Megan Hausler, Amy Hankin, Nikki Williams, Philip Arlen, William D. Figg, James Hodge, Jeffrey Schlom, James Gulley, Fatima Karzai, Ravi Madan","doi":"10.1158/1538-7445.prostateca26-pr008","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-pr008","url":null,"abstract":"Background: Although immune checkpoint inhibitors have not demonstrated clinical efficacy in unselected prostate cancer patients, there is a rationale to explore other immunotherapy strategies, including those that can activate natural killer (NK) cells. PDS01ADC is a tumor-targeting IL-12 that recognizes DNA-histone epitopes exposed on necrotic regions of tumors Preliminary clinical data have demonstrated the ability to activate NK and associated cytokines in prostate cancer patients (pts). Furthermore, in a small cohort, PDS01ADC treatment was associated with PSA declines. (Meininger, ASCO GU 2022) Preclinical modeling suggested therapeutic synergy between PDS01ADC and docetaxel. (Franks, Cancer Immunol Immunother 2023) These data provided the rationale for clinical trial NCT04633252. Phase 1 data at 3 doses of PDS01ADC demonstrated preliminary evidence of immune synergy, regardless of dose level. Herein, we present preliminary data from all mCRPC pts enrolled on the phase 1 and 2 portions of NCT04633252. (Madan, Cytokines 2023) Methods: NCT04633252 is an ongoing Phase I/II study enrolling up to 24 pts with mCRPC with progressive disease following prior therapy including androgen deprivation and an androgen pathway inhibitor. Participants in the phase 2 portion are treated with standard-of-care docetaxel (75 mg/m2 every 3 weeks) with the addition of PDS01ADC at a dose of 12 mcg/kg, given as a subcutaneous injection with each cycle of chemotherapy starting with cycle 2. The primary endpoint of the single arm, phase 2 study is to increase expected median progression free survival (PFS) on docetaxel from 4.5 months (mo) to 9 mo with the addition of PDS01ADC. Results: Thus far, 16 mCRPC pts have enrolled on both the phase 1 and 2 portions of the study with a median age of 68 (range: 45-82) and a median baseline PSA of 150 ng/dL (range:14.2-2251 ng/dL). All pts were previously treated with enzalutamide and/or abiraterone acetate, and 6/16 pts had previous docetaxel in the castrate-sensitive setting. The median PFS of these mCPRC pts is 9.6 mo (range: 4.3 to 32.2 mo). The median PSA response was a 40% decrease from pre-treatment baseline, with 13/16 pts experiencing a PSA decline and 6/16 pts with a &gt;50% PSA decline. Treatment has been well-tolerated with expected adverse events consistent with phase 1 results, without new safety signals. The most common treatment-related adverse event, beyond known docetaxel side effects, is transient fever/flu-like symptoms following PDS01ADC. Discussion: The preliminary data from the NCT04633252 study suggest that the combination of docetaxel and PDS01ADC is tolerable with emerging evidence of activity in mCRPC. This trial continues to enroll at the National Cancer Institute (NCI), Bethesda, MD. Additional NCI studies are also exploring cytokine-based strategies that can impact the pleiotropic tumor immune microenvironment in prostate cancer. Citation Format: Melissa Lauren. Abel, Aanika Warner, Renee Donah","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006222","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-ia005
Justin H. Hwang, Ali T. Arafa, Ella Boytim, Lauren Yu, Nicholas Zorko, Scott M. Dehm, Justin M. Drake, Emmanuel S. Antonarakis
Significance. Liquid biopsies from patients with metastatic castration resistant prostate cancer (mCRPC) offer a dynamic approach to assess temporal changes in the tumor genome, transcriptome, and proteome. In this study, we deployed a first-in-class extracellular vesicle (EV) proteomic assay (PMID: 39766159) using plasma from 100 prospectively enrolled mCRPC patients treated with 177Lu-PSMA-617 as well as 20 healthy male controls. We interrogated the baseline plasma samples to establish the mCRPC EV proteomic landscape, understand biological mechanisms of response/resistance, and inform patient outcomes based on progression free or overall survival (PFS, OS). Patients and Methods. Clinical variables included baseline PSA, molecular tumor volume (MTV), PSA50 response, metastatic sites, previous therapies, and survival over 12 months. The plasma EV proteome was determined through data-independent acquisition mass-spectrometry (DIA-MS) based on a spectral library we established from prior prostate cancer studies, which accounted for >6000 unique proteins. Statistical analyses (HR, OR) were performed using Cox proportional hazards and logistical regression models. Harrell’s bootstrap optimism method was used to derive optimism-corrected C-indices and AUC for outcomes. Results. In this mCRPC cohort, 91% of patients had bone metastasis, and 72% had received 3 or more systemic therapies. DIA-MS identified 5,137 proteins in EVs from mCRPC patients and 3,958 proteins in EVs from healthy controls. Notably, >1500 proteins were exclusively detected in the EVs from mCRPC patients and further evaluated. This included expected prostate cancer proteins such as PSMA, TMPRSS2, KLK2/3, and EPCAM. In addition, we found druggable therapeutic targets that we categorized as cell-surface proteins (HER2, Trop-2, STEAP1), kinases (PIK3CA, CDK6), or immune checkpoint targets (PD-L1, B7-H3, CD47). Surprisingly, HER2 expression exhibited robust positive correlations with PSMA, Trop-2, STEAP1 and B7-H3 in mCRPC patients. Given that suites of EV proteins exhibited prognostic value or were associated with treatment response, we focused on modeling key mCRPC targets. While baseline PSA exhibited modest prognostic discrimination with a C-index of 0.518 for PFS and 0.619 for OS, the addition of B7-H3 EVs improved the C-index to 0.625 for PFS and 0.694 for OS. Trop-2 similarly increased the C-index to 0.611 for PFS and 0.657 for OS. When considering PSA50 response, multivariate analysis indicated that B7-H3 (OR: 0.292, p=0.032) and Trop-2 (OR: 0.146, p=0.002) were associated with reduced PSA50 response. Baseline PSA demonstrated weak discrimination (AUC: 0.578) at predicting PSA50 response. the addition of either B7-H3 (AUC: 0.648) or Trop-2 (AUC:0.705) enhanced PSA50 response prediction. Conclusions. Altogether, plasma EV-proteomics can be deployed as a non-invasive assay that provides biological insights into advanced mCRPC patients. Our study supports the integrat
的意义。转移性去势抵抗性前列腺癌（mCRPC）患者的液体活检提供了一种动态的方法来评估肿瘤基因组、转录组和蛋白质组的时间变化。在这项研究中，我们采用了一种一流的细胞外囊泡（EV）蛋白质组学分析（PMID: 39766159），使用来自100名接受177Lu-PSMA-617治疗的mCRPC患者和20名健康男性对照的血浆。我们询问了基线血浆样本，以建立mCRPC EV蛋白质组学格局，了解反应/耐药的生物学机制，并告知基于无进展或总生存期（PFS， OS）的患者结局。患者和方法。临床变量包括基线PSA、分子肿瘤体积（MTV）、PSA50反应、转移部位、既往治疗和超过12个月的生存率。血浆EV蛋白质组是通过数据独立采集质谱法（DIA-MS）测定的，该谱库基于我们从先前的前列腺癌研究中建立的谱库，其中占&；gt；6000种独特的蛋白质。采用Cox比例风险和logistic回归模型进行统计分析（HR， OR）。采用Harrell的自举乐观方法推导出乐观修正后的c指数和结果的AUC。结果。在这个mCRPC队列中，91%的患者发生骨转移，72%的患者接受了3种或更多的全身治疗。DIA-MS在mCRPC患者的EVs中鉴定出5137种蛋白质，在健康对照组的EVs中鉴定出3958种蛋白质。值得注意的是,和gt;在mCRPC患者的EVs中检测到1500种蛋白质，并进一步评估。这包括预期的前列腺癌蛋白，如PSMA、TMPRSS2、KLK2/3和EPCAM。此外，我们发现了可药物治疗的靶点，我们将其分类为细胞表面蛋白（HER2, Trop-2, STEAP1），激酶（PIK3CA, CDK6）或免疫检查点靶点（PD-L1, B7-H3, CD47）。令人惊讶的是，在mCRPC患者中，HER2表达与PSMA、Trop-2、STEAP1和B7-H3呈显著正相关。鉴于EV蛋白组表现出预后价值或与治疗反应相关，我们专注于模拟关键的mCRPC靶点。基线PSA表现出适度的预后区分，PFS的c指数为0.518，OS为0.619，而B7-H3 ev的加入将PFS的c指数提高到0.625，OS为0.694。Trop-2同样增加了PFS的c指数为0.611，OS为0.657。在考虑PSA50反应时，多因素分析表明B7-H3 （OR: 0.292, p=0.032）和Trop-2 （OR: 0.146, p=0.002）与PSA50反应降低相关。基线PSA在预测PSA50反应方面表现出弱判别（AUC: 0.578）。添加B7-H3 （AUC: 0.648）或Trop-2 （AUC:0.705）均可增强PSA50反应预测。结论。总之，血浆ev -蛋白质组学可以作为一种非侵入性检测，为晚期mCRPC患者提供生物学见解。我们的研究支持将我们的分析和模型整合到生物标志物驱动的mCRPC试验中，以改善患者分层。引文格式：Justin H. Hwang, Ali T. Arafa, Ella Boytim, Lauren Yu, Nicholas Zorko, Scott M. Dehm, Justin M. Drake, Emmanuel S. Antonarakis。定义177Lu-PSMA-617治疗的转移性去势抵抗前列腺癌患者的细胞外囊泡蛋白质组[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。
{"title":"Abstract IA005: Defining the Extracellular Vesicle Proteome of Metastatic Castration Resistant Prostate Cancer Patients treated with 177Lu-PSMA-617","authors":"Justin H. Hwang, Ali T. Arafa, Ella Boytim, Lauren Yu, Nicholas Zorko, Scott M. Dehm, Justin M. Drake, Emmanuel S. Antonarakis","doi":"10.1158/1538-7445.prostateca26-ia005","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-ia005","url":null,"abstract":"Significance. Liquid biopsies from patients with metastatic castration resistant prostate cancer (mCRPC) offer a dynamic approach to assess temporal changes in the tumor genome, transcriptome, and proteome. In this study, we deployed a first-in-class extracellular vesicle (EV) proteomic assay (PMID: 39766159) using plasma from 100 prospectively enrolled mCRPC patients treated with 177Lu-PSMA-617 as well as 20 healthy male controls. We interrogated the baseline plasma samples to establish the mCRPC EV proteomic landscape, understand biological mechanisms of response/resistance, and inform patient outcomes based on progression free or overall survival (PFS, OS). Patients and Methods. Clinical variables included baseline PSA, molecular tumor volume (MTV), PSA50 response, metastatic sites, previous therapies, and survival over 12 months. The plasma EV proteome was determined through data-independent acquisition mass-spectrometry (DIA-MS) based on a spectral library we established from prior prostate cancer studies, which accounted for &gt;6000 unique proteins. Statistical analyses (HR, OR) were performed using Cox proportional hazards and logistical regression models. Harrell’s bootstrap optimism method was used to derive optimism-corrected C-indices and AUC for outcomes. Results. In this mCRPC cohort, 91% of patients had bone metastasis, and 72% had received 3 or more systemic therapies. DIA-MS identified 5,137 proteins in EVs from mCRPC patients and 3,958 proteins in EVs from healthy controls. Notably, &gt;1500 proteins were exclusively detected in the EVs from mCRPC patients and further evaluated. This included expected prostate cancer proteins such as PSMA, TMPRSS2, KLK2/3, and EPCAM. In addition, we found druggable therapeutic targets that we categorized as cell-surface proteins (HER2, Trop-2, STEAP1), kinases (PIK3CA, CDK6), or immune checkpoint targets (PD-L1, B7-H3, CD47). Surprisingly, HER2 expression exhibited robust positive correlations with PSMA, Trop-2, STEAP1 and B7-H3 in mCRPC patients. Given that suites of EV proteins exhibited prognostic value or were associated with treatment response, we focused on modeling key mCRPC targets. While baseline PSA exhibited modest prognostic discrimination with a C-index of 0.518 for PFS and 0.619 for OS, the addition of B7-H3 EVs improved the C-index to 0.625 for PFS and 0.694 for OS. Trop-2 similarly increased the C-index to 0.611 for PFS and 0.657 for OS. When considering PSA50 response, multivariate analysis indicated that B7-H3 (OR: 0.292, p=0.032) and Trop-2 (OR: 0.146, p=0.002) were associated with reduced PSA50 response. Baseline PSA demonstrated weak discrimination (AUC: 0.578) at predicting PSA50 response. the addition of either B7-H3 (AUC: 0.648) or Trop-2 (AUC:0.705) enhanced PSA50 response prediction. Conclusions. Altogether, plasma EV-proteomics can be deployed as a non-invasive assay that provides biological insights into advanced mCRPC patients. Our study supports the integrat","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"53 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005962","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-pr026
Ziqi Zhu, Yoon-Mi Chung, Mohammad Alyamani, Yijing Dai, Kevin D. McCarty, Evan Roberts, Sunita Sinha, Jianneng Li, Xiuxiu Li, Emad M. Gad, Zhiqun Zhou, Jinyuan Shi, Robert A. Burgess, Tatiana Y. Hargrove, Galina I. Lepesheva, Frederick P. Guengerich, Richard J. Auchus, Nima Sharifi
The canonical biosynthesis of all androgens from cholesterol in humans and other vertebrates requires two cytochrome P450 enzymes. First, cytochrome P450 11A1 (CYP11A1) cleaves six carbons from the side chain of 27-carbon cholesterol to generate 21-carbon pregnanes. Second, in a two-step process, cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1) cleaves carbons 20 and 21 from pregnanes to make 19-carbon androgens, e.g., conversion from pregnenolone to dehydroepiandrosterone (DHEA). The identification of this pathway eventually led to the development of CYP17A1 pharmacologic inhibitors for the treatment of prostate cancer. However, CYP17A1 inhibition does not completely abolish androgen biosynthesis. We discovered a CYP17A1-independent pathway for androgen synthesis in prostate cancer cells, including LNCaP, C4-2, and LAPC4. These cells produce androgens even in charcoal-stripped serum (CSS) media, as confirmed by 13C-labeled cholesterol tracing followed by liquid chromatography-mass spectrometry (LC-MS) analysis. The de novo synthesis was entirely abrogated by the knockout of 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1). As 3βHSD1 is an essential enzyme to convert the 3β-OH and Δ5-steroid A/B ring steroids to the 3-keto structures of testosterone and 5α-dihydrotestosterone (DHT), this finding confirms that the alternative pathway converges on the canonical route before the synthesis of androstenedione. No CYP17A1 activity was detectable in C4-2 cells, yet androgen production persisted, strongly indicating a bypass mechanism. Specific CYP17A1 inhibitors, including TAK700 and ASN001, failed to suppress androgen synthesis in C4-2 cells, even at concentrations designed to eliminate any residual activity. Screening a panel of oxysterols identified 17α,20-dihydroxycholesterol (DHC) as a substrate that is converted to DHEA and subsequently to testosterone and dihydrotestosterone (DHT). The conversion was confirmed by deuterium-labeled DHC as a stable isotope tracer and observed in other human reproductive cell lines. We verified that androgen receptor activity was activated by androgens metabolized from DHC. Among 57 human cytochrome P450 enzymes tested, only cytochrome P450 51A1 (CYP51A1), the human ortholog of CYP51, cleaves the DHC to DHEA. Specific CYP17A1 inhibitors, including abiraterone, galeterone, TAK700, and ASN001, failed to block CYP51A1-mediated DHC-to-DHEA conversion. DHEA accumulated in abiraterone and galeterone treated samples because the inhibitors blocked 3βHSD activity. In contrast, the broad-spectrum cytochrome P450 inhibitor ketoconazole effectively inhibited the 17-20 carbon bond cleavage, highlighting CYP51A1's distinct pharmacological role. CYP51 orthologs from vertebrates possess this activity, while invertebrate counterparts do not, suggesting the activity may co-evolved with vertebrate steroidogenesis. Finally, human prostate samples can convert d2-DHC to d2-DHEA and subsequent androgens. The clinical importance of this
人类和其他脊椎动物从胆固醇中合成雄激素需要两种细胞色素P450酶。首先，细胞色素P450 11A1 （CYP11A1）从27个碳的胆固醇侧链上切割6个碳，生成21个碳的孕烷。其次，在两步过程中，细胞色素P450 17-羟化酶/17,20-裂解酶（CYP17A1）将碳20和碳21从孕酮中分离出来，生成19碳的雄激素，例如从孕烯醇酮转化为脱氢表雄酮（DHEA）。这一途径的发现最终导致了用于治疗前列腺癌的CYP17A1药物抑制剂的开发。然而，CYP17A1抑制并不能完全消除雄激素的生物合成。我们在前列腺癌细胞中发现了一个不依赖于cyp17a1的雄激素合成通路，包括LNCaP、C4-2和LAPC4。这些细胞即使在炭剥离血清（CSS）培养基中也能产生雄激素，13c标记的胆固醇追踪和液相色谱-质谱（LC-MS）分析证实了这一点。通过敲除3β-羟基类固醇脱氢酶1型（HSD3B1），完全取消了重新合成。由于3βHSD1是将3β-OH和Δ5-steroid A/B环类固醇转化为睾酮和5α-二氢睾酮（DHT）的3-酮结构的必需酶，这一发现证实了在雄烯二酮合成之前，替代途径向规范途径收敛。在C4-2细胞中没有检测到CYP17A1活性，但雄激素的产生持续存在，强烈表明旁路机制。特异性CYP17A1抑制剂，包括TAK700和ASN001，未能抑制C4-2细胞中的雄激素合成，即使在设计的浓度消除任何残留活性。筛选一组氧化甾醇确定了17α，20-二羟基胆固醇（DHC）作为底物，转化为脱氢表雄酮，随后转化为睾酮和二氢睾酮（DHT）。氘标记的DHC作为稳定的同位素示踪剂证实了这种转化，并在其他人类生殖细胞系中观察到。我们证实雄激素受体活性被DHC代谢的雄激素激活。在检测的57种人类细胞色素P450酶中，只有CYP51的人类同源细胞色素P450 51A1 （CYP51A1）能将DHC裂解为脱氢表雄酮。特异性CYP17A1抑制剂，包括阿比特龙、galeterone、TAK700和ASN001，不能阻断cyp51a1介导的dhc到dhea的转化。由于抑制剂阻断了3βHSD活性，脱氢表雄酮在阿比特龙和加莱酮处理的样品中积累。相比之下，广谱细胞色素P450抑制剂酮康唑有效抑制了17-20碳键的裂解，凸显了CYP51A1独特的药理作用。来自脊椎动物的CYP51同源基因具有这种活性，而来自无脊椎动物的CYP51同源基因则没有，这表明这种活性可能与脊椎动物的类固醇形成共同进化。最后，人类前列腺样本可以将d2-DHC转化为d2-DHEA和随后的雄激素。这一发现的临床重要性有待进一步研究。引文格式：朱子奇、钟永密、Mohammad Alyamani、戴懿静、Kevin D. McCarty、Evan Roberts、Sunita Sinha、李建能、李秀秀、Emad M. Gad、周志群、石金元、Robert A. Burgess、Tatiana Y. Hargrove、Galina I. Lepesheva、Frederick P. Guengerich、Richard J. Auchus、Nima Sharifi。从胆固醇到性类固醇生物合成的旁路通道绕过CYP17A1[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 PR026。
{"title":"Abstract PR026: A bypass gateway from cholesterol to sex steroid biosynthesis circumnavigates CYP17A1","authors":"Ziqi Zhu, Yoon-Mi Chung, Mohammad Alyamani, Yijing Dai, Kevin D. McCarty, Evan Roberts, Sunita Sinha, Jianneng Li, Xiuxiu Li, Emad M. Gad, Zhiqun Zhou, Jinyuan Shi, Robert A. Burgess, Tatiana Y. Hargrove, Galina I. Lepesheva, Frederick P. Guengerich, Richard J. Auchus, Nima Sharifi","doi":"10.1158/1538-7445.prostateca26-pr026","DOIUrl":"https://doi.org/10.1158/1538-7445.prostateca26-pr026","url":null,"abstract":"The canonical biosynthesis of all androgens from cholesterol in humans and other vertebrates requires two cytochrome P450 enzymes. First, cytochrome P450 11A1 (CYP11A1) cleaves six carbons from the side chain of 27-carbon cholesterol to generate 21-carbon pregnanes. Second, in a two-step process, cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1) cleaves carbons 20 and 21 from pregnanes to make 19-carbon androgens, e.g., conversion from pregnenolone to dehydroepiandrosterone (DHEA). The identification of this pathway eventually led to the development of CYP17A1 pharmacologic inhibitors for the treatment of prostate cancer. However, CYP17A1 inhibition does not completely abolish androgen biosynthesis. We discovered a CYP17A1-independent pathway for androgen synthesis in prostate cancer cells, including LNCaP, C4-2, and LAPC4. These cells produce androgens even in charcoal-stripped serum (CSS) media, as confirmed by 13C-labeled cholesterol tracing followed by liquid chromatography-mass spectrometry (LC-MS) analysis. The de novo synthesis was entirely abrogated by the knockout of 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1). As 3βHSD1 is an essential enzyme to convert the 3β-OH and Δ5-steroid A/B ring steroids to the 3-keto structures of testosterone and 5α-dihydrotestosterone (DHT), this finding confirms that the alternative pathway converges on the canonical route before the synthesis of androstenedione. No CYP17A1 activity was detectable in C4-2 cells, yet androgen production persisted, strongly indicating a bypass mechanism. Specific CYP17A1 inhibitors, including TAK700 and ASN001, failed to suppress androgen synthesis in C4-2 cells, even at concentrations designed to eliminate any residual activity. Screening a panel of oxysterols identified 17α,20-dihydroxycholesterol (DHC) as a substrate that is converted to DHEA and subsequently to testosterone and dihydrotestosterone (DHT). The conversion was confirmed by deuterium-labeled DHC as a stable isotope tracer and observed in other human reproductive cell lines. We verified that androgen receptor activity was activated by androgens metabolized from DHC. Among 57 human cytochrome P450 enzymes tested, only cytochrome P450 51A1 (CYP51A1), the human ortholog of CYP51, cleaves the DHC to DHEA. Specific CYP17A1 inhibitors, including abiraterone, galeterone, TAK700, and ASN001, failed to block CYP51A1-mediated DHC-to-DHEA conversion. DHEA accumulated in abiraterone and galeterone treated samples because the inhibitors blocked 3βHSD activity. In contrast, the broad-spectrum cytochrome P450 inhibitor ketoconazole effectively inhibited the 17-20 carbon bond cleavage, highlighting CYP51A1's distinct pharmacological role. CYP51 orthologs from vertebrates possess this activity, while invertebrate counterparts do not, suggesting the activity may co-evolved with vertebrate steroidogenesis. Finally, human prostate samples can convert d2-DHC to d2-DHEA and subsequent androgens. The clinical importance of this","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"276 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005963","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-b020
Llasera Mariana Mariana, Péant Benjamin, Mes-Masson Anne-Marie, Rodier Francis, Saad Fred Fred, Annab Fayrouz
Introduction: Prostate cancer is the most commonly diagnosed cancer and the third leading cause of cancer-related death among men in Canada. Patients with castration-resistant prostate cancer (CRPC) are treated with various agents, including Enzalutamide, a second-generation hormone therapy that improves overall survival. However, in the long term, all patients eventually develop resistance. This highlights the critical need to better understand the mechanisms of Enzalutamide resistance in mCRPC and to identify new therapeutic strategies to improve patient outcomes. IκB kinase-epsilon (IKKε), a member of the IKK protein family, is involved in the inflammatory response and the inflammation phenotype of rheumatoid arthritis. IKKε has been identified as an oncogene, and deregulation of its expression has been associated with prostate cancer progression. Preliminary experiments conducted in our laboratory have shown an increased expression level of IKKε in Enzalutamide-resistant cell lines. We previously demonstrated that IKKε inhibitors, such as Amlexanox, reduce the proliferation of CRPC cells. Hypothesis: We hypothesize that inhibiting IKKε using Amlexanox restores sensitivity to Enzalutamide in Enzalutamide-resistant prostate cancer cells. Our overarching goal is to characterize the role of IKKε in the development of Enzalutamide resistance and to evaluate the therapeutic potential of the Amlexanox-Enzalutamide combination for treating mCRPC patients. Methodology and results: We obtained Enzalutamide-resistant and -sensitive CR cell lines derived from LNCaP. Cells have been treated with an increased dose of Amlexanox and Enzalutamide for 7 days to calculate the IC50 of each drug for each cell line. Based on these IC50, we performed real-time imaging assays using different dose combinations to determine the additive or synergistic effect of Amlexanox and Enzalutamide cotreatment. In addition, we confirmed IKKe and AR inhibition using Amlexanox and Enzalutamide, by Western blot assays. We also looked for the expression of apoptosis and senescence markers to determine the behavior of each studied PC cell line in response to treatments. Finally, we started Bulk RNA barcoding and sequencing (BRB-seq) assays on all LNCaP-derived cell lines treated with Enzalutamide and Amlexanox, alone or in combination. Conclusion: We aim to develop a combination therapy that can restore sensitivity to Enzalutamide, improve patients' quality of life, and more effectively control disease progression Citation Format: Llasera Mariana Mariana, Péant Benjamin, Mes-Masson Anne-Marie, Rodier Francis, Saad Fred Fred, Annab Fayrouz. Role of IKKε in resistance to second-generation hormonal therapy in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl): nr B020.
简介：前列腺癌是最常见的癌症，也是加拿大男性癌症相关死亡的第三大原因。去势抵抗性前列腺癌（CRPC）患者接受多种药物治疗，包括Enzalutamide，一种提高总生存率的第二代激素疗法。然而，从长期来看，所有患者最终都会产生耐药性。这突出了更好地了解mCRPC中Enzalutamide耐药机制和确定新的治疗策略以改善患者预后的迫切需要。IκB激酶ε (IKKε)是IKK蛋白家族的一员，参与类风湿关节炎的炎症反应和炎症表型。IKKε已被确定为一种致癌基因，其表达的失调与前列腺癌的进展有关。我们实验室进行的初步实验显示，在enzalutamide耐药细胞系中IKKε的表达水平增加。我们之前已经证明IKKε抑制剂，如Amlexanox，可以减少CRPC细胞的增殖。假设：我们假设使用氨lexanox抑制IKKε可以恢复对恩杂鲁胺耐药的前列腺癌细胞对恩杂鲁胺的敏感性。我们的总体目标是表征IKKε在恩杂鲁胺耐药发展中的作用，并评估氨lexanox-恩杂鲁胺联合治疗mCRPC患者的治疗潜力。方法和结果：我们从LNCaP获得了对恩杂鲁胺耐药和敏感的CR细胞系。用增加剂量的氨lexanox和Enzalutamide处理细胞7天，计算每种药物对每个细胞系的IC50。基于这些IC50，我们使用不同的剂量组合进行实时成像分析，以确定氨lexanox和恩杂鲁胺共同治疗的附加或协同效应。此外，通过Western blot检测，我们证实Amlexanox和Enzalutamide对IKKe和AR有抑制作用。我们还研究了凋亡和衰老标志物的表达，以确定每个研究的PC细胞系对治疗的反应。最后，我们开始对恩杂鲁胺和氨lexanox单独或联合处理的所有lncap衍生细胞系进行Bulk RNA条形码和测序（BRB-seq）检测。结论：我们的目标是开发一种能够恢复对Enzalutamide敏感性，改善患者生活质量，更有效地控制疾病进展的联合治疗方法。引文来源：Llasera Mariana， p本杰明，Mes-Masson Anne-Marie, Rodier Francis, Saad Fred Fred, Annab Fayrouz。IKKε在前列腺癌第二代激素治疗耐药中的作用[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）：B020。
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Pub Date : 2026-01-20DOI: 10.1158/1538-7445.prostateca26-pr012
Sanjana Eyunni, Rahul Mannan, Yuping Zhang, Eleanor Young, Qiuyang Zhang, Jie Luo, Matthew Pang, Somnath Mahapatra, Jean Ching-Yi Tien, James George, Mustapha Jaber, Hamzah Hakkani, Sandra E. Carson, Abigail J. Todd, Noshad Hosseini, Mahnoor Gondal, Ryan J. Rebernick, Xuhong Cao, Fengyun Su, Rui Wang, Rohit Mehra, Jing Li, Marcin Cieslik, Arul M. Chinnaiyan, Abhijit Parolia
Androgen receptor (AR) signaling is critical for the survival and proliferation of prostate cancer (PCa) cells, thus making androgen deprivation therapy (ADT; e.g., castration) the mainstay for treatment. Notably, the oncogenic transcriptional functions of AR rely on a host of chromatin-binding regulatory proteins, which includes a pioneer transcription factor called FOXA1. FOXA1 de-compacts chromatin to enable DNA binding of AR and activation of target gene expression. Our lab found FOXA1 alterations to recur within three distinct structural classes in over 35% of metastatic castration-resistant PCa (mCRPC) cases in Caucasian White men. Subsequent studies reported that FOXA1 mutations are prevalent in over 40% of primary PCa in Chinese patients, thus positioning FOXA1 as a principal oncogene in this disease. Yet, the tumorigenic potential and pathobiology of FOXA1 alterations remain unexplored in vivo. Here, we have developed and characterized the first in-field transgenic mouse models that conditionally overexpress FOXA1 mutants in the prostate luminal epithelia. Our findings reveal that truncal FOXA1 class1 mutations (i.e., wing 2 alterations) in a Trp53-null background triggered high-grade adenocarcinoma mimicking human disease, characterized by abnormal induction of NSD2 expression, extensive AR reprogramming to chimeric AR-half neo-enhancers, and sensitivity to androgen deprivation therapies. In contrast, FOXA1 class 2 mutations (i.e., C-terminal truncations) that are acquired in human mCRPC do not drive prostate luminal transformation in mice. Instead, these mutations induce intra-luminal plasticity by reprogramming differentiated cells into a progenitor stem-like state within androgen-replete normal tissues—a phenomenon otherwise induced upon castration. Class 2 mutants lead to a 20-fold expansion of Ar+/Ck8+ luminal epithelia that gain expression of stemness markers such as Trop2, Ck4, and Psca. These stem cells are similar to the Club cells detected in the human prostate gland that have been implicated in driving resistance to ADT. Mechanistically, we found the cistromically-dominant Class 2 mutants to pioneer over 40,000 neo-enhancer elements that were bound by stemness-associated transcription factors, like KLF5 and AP-1, which together instruct an androgen-insensitive luminal progenitor cell fate. Consistently, we found that Class 2-mutant mouse prostates showed minimal atrophy upon castration, with immunohistological assessment revealing a higher density of Ki67+ luminal epithelial cells relative to both wild-type and Class 1-mutant tissues. Class 2-mutant organoids also showed greater subcutaneous grafting ability in limiting-dilution assays in mice. Collectively, our data establish FOXA1 as a multifaceted oncogene in AR-dependent prostate cancers, in which divergent evolution of FOXA1 mutational classes distinctly drives either cancer formation or therapy-resistant, intra-luminal plasticity during disease progression. These findin
雄激素受体（AR）信号对于前列腺癌（PCa）细胞的存活和增殖至关重要，因此雄激素剥夺疗法（ADT，如去势）成为治疗的主要手段。值得注意的是，AR的致癌转录功能依赖于一系列染色质结合调节蛋白，其中包括一种称为FOXA1的先锋转录因子。FOXA1分解染色质，使AR的DNA结合和靶基因表达激活。我们的实验室发现，在白人男性转移性去势抵抗性前列腺癌（mCRPC）病例中，超过35%的FOXA1改变在三个不同的结构类别中复发。随后的研究报道，FOXA1突变在中国原发性PCa患者中普遍存在超过40%，从而将FOXA1定位为该疾病的主要致癌基因。然而，FOXA1改变的致瘤潜力和病理生物学在体内仍未被探索。在这里，我们开发并鉴定了第一个在前列腺腔上皮中有条件过表达FOXA1突变体的转基因小鼠模型。我们的研究结果表明，在trp53缺失的背景下，FOXA1 class1的截尾突变（即2号翼的改变）引发了模拟人类疾病的高级别腺癌，其特征是NSD2表达的异常诱导，AR重编程为嵌合AR-一半新增强子，以及对雄激素剥夺治疗的敏感性。相比之下，在人mCRPC中获得的FOXA1 2类突变（即c端截断）在小鼠中不会驱动前列腺腔转化。相反，这些突变通过在充满雄激素的正常组织中将分化的细胞重编程为祖干细胞样状态，从而诱导腔内可塑性——这种现象在去势时也会引起。2类突变导致Ar+/Ck8+管腔上皮细胞扩增20倍，从而获得诸如Trop2、Ck4和Psca等干性标志物的表达。这些干细胞与在人类前列腺中检测到的俱乐部细胞相似，这些俱乐部细胞与驱动对ADT的抵抗有关。从机制上讲，我们发现胞质显性2类突变体开拓了超过40,000个新增强子元件，这些元件与干细胞相关的转录因子结合，如KLF5和AP-1，它们共同指导雄激素不敏感的腔内祖细胞命运。与此一致的是，我们发现2类突变小鼠前列腺在去势后出现了最小程度的萎缩，免疫组织学评估显示，相对于野生型和1类突变小鼠组织，Ki67+腔上皮细胞密度更高。在小鼠有限稀释试验中，2类突变类器官也显示出更强的皮下移植能力。总的来说，我们的数据确定FOXA1在ar依赖性前列腺癌中是一个多面癌基因，其中FOXA1突变类别的不同进化明显驱动癌症形成或疾病进展期间的治疗抵抗性腔内可塑性。这些发现也代表了foxa1驱动的小鼠前列腺癌的首次报道。引用格式：Sanjana Eyunni、Rahul Mannan、张玉萍、Eleanor Young、张秋阳、罗杰、Matthew Pang、Somnath Mahapatra、Jean Ching-Yi Tien、James George、Mustapha Jaber、Hamzah Hakkani、Sandra E. Carson、Abigail J. Todd、Noshad Hosseini、Mahnoor Gondal、Ryan J. Rebernick、曹旭宏、苏凤云、王锐、Rohit Mehra、Li Jing、Marcin Cieslik、Arul M. Chinnaiyan、Abhijit Parolia。不同的FOXA1突变驱动前列腺肿瘤发生和抗治疗细胞可塑性[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(2_supl): nr PR012。
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