Lung squamous cell carcinoma (LUSC) is a lethal malignancy with limited treatment options, driven by an immunosuppressive tumor microenvironment (TME) and a paucity of actionable targets. Pathogenic LINE-1 (pL1HS) retrotransposons promote LUSC progression by fostering immune evasion. Elucidation of the mechanistic link between retrotransposon activity and TME reprogramming could help identify strategies to stimulate anti-tumor immunity. Here, we conducted integrated multi-omics analyses, including bulk and single-cell RNA-sequencing combined with proteomics, that revealed hyperactivated cGAS-STING signaling and a myeloid-derived suppressor cell (MDSC)-rich TME in pL1HS+ LUSC. Mechanistically, LINE-1 open reading frame 1 protein (L1-ORF1p) underwent liquid-liquid phase separation (LLPS) via its intrinsically disordered region, forming cytosolic condensates that scaffolded pL1HS nucleic acid, HMGN2, and cGAS into a ternary complex. This complex sustained chronic non-canonical NF-κB signaling-dependent cGAS-STING activation, which in turn drove immune suppression via MDSCs recruitment and activation. The coiled-coil domain of L1-ORF1p stabilized these condensates by binding HMGN2, perpetuating this immunosuppressive cascade. Dual targeting of pL1HS and cGAS restored anti-tumor immunity and suppressed tumor growth in preclinical models. Together, this work reveals a therapeutically actionable LLPS-driven axis that can be targeted with a combinatorial strategy to overcome immune evasion in LUSC, thereby addressing a critical unmet clinical need.
{"title":"LINE-1 Retrotransposon Protein ORF1p Forms Condensates that Drive cGAS-Induced Immune Evasion in Lung Squamous Cell Carcinoma","authors":"Biyuan Xing, Jialing Liu, Yongjie Xie, Pengpeng Liu, Lianmin Zhang, Wenjing Tian, Wenwen Yu, Hailong Wang, Jing Wang, Zeguo Sun, Weijia Zhang, Rui Zhang, Jinpu Yu","doi":"10.1158/0008-5472.can-25-2611","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2611","url":null,"abstract":"Lung squamous cell carcinoma (LUSC) is a lethal malignancy with limited treatment options, driven by an immunosuppressive tumor microenvironment (TME) and a paucity of actionable targets. Pathogenic LINE-1 (pL1HS) retrotransposons promote LUSC progression by fostering immune evasion. Elucidation of the mechanistic link between retrotransposon activity and TME reprogramming could help identify strategies to stimulate anti-tumor immunity. Here, we conducted integrated multi-omics analyses, including bulk and single-cell RNA-sequencing combined with proteomics, that revealed hyperactivated cGAS-STING signaling and a myeloid-derived suppressor cell (MDSC)-rich TME in pL1HS+ LUSC. Mechanistically, LINE-1 open reading frame 1 protein (L1-ORF1p) underwent liquid-liquid phase separation (LLPS) via its intrinsically disordered region, forming cytosolic condensates that scaffolded pL1HS nucleic acid, HMGN2, and cGAS into a ternary complex. This complex sustained chronic non-canonical NF-κB signaling-dependent cGAS-STING activation, which in turn drove immune suppression via MDSCs recruitment and activation. The coiled-coil domain of L1-ORF1p stabilized these condensates by binding HMGN2, perpetuating this immunosuppressive cascade. Dual targeting of pL1HS and cGAS restored anti-tumor immunity and suppressed tumor growth in preclinical models. Together, this work reveals a therapeutically actionable LLPS-driven axis that can be targeted with a combinatorial strategy to overcome immune evasion in LUSC, thereby addressing a critical unmet clinical need.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"29 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968456","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 : 2026-01-14DOI: 10.1158/0008-5472.can-25-2928
Phillip Thienger, Irene Paassen, Xiaosai Yao, Philip D. Rubin, Marika Lehner, Nicholas Lillis, Andrej Benjak, Sagar R. Shah, Alden King-Yung. Leung, Simone de Brot, Alina Naveed, Bence Daniel, Minyi Shi, Julien Tremblay, Joanna Triscott, Giada Andrea Cassanmagnago, Marco Bolis, Lia Mela, Himisha Beltran, Yu Chen, Salvatore Piscuoglio, Haiyuan Yu, Charlotte K.Y. Ng, David A. Quigley, Robert L. Yauch, Mark A. Rubin
Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF-targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT signaling dependent AR-negative CRPC (CRPC-WNT). The CRPC-WNT subgroup represents 11% of around 400,000 cases of CRPC worldwide who die yearly of CRPC. SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 in CRPC-WNT. Functionally, TCF7L2 maintained proliferation via the MAPK signaling axis in this subtype of CRPC. Together, these data provide a mechanistic rationale for interventions that perturb DNA binding of the pro-proliferative transcription factor TCF7L2 and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.
{"title":"A Double-Negative Prostate Cancer Subtype is Vulnerable to SWI/SNF-Targeting Degrader Molecules","authors":"Phillip Thienger, Irene Paassen, Xiaosai Yao, Philip D. Rubin, Marika Lehner, Nicholas Lillis, Andrej Benjak, Sagar R. Shah, Alden King-Yung. Leung, Simone de Brot, Alina Naveed, Bence Daniel, Minyi Shi, Julien Tremblay, Joanna Triscott, Giada Andrea Cassanmagnago, Marco Bolis, Lia Mela, Himisha Beltran, Yu Chen, Salvatore Piscuoglio, Haiyuan Yu, Charlotte K.Y. Ng, David A. Quigley, Robert L. Yauch, Mark A. Rubin","doi":"10.1158/0008-5472.can-25-2928","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2928","url":null,"abstract":"Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF-targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT signaling dependent AR-negative CRPC (CRPC-WNT). The CRPC-WNT subgroup represents 11% of around 400,000 cases of CRPC worldwide who die yearly of CRPC. SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 in CRPC-WNT. Functionally, TCF7L2 maintained proliferation via the MAPK signaling axis in this subtype of CRPC. Together, these data provide a mechanistic rationale for interventions that perturb DNA binding of the pro-proliferative transcription factor TCF7L2 and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"24 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968457","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}
Acute myeloid leukemia (AML) is driven by fusion and/or mutant proteins that disrupt cellular differentiation and apoptosis. The targeted degradation of such oncoproteins as a therapy has been successfully achieved in acute promyelocytic leukemia (APL), where the PML-RARα fusion protein is eliminated by arsenic trioxide (ATO). In APL, PML-RARα is stabilized within the PML nuclear bodies; ATO directly binds to both PML and PML-RARα, disrupts this nuclear structure, and thereby induces protein degradation and apoptosis—a process influenced by intracellular glutathione levels. In contrast, many other leukemogenic fusion proteins depend on the HSP90/HDAC6 chaperone complex for stabilization. To investigate whether the therapeutic effect of ATO could be extended to non-APL AML, we evaluated its impact on other fusion proteins existing in AML cells. At a therapeutically relevant concentration of 1 μM, ATO selectively induced the degradation of FLT3-ITD and CBFβ-SMMHC, but not of AML1-ETO or BCR-ABL. Correspondingly, cells harboring FLT3-ITD or CBFβ-SMMHC showed inherent sensitivity to ATO-induced apoptosis, which was associated with lower basal glutathione levels. Mechanistically, we found that ATO promotes HDAC6 degradation, resulting in HSP90 acetylation, and in turn facilitates the degradation of both fusion proteins. These results uncover a novel targeted degradation pathway of ATO in non-APL AML and underscore its potential as a therapeutic strategy for specific AML subtypes based on fusion oncoprotein degradation. Citation Format: Jingyi Zhang, Jiqiang Qu, Yafei Kuang, Ziyi Zhang, Samuel Waxman, Yongkui Jing. Targeted degradation of leukemogenic fusion proteins in non-APL leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr A025.
{"title":"Abstract A025: Targeted degradation of leukemogenic fusion proteins in non-APL leukemia","authors":"Jingyi Zhang, Jiqiang Qu, Yafei Kuang, Ziyi Zhang, Samuel Waxman, Yongkui Jing","doi":"10.1158/1538-7445.fusionpositive26-a025","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-a025","url":null,"abstract":"Acute myeloid leukemia (AML) is driven by fusion and/or mutant proteins that disrupt cellular differentiation and apoptosis. The targeted degradation of such oncoproteins as a therapy has been successfully achieved in acute promyelocytic leukemia (APL), where the PML-RARα fusion protein is eliminated by arsenic trioxide (ATO). In APL, PML-RARα is stabilized within the PML nuclear bodies; ATO directly binds to both PML and PML-RARα, disrupts this nuclear structure, and thereby induces protein degradation and apoptosis—a process influenced by intracellular glutathione levels. In contrast, many other leukemogenic fusion proteins depend on the HSP90/HDAC6 chaperone complex for stabilization. To investigate whether the therapeutic effect of ATO could be extended to non-APL AML, we evaluated its impact on other fusion proteins existing in AML cells. At a therapeutically relevant concentration of 1 μM, ATO selectively induced the degradation of FLT3-ITD and CBFβ-SMMHC, but not of AML1-ETO or BCR-ABL. Correspondingly, cells harboring FLT3-ITD or CBFβ-SMMHC showed inherent sensitivity to ATO-induced apoptosis, which was associated with lower basal glutathione levels. Mechanistically, we found that ATO promotes HDAC6 degradation, resulting in HSP90 acetylation, and in turn facilitates the degradation of both fusion proteins. These results uncover a novel targeted degradation pathway of ATO in non-APL AML and underscore its potential as a therapeutic strategy for specific AML subtypes based on fusion oncoprotein degradation. Citation Format: Jingyi Zhang, Jiqiang Qu, Yafei Kuang, Ziyi Zhang, Samuel Waxman, Yongkui Jing. Targeted degradation of leukemogenic fusion proteins in non-APL leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr A025.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"52 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961644","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 : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-b005
David S. Libich, Erich J. Sohn, Kandarp A. Sojitra, Aiola Stoja, Courtney N. Johnson, Jeetain Mittal, Alex A J. Bishop
Fusion oncoproteins generated by chromosomal translocations are defining molecular drivers of several pediatric cancers, functioning in part by reprogramming gene expression and disrupting cellular differentiation. Ewing sarcoma, an aggressive cancer of bone and soft tissue, exemplifies this paradigm and is driven in the majority of cases by the oncogenic fusion protein EWS::FLI1, formed by joining the low-complexity domain (LCD) of the RNA-binding protein EWS to the DNA-binding domain (DBD) of the transcription factor FLI1. EWS::FLI1 alters transcriptional and RNA processing programs and assembles into aberrant biomolecular condensates, yet the molecular basis for these fusion-driven assemblies remains poorly understood. Here, we integrate NMR spectroscopy, mutagenesis, biophysical and cellular assays, microscopy, and all-atom molecular dynamics simulations to dissect how sequence features and domain interactions shape the condensate properties of EWS and EWS::FLI1. We find that the EWS LCD undergoes extensive self-association mediated by tyrosine-rich motifs that generate compact intramolecular conformations and robust multivalent networks driving phase separation. The RNA-binding domains of EWS engage the LCD through transient electrostatic and aromatic interactions, modulating condensate dynamics, whereas the FLI1 DBD of the fusion protein directly interacts with the EWS LCD via flexible “wings”. Incorporation of the FLI1 DBD markedly alters the material properties of condensates, producing emergent biophysical behaviors distinct from either parental protein. These altered condensate properties possibly contribute to the cellular dysregulation and toxicity associated with EWS::FLI1, in part through mis-localization and aberrant interactions with native EWS that disrupt normal nuclear organization and RNA processing. Together, these findings define a molecular framework in which weak, multivalent, and chemically specific interactions give rise to the emergent properties of the EWS::FLI1 fusion protein. By linking sequence-encoded features, interdomain crosstalk, and condensate material states, we propose a mechanistic description of how fusion with ETS-family DBDs reprograms the physical behavior of EWS assemblies. These emergent condensate properties provide a potential unifying description of how EWS::FLI1 perturbs transcriptional regulation, RNA metabolism, and nuclear organization in pediatric Ewing sarcoma. Citation Format: David S. Libich, Erich J. Sohn, Kandarp A. Sojitra, Aiola Stoja, Courtney N. Johnson, Jeetain Mittal, Alex A J. Bishop. Emergent condensate behaviors of the EWS::FLI1 fusion protein in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr B005.
染色体易位产生的融合癌蛋白定义了几种儿科癌症的分子驱动因素，其部分功能是通过基因表达重编程和破坏细胞分化。尤文氏肉瘤（Ewing sarcoma）是一种侵袭性骨和软组织的癌症，在大多数情况下是由致癌融合蛋白EWS::FLI1驱动的，EWS::FLI1通过将rna结合蛋白EWS的低复杂性结构域（LCD）与转录因子FLI1的dna结合结构域（DBD）结合而形成。EWS::FLI1改变转录和RNA加工程序，并组装成异常的生物分子凝聚体，但这些融合驱动组装的分子基础仍然知之甚少。在这里，我们整合了核磁共振光谱、诱变、生物物理和细胞分析、显微镜和全原子分子动力学模拟来剖析序列特征和结构域相互作用如何塑造EWS和EWS::FLI1的凝聚特性。我们发现EWS LCD经历了广泛的自结合，由富含酪氨酸的基序介导，产生紧凑的分子内构象和强大的多价网络驱动相分离。EWS的rna结合域通过瞬态静电和芳香相互作用与LCD结合，调节凝聚动力学，而融合蛋白的FLI1 DBD通过柔性“翅膀”直接与EWS LCD相互作用。FLI1 DBD的加入显著改变了凝聚物的物质特性，产生了不同于亲本蛋白的紧急生物物理行为。这些冷凝物特性的改变可能导致与EWS::FLI1相关的细胞失调和毒性，部分原因是EWS的错误定位和与天然EWS的异常相互作用破坏了正常的核组织和RNA加工。总之，这些发现定义了一个分子框架，在这个框架中，弱的、多价的和化学特异性的相互作用产生了EWS::FLI1融合蛋白的涌现特性。通过连接序列编码特征、域间串扰和凝聚材料状态，我们提出了与ets家族dbd融合如何重编程EWS组件物理行为的机制描述。这些涌现的凝聚物特性为EWS::FLI1如何干扰儿童尤文氏肉瘤的转录调控、RNA代谢和核组织提供了潜在的统一描述。引用格式：David S. Libich, Erich J. Sohn, Kandarp A. Sojitra, Aiola Stoja, Courtney N. Johnson, Jeetain Mittal, Alex A. Bishop。EWS::FLI1融合蛋白在Ewing肉瘤中的凝析行为[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr B005。
{"title":"Abstract B005: Emergent condensate behaviors of the EWS::FLI1 fusion protein in Ewing sarcoma","authors":"David S. Libich, Erich J. Sohn, Kandarp A. Sojitra, Aiola Stoja, Courtney N. Johnson, Jeetain Mittal, Alex A J. Bishop","doi":"10.1158/1538-7445.fusionpositive26-b005","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-b005","url":null,"abstract":"Fusion oncoproteins generated by chromosomal translocations are defining molecular drivers of several pediatric cancers, functioning in part by reprogramming gene expression and disrupting cellular differentiation. Ewing sarcoma, an aggressive cancer of bone and soft tissue, exemplifies this paradigm and is driven in the majority of cases by the oncogenic fusion protein EWS::FLI1, formed by joining the low-complexity domain (LCD) of the RNA-binding protein EWS to the DNA-binding domain (DBD) of the transcription factor FLI1. EWS::FLI1 alters transcriptional and RNA processing programs and assembles into aberrant biomolecular condensates, yet the molecular basis for these fusion-driven assemblies remains poorly understood. Here, we integrate NMR spectroscopy, mutagenesis, biophysical and cellular assays, microscopy, and all-atom molecular dynamics simulations to dissect how sequence features and domain interactions shape the condensate properties of EWS and EWS::FLI1. We find that the EWS LCD undergoes extensive self-association mediated by tyrosine-rich motifs that generate compact intramolecular conformations and robust multivalent networks driving phase separation. The RNA-binding domains of EWS engage the LCD through transient electrostatic and aromatic interactions, modulating condensate dynamics, whereas the FLI1 DBD of the fusion protein directly interacts with the EWS LCD via flexible “wings”. Incorporation of the FLI1 DBD markedly alters the material properties of condensates, producing emergent biophysical behaviors distinct from either parental protein. These altered condensate properties possibly contribute to the cellular dysregulation and toxicity associated with EWS::FLI1, in part through mis-localization and aberrant interactions with native EWS that disrupt normal nuclear organization and RNA processing. Together, these findings define a molecular framework in which weak, multivalent, and chemically specific interactions give rise to the emergent properties of the EWS::FLI1 fusion protein. By linking sequence-encoded features, interdomain crosstalk, and condensate material states, we propose a mechanistic description of how fusion with ETS-family DBDs reprograms the physical behavior of EWS assemblies. These emergent condensate properties provide a potential unifying description of how EWS::FLI1 perturbs transcriptional regulation, RNA metabolism, and nuclear organization in pediatric Ewing sarcoma. Citation Format: David S. Libich, Erich J. Sohn, Kandarp A. Sojitra, Aiola Stoja, Courtney N. Johnson, Jeetain Mittal, Alex A J. Bishop. Emergent condensate behaviors of the EWS::FLI1 fusion protein in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr B005.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"46 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961982","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 : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a020
Bradley T. Stevens, Jamaica F. Siwak, Yang Zhang, Shondra M. Pruett-Miller, Brian J. Abraham, Mark E. Hatley
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Alveolar RMS (ARMS), an aggressive subtype of RMS, is driven by either t(2;13)(q35;q14) or t(1;13)(p36;q14) resulting in the PAX3-FOXO1 (P3F) and PAX7-FOXO1 (P7F) fusion oncoproteins, respectively. Despite rigorous scientific advances and clinical trials, the survival rate for high-risk ARMS has remained at 20% over the last three decades. A deeper understanding of the basic biology driving P3F mediated tumorigenesis is needed to discover novel therapeutic targets. Current in vivo model systems fail to faithfully recapitulate the human disease in terms of timing and location and are complicated by the formation of other tumor types. A deeper understanding of the cell(s) of origin and mechanisms of P3F tumor initiation are essential to enhancing models and preclinical efforts. To explore alternative cells of origin and endogenous regulation of P3F during development, we generated iPSCs harboring the canonical t(2;13) P3F translocation that we term t(2;13)-iPSCs (tiPSCs). tiPSCs injected into immunocompromised mice formed teratomas with discrete regions of FP-RMS that express the PAX3::FOXO1 oncofusion protein. Furthermore, directed differentiation of tiPSCs into muscle cells resulted in P3F expression and an abrogation in normal developmental trajectory. These cells injected into immunocompromised mice resulted in tumors with ARMS characteristics. Utilizing tiPSCs to explore developmental arrest we employed organoid assays that directly model human somitogenesis. Wild-type iPSCs undergo normal anterior-posterior patterning and somite formation; however, tiPSCs form somite-like condensations but fail to undergo anterior-posterior patterning upon P3F expression. Our novel cellular model provides a unique platform to 1) uncover how P3F establishes and maintains ARMS cell state(s), 2) dissect the specific dependencies required to maintain the ARMS cell state(s), and 3) uncover how P3F is endogenously regulated during human development. Understanding the fundamental mechanism of P3F-driven tumorigenesis from PAX3::FOXO1 oncofusion gene regulation to cellular transformation provides greater resolution into the key disease determinants to generate faithful model systems to focus pre-clinical efforts. Citation Format: Bradley T. Stevens, Jamaica F. Siwak, Yang Zhang, Shondra M. Pruett-Miller, Brian J. Abraham, Mark E. Hatley. Insights into human alveolar rhabdomyosarcoma initiation using a human t(2;13) induced pluripotent stem cell model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr A020.
横纹肌肉瘤（RMS）是最常见的儿童软组织肉瘤。肺泡型RMS （ARMS）是一种侵袭性RMS亚型，由t(2;13)（q35;q14）或t(1;13)（p36;q14）驱动，分别产生PAX3-FOXO1 （P3F）和PAX7-FOXO1 （P7F）融合癌蛋白。尽管有严格的科学进步和临床试验，但在过去三十年中，高风险ARMS的存活率一直保持在20%。需要更深入地了解驱动P3F介导的肿瘤发生的基本生物学，以发现新的治疗靶点。目前的体内模型系统不能在时间和位置上忠实地概括人类疾病，并且由于其他肿瘤类型的形成而变得复杂。更深入地了解P3F肿瘤的起源细胞和机制对于增强模型和临床前工作至关重要。为了探索P3F在发育过程中的替代细胞来源和内源性调控，我们生成了具有典型t(2;13) P3F易位的iPSCs，我们将其称为t(2;13)-iPSCs （tiPSCs）。注射到免疫功能低下小鼠的tiPSCs形成畸胎瘤，其FP-RMS的离散区域表达PAX3::FOXO1混淆蛋白。此外，tiPSCs定向分化为肌肉细胞导致P3F的表达，并取消了正常的发育轨迹。将这些细胞注射到免疫功能低下的小鼠体内，产生具有ARMS特征的肿瘤。利用tiPSCs探索发育阻滞，我们采用类器官试验直接模拟人类体细胞发生。野生型iPSCs经历正常的前后模式和体形成；然而，在P3F表达后，tiPSCs形成了somite样凝聚，但没有经历前后模式。我们的新细胞模型提供了一个独特的平台，1)揭示P3F如何建立和维持ARMS细胞状态，2)解剖维持ARMS细胞状态所需的特定依赖性，以及3)揭示P3F在人类发育过程中如何内源性调节。了解p3f驱动肿瘤发生的基本机制，从PAX3::FOXO1混淆基因调控到细胞转化，可以更好地解决关键疾病决定因素，从而产生忠实的模型系统，集中临床前工作。引文格式：Bradley T. Stevens, Jamaica F. Siwak, Yang Zhang, Shondra M. pruette - miller, Brian J. Abraham, Mark E. Hatley。利用人t（2;13）诱导的多能干细胞模型研究人肺泡横纹肌肉瘤的发生[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_supl): no A020。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a005
Zoran Gatalica, Inga Rose, Semir Vranic
Introduction: A commercial biorepository of tumor samples with associated clinical data is crucial for discovering and validating biomarkers and advancing all stages of cancer research. Although oncogenic fusions are highly specific and attractive drug targets, the progress is limited by their diversity and low (1-4%) prevalence in solid tumors, outside prostate adenocarcinoma (>30% with a characteristic TMPRSS2::ERG fusion). Systematic, cost effective evaluation of banked tumor samples for the oncogenic fusions could accelerate such research efforts. Material and Methods: We examined formalin-fixed paraffin-embedded tumor samples from a commercial biorepository (Reference Medicine, Phoenix, AZ) using a workflow which included expert pathology review, whole slide scanning, construction of multi-tumor tissue microarrays (TMA) immunohistochemistry (IHC) and genomic profiling with commercially available next generation sequencing (NGS) panels. More than 500 tumors were reviewed by board-certified pathologists; selected cases were then cored for TMAs. Immunohistochemistry for ALK and ROS1 proteins' expression were performed on TMAs. Results: IHC for ALK and ROS1 identified two positive cases, one for ROS1 and one for ALK. Thirty eight tumors underwent NGS and both IHC-positive cases were confirmed to harbor gene fusions (EML4::ALK and EZR::ROS1, respectively). All other cases were fusion-negative, concordant with the IHC result. Conclusions: Properly characterized tissue samples are essential for image analysis, biomarker detection and genomic profiling. Rigorous pathologic review helps avoid archiving of poorly preserved samples. IHC screening of TMAs provides a cost-effective approach for identification of fusion events, particularly in non-small cell lung carcinomas, while preserving material for multiple downstream applications. Citation Format: Zoran Gatalica, Inga Rose, Semir Vranic. Detection of fusion oncogenes in routinely collected biorepository samples [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr A005.
导读：商业肿瘤样本生物库与相关临床数据对于发现和验证生物标志物以及推进癌症研究的各个阶段至关重要。虽然癌性融合是高度特异性和有吸引力的药物靶点，但其多样性和在实体瘤和前列腺外腺癌（>；30%具有特征性TMPRSS2::ERG融合）中的低患病率（1-4%）限制了进展。对肿瘤样本进行系统的、经济有效的评估，以寻找致瘤融合物，可以加快这方面的研究工作。材料和方法：我们检查了来自商业生物库（参考医学，凤凰城，AZ）的福尔马林固定石蜡包埋肿瘤样本，使用的工作流程包括专家病理学审查，全片扫描，多肿瘤组织微阵列（TMA）免疫组织化学（IHC）构建和商用下一代测序（NGS）面板的基因组分析。超过500个肿瘤由委员会认证的病理学家检查；然后对选定的病例进行tma分组。对TMAs进行ALK和ROS1蛋白表达的免疫组化检测。结果：ALK和ROS1免疫组化检测阳性2例，ROS1阳性1例，ALK阳性1例。38例肿瘤行NGS，两例ihc阳性病例均证实存在基因融合（分别为EML4::ALK和EZR::ROS1）。其他病例均为融合阴性，与免疫组化结果一致。结论：正确表征的组织样本对图像分析、生物标志物检测和基因组分析至关重要。严格的病理检查有助于避免存档保存不良的样本。IHC筛选tma为鉴定融合事件提供了一种经济有效的方法，特别是在非小细胞肺癌中，同时保留了多种下游应用的材料。引文格式：Zoran Gatalica， Inga Rose, Semir Vranic。常规生物库标本中融合癌基因的检测[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr A005。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-b020
Sarah Gawlak, Emily Isenhart, Joyce Ohm
Sarcomas constitute a large group of rare, heterogeneous cancers of mesenchymal lineage arising in the bone and soft tissues of children and young adults. Each sarcoma subtype is characterized by distinct clinical, histological, and genetic characteristics. The heterogeneity of these sarcoma subtypes is a contributing factor to poor survival outcomes observed in patients. Despite their diversity, many subtypes harbor a balanced chromosomal translocation fusing the Ewing Sarcoma RNA binding protein 1 (EWSR1) gene with a gene encoding a transcription factor (TF). Balanced translocations generate two distinct fusions: [1] a canonical fusion consisting of the N-terminal transactivation domain of EWSR1 and the C-terminal DNA-binding domain of a TF and [2] a reciprocal fusion harboring the N-terminus of the TF and C-terminal RNA-binding domain of EWSR1. Ewing sarcoma is one sarcoma subtype that harbors canonical EWSR1-FLI1 and reciprocal FLI1-EWSR1 fusions. The oncogenic roles of EWSR1-FLI1 are well-established in that the fusion protein promotes tumorigenesis in precursor cells through the rewiring of transcriptional programs and modulation of the epigenetic landscape. The role of FLI1-EWSR1 in Ewing sarcoma tumorigenesis, however, is unclear. Here, we begin to characterize the functions of FLI1-EWSR1. We developed lentiviral vectors carrying HA-tagged canonical and FLAG-tagged reciprocal fusions. To date, we have introduced these vectors into the fusion-negative fibrosarcoma cell line HT-1080 and Ewing sarcoma cell lines A673 and TC-32. RNA-seq analyses show that FLI1-EWSR1 expression in A673 leads to significant changes in Notch, Wnt, and Hedgehog signaling pathways, as well as in epithelial-mesenchymal transition and RNA-related processes. These findings suggest roles for FLI1-EWSR1 in extracellular matrix remodeling and potential increases in metastatic potential of cells expressing the reciprocal fusion. Ongoing studies aim to evaluate the effects of the reciprocal FLI1-EWSR1 on Ewing sarcoma tumorigenesis and the epigenome, with hopes of uncovering potentially targetable vulnerabilities, paving the road for the development of novel treatments in a patient population in desperate need of effective therapies. Citation Format: Sarah Gawlak, Emily Isenhart, Joyce Ohm. Establishing roles for the FLI1-EWSR1 reciprocal fusion protein in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr B020.
{"title":"Abstract B020: Establishing roles for the FLI1-EWSR1 reciprocal fusion protein in Ewing sarcoma","authors":"Sarah Gawlak, Emily Isenhart, Joyce Ohm","doi":"10.1158/1538-7445.fusionpositive26-b020","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-b020","url":null,"abstract":"Sarcomas constitute a large group of rare, heterogeneous cancers of mesenchymal lineage arising in the bone and soft tissues of children and young adults. Each sarcoma subtype is characterized by distinct clinical, histological, and genetic characteristics. The heterogeneity of these sarcoma subtypes is a contributing factor to poor survival outcomes observed in patients. Despite their diversity, many subtypes harbor a balanced chromosomal translocation fusing the Ewing Sarcoma RNA binding protein 1 (EWSR1) gene with a gene encoding a transcription factor (TF). Balanced translocations generate two distinct fusions: [1] a canonical fusion consisting of the N-terminal transactivation domain of EWSR1 and the C-terminal DNA-binding domain of a TF and [2] a reciprocal fusion harboring the N-terminus of the TF and C-terminal RNA-binding domain of EWSR1. Ewing sarcoma is one sarcoma subtype that harbors canonical EWSR1-FLI1 and reciprocal FLI1-EWSR1 fusions. The oncogenic roles of EWSR1-FLI1 are well-established in that the fusion protein promotes tumorigenesis in precursor cells through the rewiring of transcriptional programs and modulation of the epigenetic landscape. The role of FLI1-EWSR1 in Ewing sarcoma tumorigenesis, however, is unclear. Here, we begin to characterize the functions of FLI1-EWSR1. We developed lentiviral vectors carrying HA-tagged canonical and FLAG-tagged reciprocal fusions. To date, we have introduced these vectors into the fusion-negative fibrosarcoma cell line HT-1080 and Ewing sarcoma cell lines A673 and TC-32. RNA-seq analyses show that FLI1-EWSR1 expression in A673 leads to significant changes in Notch, Wnt, and Hedgehog signaling pathways, as well as in epithelial-mesenchymal transition and RNA-related processes. These findings suggest roles for FLI1-EWSR1 in extracellular matrix remodeling and potential increases in metastatic potential of cells expressing the reciprocal fusion. Ongoing studies aim to evaluate the effects of the reciprocal FLI1-EWSR1 on Ewing sarcoma tumorigenesis and the epigenome, with hopes of uncovering potentially targetable vulnerabilities, paving the road for the development of novel treatments in a patient population in desperate need of effective therapies. Citation Format: Sarah Gawlak, Emily Isenhart, Joyce Ohm. Establishing roles for the FLI1-EWSR1 reciprocal fusion protein in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr B020.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"49 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962016","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 : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-b027
Kelly M. Cagin, Keri L. Denson, Sierra R. Broad, Wara M. Naeem, Arsalan M. Khan, Michael M. Liptay, Christopher W. Seder, Jeffrey A. Borgia
Introduction: In Non-Small Cell Lung Cancer (NSCLC), low-fidelity transcription mechanisms such as ecDNA (extra-chromosomal DNA) are an increasingly relevant aspect of progression and prognosis, warranting comprehensive investigation into stability and prevalence of chimeric RNA transcripts. Here, we describe global distribution of fusion transcripts in encounter-matched primary tumor and lymph node metastases and their prognostic implications. Methods: RNAseq was performed on resected FFPE (encounter-matched primary and lymph nodes) from 121 stage IIB-IIIA (T1-4N1-2M0) NSCLC patients, in addition to 693 Stage IA1-IB cases (T1a-2aN0M0). STAR and STAR-Fusion were used to align data to the GRCh37 genome. Differential gene expression was based on specimen source (primary or lymph node). Aggregate analyses were also performed, including determination of a fusion burden metric, assessing the relationship between primary tumors, lymph node metastases, and recurrence. Deconvolution of Tumor Microenvironment was performed via Quantiseq. Results: Comparing primary tumors to paired lymph node metastases, 7,930 ensembl IDs were differentially-expressed at FDR < 0.001 (n=101 pairs). A total of 613 fusions (685 unique transcripts) were detected from paired primaries and lymph node metastases (n = 242). Frequency of specific gene fusions in primaries ranged from 0-0.963 (median 0.019), compared to 0-0.870 (median 0.0093) in LN metastases (p=1.87×10-4). We observed fusion of TULP4-RP11-732M18.3 as pervasive in NSCLC, occurring in 84-87% of primary tumors and lymph nodes, with a 91% retention rate. Conversely, fusions involving CCDC7 or SEPT14 were preferentially observed in metastases, where 82% of CCDC7 fusions and 75% of SEPT14 fusions were not observed in the primary tumor despite occurring at high frequency (66% and 18.5%, respectively) among LN metastases. Interestingly, median fusion burden (unique gene-gene fusions) for primaries was 14 compared to 11 (p=2.06×10-7) in LN metastases (median change -4). Among N0 cases that did not receive adjuvant therapy, median fusion burden in non-recurrent tumors was 15 (n=570), compared to 13 in those that recurred over 3-60 months (n=123; p = 0.04). Interestingly, there was no significant difference in fusion burden between recurrent cases and primary tumors with LN metastases (n = 108). For both recurrent cases and LN-paired primaries, the difference in fusion burden compared to LN metastases (n = 110) was significant (p=2.10×10-4 and 2.06×10-7). A subset of LN metastases (n=27) increased in fusion burden relative to the primary tumor; these primaries uniquely exhibited 33% decrease in regulatory T cell content (p=0.008), 20% decrease in M2 macrophage content (p = 0.01 with M1 macrophages static), and 40% decrease in B-cell content (p=0.05). Conclusions: Fusion transcripts are pervasive in RNAseq data, suggesting a broader and more variable landscape than accounted for by primary tumors alone. Concurrent ongo
在非小细胞肺癌（NSCLC）中，低保真度的转录机制，如ecDNA（染色体外DNA）在进展和预后中越来越重要，需要对嵌合RNA转录物的稳定性和患病率进行全面的研究。在这里，我们描述了融合转录物在遭遇匹配的原发肿瘤和淋巴结转移中的全球分布及其预后意义。方法：对121例IIB-IIIA期（T1-4N1-2M0） NSCLC患者切除的FFPE（遭遇匹配的原发和淋巴结）以及693例iib期（T1a-2aN0M0）患者进行RNAseq。使用STAR和STAR- fusion将数据与GRCh37基因组进行比对。差异基因表达基于标本来源（原发或淋巴结）。还进行了综合分析，包括确定融合负担指标，评估原发肿瘤，淋巴结转移和复发之间的关系。通过Quantiseq对肿瘤微环境进行反卷积。结果：将原发肿瘤与配对淋巴结转移瘤进行比较，在FDR &；lt；0.001 （n=101对）。从配对的原发瘤和淋巴结转移瘤（n = 242）中共检测到613个融合（685个独特转录本）。原发性肿瘤中特异性基因融合的频率为0-0.963（中位数为0.019），而LN转移瘤中特异性基因融合的频率为0-0.870（中位数为0.0093）（p=1.87×10-4）。我们观察到TULP4-RP11-732M18.3的融合在NSCLC中普遍存在，发生在84-87%的原发肿瘤和淋巴结中，保留率为91%。相反，涉及CCDC7或SEPT14的融合在转移中优先观察到，其中82%的CCDC7融合和75%的SEPT14融合在原发肿瘤中未观察到，尽管在LN转移中发生的频率很高（分别为66%和18.5%）。有趣的是，原发性肿瘤的中位融合负荷（独特基因融合）为14，而LN转移瘤的中位融合负荷为11 (p=2.06×10-7)（中位变化为-4）。在未接受辅助治疗的0例中，非复发肿瘤的中位融合负担为15例（n=570），而复发超过3-60个月的患者中位融合负担为13例（n=123; p = 0.04）。有趣的是，复发病例和合并LN转移的原发肿瘤在融合负荷方面没有显著差异（n = 108）。对于复发病例和LN配对原发病例，与LN转移病例（n = 110）相比，融合负荷的差异是显著的（p=2.10×10-4和2.06×10-7）。相对于原发肿瘤，一部分LN转移灶（n=27）的融合负担增加；这些原代小鼠的调节性T细胞含量降低33% (p=0.008)， M2巨噬细胞含量降低20% （p= 0.01， M1巨噬细胞静止），b细胞含量降低40% （p=0.05）。结论：融合转录物在RNAseq数据中普遍存在，这表明与单独的原发肿瘤相比，融合转录物具有更广泛和更可变的特征。同时正在进行的研究探讨了ecDNA在与NSCLC进展和转移相关的融合负荷变化中的作用。引文格式：Kelly M. Cagin, Keri L. Denson, Sierra R. Broad, Wara M. Naeem, Arsalan M. Khan, Michael M. Liptay, Christopher W. Seder, Jeffrey A. BorgiaNSCLC原发性淋巴结对融合转录物与复发的全球分析[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): no B027。
{"title":"Abstract B027: A global analysis of fusion transcripts and recurrence in NSCLC primary-lymph node pairs","authors":"Kelly M. Cagin, Keri L. Denson, Sierra R. Broad, Wara M. Naeem, Arsalan M. Khan, Michael M. Liptay, Christopher W. Seder, Jeffrey A. Borgia","doi":"10.1158/1538-7445.fusionpositive26-b027","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-b027","url":null,"abstract":"Introduction: In Non-Small Cell Lung Cancer (NSCLC), low-fidelity transcription mechanisms such as ecDNA (extra-chromosomal DNA) are an increasingly relevant aspect of progression and prognosis, warranting comprehensive investigation into stability and prevalence of chimeric RNA transcripts. Here, we describe global distribution of fusion transcripts in encounter-matched primary tumor and lymph node metastases and their prognostic implications. Methods: RNAseq was performed on resected FFPE (encounter-matched primary and lymph nodes) from 121 stage IIB-IIIA (T1-4N1-2M0) NSCLC patients, in addition to 693 Stage IA1-IB cases (T1a-2aN0M0). STAR and STAR-Fusion were used to align data to the GRCh37 genome. Differential gene expression was based on specimen source (primary or lymph node). Aggregate analyses were also performed, including determination of a fusion burden metric, assessing the relationship between primary tumors, lymph node metastases, and recurrence. Deconvolution of Tumor Microenvironment was performed via Quantiseq. Results: Comparing primary tumors to paired lymph node metastases, 7,930 ensembl IDs were differentially-expressed at FDR &lt; 0.001 (n=101 pairs). A total of 613 fusions (685 unique transcripts) were detected from paired primaries and lymph node metastases (n = 242). Frequency of specific gene fusions in primaries ranged from 0-0.963 (median 0.019), compared to 0-0.870 (median 0.0093) in LN metastases (p=1.87×10-4). We observed fusion of TULP4-RP11-732M18.3 as pervasive in NSCLC, occurring in 84-87% of primary tumors and lymph nodes, with a 91% retention rate. Conversely, fusions involving CCDC7 or SEPT14 were preferentially observed in metastases, where 82% of CCDC7 fusions and 75% of SEPT14 fusions were not observed in the primary tumor despite occurring at high frequency (66% and 18.5%, respectively) among LN metastases. Interestingly, median fusion burden (unique gene-gene fusions) for primaries was 14 compared to 11 (p=2.06×10-7) in LN metastases (median change -4). Among N0 cases that did not receive adjuvant therapy, median fusion burden in non-recurrent tumors was 15 (n=570), compared to 13 in those that recurred over 3-60 months (n=123; p = 0.04). Interestingly, there was no significant difference in fusion burden between recurrent cases and primary tumors with LN metastases (n = 108). For both recurrent cases and LN-paired primaries, the difference in fusion burden compared to LN metastases (n = 110) was significant (p=2.10×10-4 and 2.06×10-7). A subset of LN metastases (n=27) increased in fusion burden relative to the primary tumor; these primaries uniquely exhibited 33% decrease in regulatory T cell content (p=0.008), 20% decrease in M2 macrophage content (p = 0.01 with M1 macrophages static), and 40% decrease in B-cell content (p=0.05). Conclusions: Fusion transcripts are pervasive in RNAseq data, suggesting a broader and more variable landscape than accounted for by primary tumors alone. Concurrent ongo","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"12 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961888","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 : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-b025
Blake Holcomb, Ha Won Lee, Pete Hall, Shilpa Narina, Amanda Bland, Siri Ippagunta, Tuyu Zheng, Amir Arabzade, Nic Laboe, Patrick Connelly, Shondra Miler, Taosheng Chen, Stephen Mack
Treatments for childhood brain cancer, the leading cause of disease mortality in children, has not changed in the last three decades and constitutes surgery combined with cytotoxic chemo- and radio- therapy. RT is not always curative, and the mechanisms that promote resistance to radiation for many childhood cancers remains elusive. We found the ZFTA-RELA (ZR) fusion oncoprotein (FO), a potent driver of Ependymoma (EPN), drives a radio-resistant phenotype, but the mechanism underlying this observation is unknown. We hypothesized that radio-resistance mediated by ZR arises from direct ZR driven transcription. Analysis of numerous mouse and human datasets reveals ZR upregulates pathways associated with radio-resistance. We demonstrate the importance of ZR transcriptional programs on radiosensitivity by abrogating the DNA binding ability of ZR to sensitize EPN cells to RT. To identify ZR target genes that mediate radiosensitivity, we performed CRISPR-Cas12 dropout screens in both mouse and human EPN cell lines and identified >150 genes that sensitize EPN to RT, including canonical regulators of homologous recombination repair and the NFKβ pathway. In parallel, we performed high throughput drug screening to identify pharmacologic radiosensitizers in EPN and identified several combinations containing PARP1 inhibitors that are effective in vitro and tolerable in vivo. These data represent novel efforts to identify genetic and chemical radiosensitizers in EPN, and demonstrate how fusion oncoproteins like ZR hijack normal transcriptional programs to promote resistance to conventional therapy. Citation Format: Blake Holcomb, Ha Won Lee, Pete Hall, Shilpa Narina, Amanda Bland, Siri Ippagunta, Tuyu Zheng, Amir Arabzade, Nic Laboe, Patrick Connelly, Shondra Miler, Taosheng Chen, Stephen Mack. Elucidating the role of ZFTA-RELA in radiation resistance in ependymoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr B025.
儿童脑癌是儿童疾病死亡的主要原因，治疗方法在过去三十年中没有改变，包括手术与细胞毒性化疗和放射治疗相结合。放射治疗并不总是能治愈，促进许多儿童癌症对放射抵抗的机制仍然难以捉摸。我们发现zfa - rela （ZR）融合癌蛋白（FO）是室管膜瘤（EPN）的一个强有力的驱动因子，驱动放射抗性表型，但这一观察结果的机制尚不清楚。我们假设由ZR介导的无线电抗性来自于ZR直接驱动的转录。对大量小鼠和人类数据集的分析显示，ZR上调与无线电抗性相关的通路。我们通过取消ZR的DNA结合能力使EPN细胞对rt敏感，证明了ZR转录程序对放射敏感性的重要性。为了鉴定介导放射敏感性的ZR靶基因，我们在小鼠和人类EPN细胞系中进行了CRISPR-Cas12 dropout筛选，并鉴定了&；gt；150个使EPN对RT敏感的基因，包括同源重组修复和NFKβ途径的典型调节因子。同时，我们进行了高通量药物筛选，以确定EPN中的药理学放射增敏剂，并确定了几种含有PARP1抑制剂的体外有效和体内耐受的组合。这些数据代表了在EPN中识别遗传和化学放射增敏剂的新努力，并展示了融合癌蛋白如ZR如何劫持正常转录程序以促进对传统治疗的抗性。引文格式：Blake Holcomb， Ha Won Lee, Pete Hall, Shilpa Narina, Amanda Bland, Siri Ippagunta, Tuyu Zheng, Amir Arabzade, Nic Laboe, Patrick Connelly, Shondra miller, Taosheng Chen, Stephen Mack。阐明zfa - rela在室管膜瘤放射抵抗中的作用[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr B025。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-b008
Monica Pomaville, Hyojeong Hwang, Alexis Boulter, Tina Glisovic-Aplenc, Praneeth Bommisetti, Katelyn Oranges, Brandi Nelson, Jeffrey Schubert, Feng Xu, Jinhua Wu, Gregory M. Podsakoff, Margaret Tartaglione, Olivia Caradonio, Ellen Maple, Johannes Van Der Loo, Aashim Bhatia, Michael LaRiviere, Madison Hollawell, Mateusz Koptyra, Marilyn Li, Theodore W. Laetsch, Peter Madsen, Jessica B. Foster, Richard Aplenc, Fange Liu
Introduction Although driver oncogenic fusions offer an appealing therapeutic target, there is a critical shortage of targeted therapies against many fusions. Customizable direct target inhibition would address this gap. We developed an individualized antisense oligonucleotide (ASO) targeting the NFIA::CBFA2T3 fusion for a patient with relapsed acute myelogenous leukemia (AML). Diagnosed at 5 months of age with isolated central nervous system (CNS) AML, the patient underwent surgical resection, radiation therapy, and multiple rounds of systemic and intrathecal (IT)/intraventricular chemotherapy over 18 months. Ultimately, widespread leptomeningeal and extra-CNS AML progression occurred, requiring extraventricular drain (EVD) placement prior to ASO administration. We hypothesized the ASO would eliminate NFIA::CBFA2T3 fusion expression and reduce viability of fusion-bearing cells. Methods CLIA-certified whole transcriptome RNA sequencing was performed at relapse. A panel of five unique ASO constructs were designed against the NFIA::CBFA2T3 fusion breakpoint. Constructs were tested in 3 model cell lines and 1 patient-derived cell line. Neurotoxicity of the lead ASO was evaluated in NOD scid gamma (NSG) mice. A single patient IND application with a dose escalation schema received IRB and FDA approval. GMP-grade ASO (2 mg) was administered via IT injection at disease progression after informed consent was obtained. Adverse events were reported per CTCAE v5.0. Pharmacokinetic analysis on cerebrospinal fluid (CSF) and peripheral blood was performed using liquid chromatography/mass spectrometry. Results The lead ASO diminished NFIA::CBFA2T3 transcript expression by 83% in HEK293T cells expressing NFIA::CBFA2T3 and reduced cell number by 57% (p<0.05) in the patient-derived cell line. There was no decrease of endogenous NFIA mRNA or growth-inhibitory effect to non-fusion-bearing cells. Animal models showed no signs of toxicity. Within 4 months of pre-clinical testing initiation, ASO was administered during a period of rapid disease progression. Surrounding administration, the patient experienced elevated CSF output (maximum 386 mL/day), cerebral edema, and elevated CSF cytokines IL-6 (18-905 pg/mL) and IL-8 (199-4039 pg/mL). Adverse events grade 3 or above with possible or probable attribution to ASO included depressed level of consciousness, cerebral edema, hydrocephalus, and seizure. Maximal ASO CSF concentration was 648 ng/mL at 48 hours and was undetectable by day 5 post ASO. The ASO was not detected in peripheral blood. The patient experienced further AML progression and died 21 days post ASO. Conclusion An NFIA::CBFA2T3 ASO was engineered and demonstrated decreased transcript expression preclinically. The successful clinical delivery demonstrates proof-of-principle for personalized ASOs in pediatric oncologic care. Toxicity attribution is complicated by rapid disease progression. Ongoing work will more deeply phenotype this patient’s clinical
虽然驱动致癌融合提供了一个有吸引力的治疗靶点，但针对许多融合的靶向治疗严重缺乏。可定制的直接目标抑制将解决这一差距。我们为复发性急性髓性白血病（AML）患者开发了一种针对NFIA::CBFA2T3融合的个体化反义寡核苷酸（ASO）。患者在5个月大时被诊断为孤立性中枢神经系统（CNS） AML，在18个月的时间里接受了手术切除、放射治疗和多轮全身和鞘内(IT)/脑室化疗。最终，发生了广泛的脑膜外和中枢外AML进展，需要在ASO治疗前放置室外引流（EVD）。我们假设ASO会消除NFIA::CBFA2T3融合表达并降低融合细胞的活力。方法复发时进行clia认证的全转录组RNA测序。针对NFIA::CBFA2T3融合断点设计了5个独特的ASO结构。构建体在3个模型细胞系和1个患者来源细胞系中进行了测试。在NOD scid γ (NSG)小鼠中评价了ASO铅的神经毒性。剂量递增方案的单个患者IND申请获得了IRB和FDA的批准。在获得知情同意后，在疾病进展时通过IT注射给予gmp级ASO （2mg）。根据CTCAE v5.0报告了不良事件。采用液相色谱/质谱法对脑脊液和外周血进行药代动力学分析。结果在表达NFIA::CBFA2T3的HEK293T细胞中，导联ASO使NFIA::CBFA2T3转录物的表达降低了83%，使患者来源细胞系中细胞数量减少了57% （p<0.05）。内源性NFIA mRNA含量没有减少，对非融合细胞也没有抑制生长的作用。动物模型未显示出毒性迹象。在临床前试验开始的4个月内，在疾病快速进展期间给予ASO。在给药前后，患者出现脑脊液输出量升高（最大386 mL/天）、脑水肿和脑脊液细胞因子IL-6 （18-905 pg/mL）和IL-8 （199-4039 pg/mL）升高。可能或可能归因于ASO的3级或以上不良事件包括意识水平下降、脑水肿、脑积水和癫痫发作。48小时最大ASO CSF浓度为648 ng/mL， ASO后第5天检测不到。外周血未检出ASO。患者急性髓性白血病进一步恶化，ASO后21天死亡。结论NFIA::CBFA2T3 ASO在临床前表达降低。成功的临床交付证明了儿科肿瘤护理中个性化aso的原理。由于疾病进展迅速，毒性归属变得复杂。正在进行的工作将更深入地揭示该患者的临床过程，并开发ASO平台试验。引文格式：Monica Pomaville， Hyojeong Hwang, Alexis Boulter, Tina glisovicc - applenc, Praneeth Bommisetti, Katelyn Oranges, Brandi Nelson, Jeffrey Schubert, Feng Xu，金花Wu， Gregory M. Podsakoff, Margaret Tartaglione, Olivia Caradonio, Ellen Maple, Johannes Van Der Loo, Aashim Bhatia, Michael LaRiviere, Madison Hollawell, Mateusz Koptyra, Marilyn Li, Theodore W. Laetsch, Peter Madsen, Jessica B. Foster, Richard applenc, Fange Liu。个体化反义寡核苷酸治疗复发性NFIA::CBFA2T3急性髓性白血病1例[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr B008。
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