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。
{"title":"Abstract B008: Personalized antisense oligonucleotide treatment in a patient with relapsed NFIA :: CBFA2T3 acute myelogenous leukemia","authors":"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","doi":"10.1158/1538-7445.fusionpositive26-b008","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-b008","url":null,"abstract":"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&lt;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 ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"4 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962041","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-b030
Shaza M. Sayed Ahmed, Valentina Fogglizo, Zane Mamman, Courtney Lynn. Binaco, Sherifah Kemigisha Muzungu, Paola Roa, Amanda Kulick, Elisa de Stanchina, Matteo Repetto, Yonina R. Murciano-Goroff, Ezra Rosen, Sandra Misale, Eneda Toska, Robert Shoemaker, Alexander Drilon, Emiliano Cocco
Background: Sequential Tyrosine Kinase Inhibitor (TKI) therapy is a well-established strategy to overcome on-target resistance in ALK, ROS1, TRK, and RET kinase fusion-positive (+) tumors. However, this approach does not address off-target resistance that occurs when tumors acquire oncogenic alterations that activate bypass signaling pathways. A hallmark of off-target resistance is the sustained activation of ERK, a process driven by the hyperactivation of Receptor Tyrosine Kinases (RTKs) and/or acquired alterations within the downstream RAS-MAPK signaling pathway. Hypothesis: We hypothesize that inhibition of the MAPK/ERK pathway (using SHP2i or ERKi) can overcome off-target resistance by resensitizing tumors to their original TKIs. Methods: We generated multiple transduced and patient-derived kinase fusion+ cell lines and PDXs with off-target resistance to TKIs. These included ALK, TRK, and RET fusion+ models carrying MET or IGF1R amplification as well as ALK, TRK, and ROS1 fusion+ models carrying a KRAS mutation. The activity and safety of next-generation ERKi (ulixertinib, temuterkib, ERAS-007) or SHP2i (TNO-155, BBP-398, ERAS-601) as monotherapies or combined with TKIs was tested using viability assays, synergy tests, downstream signaling profiling, and in vivo tolerability and efficacy studies. Results: ERK and SHP2 inhibition was able to resensitize all models to the original TKIs in vitro. Among the SHP2is tested, TNO-155 and ERAS-601 were equally active, and both synergized (BLISS score >10) with TKIs (e.g., BLISS scores of 23.38 and 33.88 for TNO+TKI and 601+TKI, respectively in an ALK+, IGF1R amplified model). Among ERKis, only ERAS-007 resensitized these cell lines to TKIs, with BLISS scores up to 25.36. Notably, ERAS-007 also demonstrated potent single-agent activity at nanomolar concentrations in most models (e.g., 90.6% cell growth inhibition at 25 nM in an ALK+, KRAS mutant cell line; P=.000018). Mechanistically, dual inhibition using SHP2i or ERAS-007 in combination with TKIs completely suppressed phosphorylation of RSK1, a direct downstream substrate of ERK. To determine the optimal drugs’ doses for the in vivo testing, we performed a 12-day tolerability study in healthy mice and found that standard doses of TKIs combined with 30mg/kg QD of SHP2i or ERKi did not cause toxicity (no mouse weight loss or impaired liver/kidney function). Importantly, these combinatorial regimens were significantly more effective than each of the single agents in inhibiting tumor growth in xenografts derived from an ALK+, IGF1R amplified NSCLC cell line (P=.006584 for SHP2i+TKI and P=.013847 for ERKi+TKI) and in a PDX derived from a TRK+, KRAS G12D mutant tumor (P<.000001 for SHP2i+TKI and P=.003215 for ERKi+TKI). Conclusions: ERKi or SHP2i synergize with TKIs in kinase fusion+ tumors with off-target resistance to therapy. Defining the biochemical properties of clinically available ERKis and SHP2is is crucial to design effective and tol
背景：序贯酪氨酸激酶抑制剂（TKI）治疗是克服ALK、ROS1、TRK和RET激酶融合阳性（+）肿瘤的靶向耐药的一种成熟策略。然而，这种方法并不能解决肿瘤获得激活旁路信号通路的致癌改变时发生的脱靶耐药。脱靶耐药的一个标志是ERK的持续激活，这是一个由受体酪氨酸激酶（rtk）的过度激活和/或下游RAS-MAPK信号通路内获得性改变驱动的过程。假设：我们假设抑制MAPK/ERK通路（使用SHP2i或ERKi）可以通过使肿瘤对其原始TKIs重新敏感来克服脱靶耐药。方法：我们产生了多种转导的和患者来源的激酶融合+细胞系和对TKIs具有脱靶抗性的PDXs。其中包括携带MET或IGF1R扩增的ALK、TRK和RET融合+模型，以及携带KRAS突变的ALK、TRK和ROS1融合+模型。下一代ERKi （ulixertinib, temuterkib, ERAS-007）或SHP2i （TNO-155, BBP-398, ERAS-601）作为单一疗法或与TKIs联合使用的活性和安全性通过活力分析，协同试验，下游信号分析和体内耐受性和有效性研究进行了测试。结果：ERK和SHP2抑制能够使所有模型在体外对原始TKIs重新敏感。在测试的SHP2is中，TNO-155和era -601同样活跃，并且都与TKI协同（BLISS评分&；gt;10）（例如，在ALK+， IGF1R扩增模型中，TNO+TKI和601+TKI的BLISS评分分别为23.38和33.88）。在ERKis中，只有ERAS-007使这些细胞系对TKIs重敏，BLISS评分高达25.36。值得注意的是，在大多数模型中，ERAS-007在纳摩尔浓度下也显示出强大的单药活性（例如，在ALK+， KRAS突变细胞系中，25 nM下有90.6%的细胞生长抑制；P= 0.000018）。在机制上，使用SHP2i或ERAS-007联合TKIs的双重抑制完全抑制了RSK1的磷酸化，RSK1是ERK的直接下游底物。为了确定体内试验的最佳药物剂量，我们对健康小鼠进行了为期12天的耐受性研究，发现标准剂量的TKIs联合30mg/kg QD的SHP2i或ERKi不会引起毒性（小鼠体重减轻或肝肾功能受损）。重要的是，在抑制来自ALK+、IGF1R扩增的NSCLC细胞系的异种移植物（SHP2i+TKI的P= 0.006584， ERKi+TKI的P= 0.013847）和来自TRK+、KRAS G12D突变肿瘤的PDX （P<）的肿瘤生长方面，这些组合方案明显比每一种单一药物更有效。SHP2i+TKI为000001，ERKi+TKI为P=.003215)。结论：ERKi或SHP2i在激酶融合+脱靶耐药肿瘤中与TKIs协同作用。明确临床可用的ERKis和SHP2is的生化特性对于设计有效和耐受的联合疗法来治疗tki耐药激酶融合+肿瘤患者至关重要。引文格式：Shaza M. Sayed Ahmed, Valentina Fogglizo, Zane Mamman, Courtney Lynn。Binaco、Sherifah Kemigisha Muzungu、Paola Roa、Amanda Kulick、Elisa de Stanchina、Matteo Repetto、Yonina R. Murciano-Goroff、Ezra Rosen、Sandra Misale、Eneda Toska、Robert Shoemaker、Alexander Drilon、Emiliano Cocco。克服激酶融合驱动肿瘤的脱靶耐药[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 B030。
{"title":"Abstract B030: Overcoming off-target resistance to therapy in tumors driven by kinase fusions","authors":"Shaza M. Sayed Ahmed, Valentina Fogglizo, Zane Mamman, Courtney Lynn. Binaco, Sherifah Kemigisha Muzungu, Paola Roa, Amanda Kulick, Elisa de Stanchina, Matteo Repetto, Yonina R. Murciano-Goroff, Ezra Rosen, Sandra Misale, Eneda Toska, Robert Shoemaker, Alexander Drilon, Emiliano Cocco","doi":"10.1158/1538-7445.fusionpositive26-b030","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-b030","url":null,"abstract":"Background: Sequential Tyrosine Kinase Inhibitor (TKI) therapy is a well-established strategy to overcome on-target resistance in ALK, ROS1, TRK, and RET kinase fusion-positive (+) tumors. However, this approach does not address off-target resistance that occurs when tumors acquire oncogenic alterations that activate bypass signaling pathways. A hallmark of off-target resistance is the sustained activation of ERK, a process driven by the hyperactivation of Receptor Tyrosine Kinases (RTKs) and/or acquired alterations within the downstream RAS-MAPK signaling pathway. Hypothesis: We hypothesize that inhibition of the MAPK/ERK pathway (using SHP2i or ERKi) can overcome off-target resistance by resensitizing tumors to their original TKIs. Methods: We generated multiple transduced and patient-derived kinase fusion+ cell lines and PDXs with off-target resistance to TKIs. These included ALK, TRK, and RET fusion+ models carrying MET or IGF1R amplification as well as ALK, TRK, and ROS1 fusion+ models carrying a KRAS mutation. The activity and safety of next-generation ERKi (ulixertinib, temuterkib, ERAS-007) or SHP2i (TNO-155, BBP-398, ERAS-601) as monotherapies or combined with TKIs was tested using viability assays, synergy tests, downstream signaling profiling, and in vivo tolerability and efficacy studies. Results: ERK and SHP2 inhibition was able to resensitize all models to the original TKIs in vitro. Among the SHP2is tested, TNO-155 and ERAS-601 were equally active, and both synergized (BLISS score &gt;10) with TKIs (e.g., BLISS scores of 23.38 and 33.88 for TNO+TKI and 601+TKI, respectively in an ALK+, IGF1R amplified model). Among ERKis, only ERAS-007 resensitized these cell lines to TKIs, with BLISS scores up to 25.36. Notably, ERAS-007 also demonstrated potent single-agent activity at nanomolar concentrations in most models (e.g., 90.6% cell growth inhibition at 25 nM in an ALK+, KRAS mutant cell line; P=.000018). Mechanistically, dual inhibition using SHP2i or ERAS-007 in combination with TKIs completely suppressed phosphorylation of RSK1, a direct downstream substrate of ERK. To determine the optimal drugs’ doses for the in vivo testing, we performed a 12-day tolerability study in healthy mice and found that standard doses of TKIs combined with 30mg/kg QD of SHP2i or ERKi did not cause toxicity (no mouse weight loss or impaired liver/kidney function). Importantly, these combinatorial regimens were significantly more effective than each of the single agents in inhibiting tumor growth in xenografts derived from an ALK+, IGF1R amplified NSCLC cell line (P=.006584 for SHP2i+TKI and P=.013847 for ERKi+TKI) and in a PDX derived from a TRK+, KRAS G12D mutant tumor (P&lt;.000001 for SHP2i+TKI and P=.003215 for ERKi+TKI). Conclusions: ERKi or SHP2i synergize with TKIs in kinase fusion+ tumors with off-target resistance to therapy. Defining the biochemical properties of clinically available ERKis and SHP2is is crucial to design effective and tol","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"29 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962073","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-a013
Alex Hastie
Introduction: Molecular testing in lung and other solid tumors has led to the identification of driver mutations that can be effectively targeted by new therapeutics. In addition to single point mutations that activate signaling proteins such as EGFR and KRAS, the presence of various fusion proteins that lead to protein overexpression and activation of key pathways have become prominent drug targets. Detection of these fusion proteins by FISH or sequencing is possible but may be limited due to changes in breakpoint location, the panel may not target the specific exons or fusion partner, or RNA quality may be affected by sample fixation or processing. This study aims to improve detection rate of targetable fusions and rearrangements in solid tumors using a new method called Hi-C sequencing. Methods: Hi-C sequencing is a novel whole genome DNA-sequencing assay for detection of structural variation based on unique Hi-C chemistry which leverages sequencing of linked pairs of reads which occur nearby one another in 3-dimensional and linear space, from FFPE samples. Linking reads amplifies the rearrangement signal giving it much higher sensitivity and overcoming non-unique sequences masking fusions. In previous studies, Hi-C has been shown to detect gene fusions and rearrangements in many different tumor types missed by other clinical testing modalities such as FISH and RNA sequencing. Results: In a set of 110 NSCLC samples, Hi-C sequencing demonstrated 100% concordance with FISH and/or RNA sequencing results (10/10, including 4 ALK, 2 MET, 2 ROS, 1 NTRK, and 1 RET fusions). The remainder of samples were previously determined by standard DNA and RNA sequencing to be negative for drivers such as EGFR and KRAS mutations and fusions of ALK, MET, NTRK, RET, and ROS. In this cohort, we have detected biomarkers related to drug sensitivity in 15 cases. These include targetable fusions such as NTRK2 (1), NRG1 (1), PRKCA (1), loss of function variants indicating sensitivity to checkpoint inhibitors (2 cases), or PARP inhibitors (6), and others (4). In addition, noncanonical fusions were detected in NRG1 (1), and ALK (1), both retaining their functional domains and potentially indicating sensitivity to inhibitors. Finally, we detected additional rearrangements proximal to targetable genes which led to increased and exogenous expression of their gene products, revealing additional potential targetable biomarkers. Conclusions: Encouraging results from this study suggest that Hi-C sequencing may be a valuable tool in the molecular classification of solid tumors and could lead to improvement in patient care. Hi-C can detect gene fusions and rearrangements that are known to drive cancer and may be used for therapy selection, including in cases which were negative by standard genetic testing. Citation Format: Alex Hastie. Hi-C DNA Sequencing of Solid Tumors for Rearrangements and Fusions Detects Targetable Biomarkers Missed by RNA Sequencing [abstract]. In: Proceeding
在肺和其他实体肿瘤的分子检测已经导致驱动突变的识别，可以有效地靶向新的治疗方法。除了激活信号蛋白如EGFR和KRAS的单点突变外，各种融合蛋白的存在导致蛋白质过表达和关键途径的激活已成为突出的药物靶点。通过FISH或测序检测这些融合蛋白是可能的，但可能由于断点位置的变化而受到限制，面板可能不针对特定的外显子或融合伙伴，或者RNA质量可能受到样品固定或处理的影响。本研究旨在利用一种名为Hi-C测序的新方法提高实体肿瘤中可靶向融合和重排的检出率。方法：Hi-C测序是一种新型的全基因组dna测序方法，用于检测基于独特的Hi-C化学的结构变异，该方法利用FFPE样品中在三维和线性空间中彼此相邻的连接对的测序。链接读取放大重排信号，使其具有更高的灵敏度，并克服了非唯一序列掩盖融合。在先前的研究中，Hi-C已被证明可以检测许多不同肿瘤类型的基因融合和重排，而其他临床检测方式（如FISH和RNA测序）无法检测到。结果：在一组110个NSCLC样本中，Hi-C测序显示与FISH和/或RNA测序结果100%一致（10/10，包括4个ALK， 2个MET， 2个ROS， 1个NTRK和1个RET融合）。其余样品先前通过标准DNA和RNA测序确定为EGFR和KRAS突变以及ALK、MET、NTRK、RET和ROS融合等驱动因素阴性。在这个队列中，我们在15个病例中检测到与药物敏感性相关的生物标志物。这些包括可靶向的融合，如NTRK2(1)、NRG1(1)、PRKCA(1)、表明对检查点抑制剂敏感的功能变异丧失（2例）或PARP抑制剂（6例）等（4例）。此外，在NRG1(1)和ALK(1)中检测到非典型融合，两者都保留了其功能域，并可能表明对抑制剂的敏感性。最后，我们检测到在靶标基因附近的其他重排，这些重排导致其基因产物的外源表达增加，从而揭示了其他潜在的靶标生物标志物。结论：本研究令人鼓舞的结果表明，Hi-C测序可能是实体肿瘤分子分类的一种有价值的工具，并可能导致患者护理的改善。Hi-C可以检测已知导致癌症的基因融合和重排，并可用于治疗选择，包括在标准基因检测呈阴性的情况下。引文格式：Alex Hastie。实体肿瘤重排和融合的Hi-C DNA测序检测RNA测序缺失的可靶向生物标志物[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 A013。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-b031
Daniel F. Guevara-Diaz, David Requena, Sanford M. Simon
Fibrolamellar Carcinoma (FLC) is a liver cancer of adolescents and young adults driven by the fusion of DNAJB1, a heat shock protein and PRKACA, the catalytic subunit of protein kinase A (PKA). It is characterized by increased PKA activity leading to widespread changes. A profile of FLC at genomics, transcriptomics, methylomics and proteomics in a multi-omic study that studied 1,412 tumor-normal paired liver samples from patients with FLC, Hepatoblastoma, Intrahepatic Cholangiocarcinoma, and Hepatocellular Carcinoma, yielded the FLC Data Base (FLC-DB). To facilitate the visualization of the multiomics, we developed a user-friendly web interface for the FLC-DB. It uses functions from the R-library OmicsKit and enables interactive exploration for non-bioinformaticians to retrieve information and generate publication-ready plots. It comprises 3 main tabs. First, Documentation, which describes the samples and datasets, the transcriptomic FLC Signature, and a reduced set of 35 genes with strong and recurrent upregulation across all samples, selected for clinical purposes. Second, the Transcriptomics tab, where users can interactively explore the distribution of gene counts across liver cancers, comparing normal samples against tumors and tumor subtypes. This has the option to directly perform Differential Expression Analysis using subsets that can be dynamically defined by the user in the web interface. Third, the Genomics tab, which allows exploration of Single Nucleotide Variants (SNV) from Whole-Genome and Whole-Exome Sequencing (WGS/WES) and download of the SNVs annotations and perform downstream analyses. This allows exploring questions such as: Is a transcript consistently upregulated across FLC studies? Are there recurrent SNVs in FLC? What gene signatures are shared between FLC and HBL? The FLC-DB web interface facilitates exploration of complex multi-omics data, broadening its access to non-bioinformatic researchers, patients and the community. It is currently available at https://fibrolamellardatabase.org/. Citation Format: Daniel F. Guevara-Diaz, David Requena, Sanford M. Simon. The fibrolamellar carcinoma database [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 B031.
纤维板层癌（FLC）是一种由DNAJB1（一种热休克蛋白）和PRKACA（蛋白激酶a （PKA）的催化亚基）融合驱动的青少年和年轻人肝癌。其特点是PKA活性增加，导致广泛的变化。在一项多组学研究中，FLC的基因组学、转录组学、甲基组学和蛋白质组学分析了来自FLC、肝母细胞瘤、肝内胆管癌和肝细胞癌患者的1412例肿瘤-正常配对肝脏样本，建立了FLC数据库（FLC- db）。为了方便多组学的可视化，我们为FLC-DB开发了一个用户友好的web界面。它使用r库OmicsKit的功能，为非生物信息学家检索信息和生成出版准备图提供了交互式探索。它包括3个主要选项卡。首先，文档，描述了样本和数据集，转录组FLC特征，以及在所有样本中具有强烈和反复上调的35个基因的减少集，选择用于临床目的。其次是转录组学选项卡，用户可以交互式地探索肝癌基因计数的分布，将正常样本与肿瘤和肿瘤亚型进行比较。这个选项可以直接使用子集执行差分表达式分析，这些子集可以由用户在web界面中动态定义。第三，基因组选项卡，允许从全基因组和全外显子组测序（WGS/WES）中探索单核苷酸变异（SNV），下载SNV注释并进行下游分析。这允许探索以下问题：在FLC研究中，转录本是否一致上调？FLC是否有复发性snv ？FLC和HBL共有哪些基因特征？FLC-DB网络界面促进了复杂的多组学数据的探索，扩大了非生物信息学研究人员、患者和社区的访问范围。它目前可在https://fibrolamellardatabase.org/上获得。引用格式：Daniel F. Guevara-Diaz, David Requena, Sanford M. Simon。纤维板层癌数据库[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 B031。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a006
Hyojeong Hwang, Jinhua Wu, Jeffery Schubert, Meha Patel, Natali Naveh, Netta Golenberg, Minjie Luo, Yiming Zhong, Lea F Surrey, Marilyn M Li, Monica Pomaville, Kathy Fange Liu, Derek Wong
Introduction: Aside from standard surgical resection followed by chemo/radiation therapy, there is a dearth of effective therapies for tumors of the central nervous system (CNS) despite increasing understanding of the molecular mechanisms driving oncogenesis and progression. Antisense oligonucleotides (ASOs) have emerged as a powerful method to target disease-causing transcripts through sequence-specific translational blocking or degradation. However, while it is known that oncogenic fusions drive some CNS tumors, few studies have investigated and characterized the landscape of oncogenic fusions and variation in breakpoints, pertinent for the translation of ASOs into a viable therapy. Methods: We performed retrospective analysis of CNS tumors from 1690 patients profiled at the Children’s Hospital of Philadelphia as part of routine clinical molecular workup. Additionally, we have developed an ASO-based therapeutic platform to design ASOs which target the fusion junctions and validate their efficacy in eliminating the targeted fusion transcripts. Results: Our cohort spanned both pediatric (980/1690) and adult (710/1690) ages (range = 0 - 91) and histologic subtypes. In total, 21% of CNS tumor patients (354/1690) harbored an oncogenic fusion; Grade 1 = 38% (218/567), Grade 2 = 6% (12/211), Grade 3 = 12% (22/176), and Grade 4 = 13% (75/570). Fusions were most common in glial neoplasms (27%, 328/1213) followed by ependymal tumors driven by ZFTA rearranged supratentorial ependymoma (13%, 20/150), and mesenchymal tumors (28%, 5/18). The most common fusions included BRAF in Grade 1 tumors and MET and EGFR in Grade 4 tumors. NTRK1/2/3 fusions, which have promiscuous partners spanned all grades, and FGFR1/2/3 fusions were only found in Grade 1 or 4 tumors, most often fused to TACC1 or TACC3. BRAF, NTRK2, and MET fusions had the highest number of unique partners. Investigating unique transcripts, nearly all fusions had conserved breakpoints except for KIAA1549::BRAF fusions, which had 15 unique transcripts. Interestingly, while ZFTA::RELA fusions had relatively conserved breakpoints, all tumors expressed at least 2 unique transcripts (1 major), suggesting co-existence of different chimeric isoforms. MYB::QKI fusions, identified in low-grade gliomas, was selected as a pilot target to evaluate the ASO-based therapeutic platform. A list of five ASOs were tested in mammalian cells expressing MYB::QKI fusion reporters. The most effective ASO was found to reduce MYB-QKI reporter fluorescent signal by ∼83% and fusion transcript level by ∼63% compared to the negative ASO, as measured by cellular imaging and RT-qPCR, respectively. Conclusion: In the current landscape, where therapeutic options for fusion-driven tumors in the CNS are limited, this ASO-based therapeutic platform presents a new avenue for developing personalized nucleic acid-based therapies aimed at improving clinical outcomes for individuals with CNS tumors. Citation Format: Hyojeong Hwang, Jinhua Wu,
导论：除了标准的手术切除和化疗/放疗之外，尽管人们对中枢神经系统（CNS）肿瘤发生和发展的分子机制了解越来越多，但缺乏有效的治疗方法。反义寡核苷酸（ASOs）已成为一种通过序列特异性翻译阻断或降解靶向致病转录物的强大方法。然而，虽然已知致癌融合驱动一些中枢神经系统肿瘤，但很少有研究调查和描述致癌融合的景观和断点的变化，这与ASOs转化为可行的治疗有关。方法：作为常规临床分子检查的一部分，我们对费城儿童医院1690例患者的中枢神经系统肿瘤进行了回顾性分析。此外，我们已经开发了一个基于aso的治疗平台来设计靶向融合连接的aso，并验证其在消除靶向融合转录本方面的功效。结果：我们的队列跨越了儿童（980/1690）和成人（710/1690）年龄（范围= 0 - 91）和组织学亚型。总的来说，21%的中枢神经系统肿瘤患者（354/1690）存在癌性融合；1级= 38%(218/567)，2级= 6%(12/211)，3级= 12%(22/176)，4级= 13%（75/570）。融合在神经胶质肿瘤中最常见（27%,328/1213），其次是由ZFTA重排幕上室管膜瘤驱动的室管膜肿瘤（13%,20/150）和间充质肿瘤（28%,5/18）。最常见的融合包括1级肿瘤中的BRAF和4级肿瘤中的MET和EGFR。NTRK1/2/3融合，具有混杂的伴侣，跨越所有级别，FGFR1/2/3融合仅在1级或4级肿瘤中发现，最常与TACC1或TACC3融合。BRAF、NTRK2和MET融合的唯一伴侣数量最多。研究独特的转录本，除了KIAA1549::BRAF融合有15个独特的转录本外，几乎所有的融合都有保守的断点。有趣的是，虽然ZFTA::RELA融合具有相对保守的断点，但所有肿瘤都表达至少2个独特的转录本（1个主要），表明不同嵌合亚型共存。在低级别胶质瘤中发现的MYB::QKI融合物被选为评估基于aso的治疗平台的试点靶点。在表达MYB::QKI融合报告基因的哺乳动物细胞中测试了5种aso。通过细胞成像和RT-qPCR检测，发现与阴性ASO相比，最有效的ASO可将MYB-QKI报告因子荧光信号减少约83%，融合转录物水平减少约63%。结论：在目前的情况下，对于中枢神经系统融合驱动肿瘤的治疗选择是有限的，这个基于aso的治疗平台为开发个性化的基于核酸的治疗提供了一条新的途径，旨在改善中枢神经系统肿瘤患者的临床结果。引文格式：Hyojeong Hwang，金华Wu， Jeffery Schubert, Meha Patel, Natali Naveh, Netta Golenberg，罗敏杰，钟义明，Lea F Surrey, Marilyn M Li, Monica Pomaville, Kathy Fange Liu, Derek Wong。融合驱动中枢神经系统肿瘤的转录组学景观，用于设计和验证连接特异性反义寡核苷酸介导的融合癌基因靶向[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 A006。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a030
Nafiseh Jafari, Yabin Lu, Jason Saenz, Carlos Hernandez, Daniel Cedeno, Cameron Van Dieren, Mayer Saidian
Introduction: Fusion-driven oncogenesis is a hallmark of multiple malignancies, with transcripts such as TMPRSS2-ERG, EML4-ALK, FGFR3-TACC3, ETV6-NTRK3, CCDC6-RET, SLC34A2-ROS1, and BCR-ABL1 representing clinically actionable biomarkers for targeted therapies. Accurate detection of these RNA fusions in plasma requires extraction methods that efficiently recover cfRNA molecules, which are typically present at very low abundance. This study assessed the performance and reproducibility of an optimized cfRNA extraction workflow for fusion transcript detection from plasma samples. Methods: Synthetic RNA standards and fusion-positive cell line reference materials were spiked into plasma to mimic clinically relevant fusion transcript abundance. cfRNA was extracted from 10 mL plasma aliquots using a magnetic–capture–based workflow designed to maximize RNA yield. Extracted cfRNA was reverse transcribed and analyzed by singleplex PCR (aggregated to panel coverage) targeting the seven representative RNA fusions listed above. Extraction performance was evaluated by RNA yield, consistency across replicates, and quantitative recovery of fusion-specific transcripts relative to known input copies. Results: The extraction workflow demonstrated high efficiency and consistency in recovering low-abundance RNA from plasma. Total cfRNA yield per 10 mL of plasma demonstrated consistent recovery across replicates, with low variability. All seven target fusions (TMPRSS2-ERG, EML4-ALK, FGFR3-TACC3, ETV6-NTRK3, CCDC6-RET, SLC34A2-ROS1, BCR-ABL1) were successfully detected using singleplex PCR from cfRNA eluates. Extraction reproducibility was maintained across plasma samples with variable background RNA content, and no inhibition was observed in downstream amplification reactions. The data indicate that the majority of fusion transcripts in plasma cfRNA are captured, highlighting the importance of preserving cfRNA species during extraction. Conclusion: Efficient cfRNA extraction from plasma is essential for accurate and sensitive detection of RNA fusions that define actionable cancer subtypes. This study demonstrates a robust and reproducible extraction workflow capable of recovering low-copy fusion transcripts spanning multiple gene families relevant to prostate, lung, bladder, pediatric, and hematologic malignancies. High-quality cfRNA recovery from plasma enables reliable downstream singleplex PCR/ddPCR or sequencing-based detection of TMPRSS2-ERG, EML4-ALK, FGFR3-TACC3, ETV6-NTRK3, CCDC6-RET, SLC34A2-ROS1, and BCR-ABL1, supporting the use of liquid biopsy–derived RNA as a viable substrate for clinical and translational research applications. ChatGPT was used to improve the clarity of the abstract. Citation Format: Nafiseh Jafari, Yabin Lu, Jason Saenz, Carlos Hernandez, Daniel Cedeno, Cameron Van Dieren, Mayer Saidian. Detection of Clinically Actionable RNA Fusions Across Multiple Cancer Types Using Optimized cfRNA Extraction from Diverse Sample Matrices [abstract]. In
融合驱动的肿瘤发生是多种恶性肿瘤的标志，转录物如TMPRSS2-ERG、EML4-ALK、FGFR3-TACC3、ETV6-NTRK3、CCDC6-RET、SLC34A2-ROS1和BCR-ABL1代表了临床可用于靶向治疗的生物标志物。准确检测血浆中这些RNA融合需要有效提取cfRNA分子的方法，这些分子通常以非常低的丰度存在。本研究评估了优化的cfRNA提取工作流程的性能和可重复性，用于从血浆样本中检测融合转录物。方法：将合成RNA标准物和融合阳性细胞系参比物加入血浆中，模拟临床相关的融合转录物丰度。从10ml血浆等分液中提取cfRNA，采用基于磁捕获的工作流程，旨在最大限度地提高RNA产量。对提取的cfRNA进行逆转录，并针对上面列出的7种代表性RNA融合进行单重PCR（聚合到面板覆盖率）分析。提取性能通过RNA产量、重复一致性和相对于已知输入拷贝的融合特异性转录物的定量恢复来评估。结果：该提取流程可高效、一致地从血浆中提取低丰度RNA。每10ml血浆的总cfRNA产量在重复中表现出一致的恢复，具有低变异性。所有7个目标融合物（TMPRSS2-ERG、EML4-ALK、FGFR3-TACC3、ETV6-NTRK3、CCDC6-RET、SLC34A2-ROS1、BCR-ABL1）均通过cfRNA的单重PCR检测成功。在不同背景RNA含量的血浆样品中，提取的重复性保持不变，并且在下游扩增反应中没有观察到抑制作用。数据表明，血浆cfRNA中的大多数融合转录本被捕获，强调了在提取过程中保存cfRNA物种的重要性。结论：从血浆中高效提取cfRNA对于准确、灵敏地检测RNA融合以确定可操作的癌症亚型至关重要。这项研究展示了一个强大的、可重复的提取工作流程，能够恢复与前列腺、肺、膀胱、儿科和血液系统恶性肿瘤相关的多个基因家族的低拷贝融合转录物。从血浆中回收高质量的cfRNA，可实现可靠的下游单链PCR/ddPCR或基于测序的TMPRSS2-ERG、EML4-ALK、FGFR3-TACC3、ETV6-NTRK3、CCDC6-RET、SLC34A2-ROS1和BCR-ABL1检测，支持将液体活检衍生的RNA作为临床和转化研究应用的可行底物。使用ChatGPT来提高摘要的清晰度。引文格式：Nafiseh Jafari， Yabin Lu, Jason Saenz, Carlos Hernandez, Daniel Cedeno, Cameron Van Dieren, Mayer Saidian。利用从不同样品基质中提取优化的cfRNA，检测多种癌症类型中临床可操作的RNA融合[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): nr A030。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-lt003
Jihye Yoon, Elisabeth Denby, Wei Yang, Run Zhang, Emily B. Casey, Riddhi M. Patel, Yanan Li, J. Michael White, Luis Batista, Jeffrey Magee
Mutations that drive pediatric acute myeloid leukemia (AML) are often age-restricted. NUP98 rearrangements (NUP98r) cause high-risk AML primarily in early-to-mid childhood but are rare in adults. Moreover, NUP98r AML almost never occurs before birth. This pattern suggests that there are developmental windows and associated molecular programs that modulate the transforming effects of mutations like NUP98r, raising the questions of why NUP98r-driven AML predominates in early-to-mid childhood. To address these questions, we developed a novel strategy to model NUP98r AML initiation during different stages of life. We generated mouse induced pluripotent stem cells (iPSCs) that give rise to chimeric mice that express NUP98::HOXA9 (NHA9) specifically in the blood and at specific stages of ontogeny and aging. A similar approach was used to express NHA9 mutants (e.g., intrinsically disordered region or homeodomain mutants) and NUP98::KDM5A (NK). This strategy allows us to efficiently model effects of diverse NUP98 fusions in situ without complex mouse breeding strategies. To test whether NHA9 initiates AML more efficiently in fetal, neonatal, juvenile, or adult mice, we induced NHA9 at embryonic day (E)10.5, postnatal day (P)0, P21, 8 weeks, or 8 months old. We introduced a cooperating Flt3-internal tandem duplication through genome editing. NHA9-expressing juvenile and adult progenitors gave rise to AML with high penetrance whereas fetal and neonatal progenitors did not. This raised the question of why fetal/neonatal progenitors resist transformation and how resistance is overcome in contexts of infant NUP98r AML. To understand why fetal/neonatal progenitors resist transformation, we performed single-cell RNA sequencing on NHA9-expressing progenitor cells after fetal, juvenile, or adult induction. NHA9 drove precocious erythroid differentiation at the expense of self-renewing progenitors in fetal but not juvenile or adult mice. The erythroid bias required a functional homeodomain. Interestingly, mutating the intrinsically disordered region (IDR) proved highly toxic to hematopoietic progenitors in vivo but not in vitro, again reflecting the importance of context in fusion protein function. Fetal NK expression also elicited precocious erythroid differentiation, though the effects were less severe than NHA9. Thus, NK mutations may overcome engrained fetal barriers to transformation more efficiently than NHA9. These results show that age greatly influences the capacity of oncoproteins to drive leukemic transformation and that when infant NUP98r AML does arise, it must overcome barriers to transformation that reflect fetal/neonatal ontogeny. Citation Format: Jihye Yoon, Elisabeth Denby, Wei Yang, Run Zhang, Emily B. Casey, Riddhi M. Patel, Yanan Li, J. Michael White, Luis Batista, Jeffrey Magee. Fetal differentiation programs afford a protective barrier to NUP98 fusion-driven AML initiation [abstract]. In: Proceedings of the AACR Special Conference in Cancer
驱动儿童急性髓性白血病（AML）的突变通常是年龄限制的。NUP98重排（NUP98r）主要在儿童早期至中期引起高风险AML，但在成人中罕见。此外，NUP98r AML几乎从未在出生前发生。这种模式表明存在发育窗口和相关的分子程序来调节NUP98r等突变的转化效应，这就提出了为什么NUP98r驱动的AML在儿童早期到中期占主导地位的问题。为了解决这些问题，我们开发了一种新的策略来模拟NUP98r在不同生命阶段的AML起始。我们制备了小鼠诱导多能干细胞（iPSCs），产生了嵌合小鼠，这些嵌合小鼠在血液中特异性表达NUP98::HOXA9 (NHA9)，并在个体发育和衰老的特定阶段表达。用类似的方法表达NHA9突变体（例如，内在无序区或同源结构域突变体）和NUP98::KDM5A （NK）。这种策略使我们能够有效地模拟不同的NUP98原位融合效应，而无需复杂的小鼠育种策略。为了测试NHA9是否在胎儿、新生儿、幼年或成年小鼠中更有效地引发AML，我们在胚胎日(E)10.5，出生后(P)0, P21, 8周或8个月大时诱导NHA9。我们通过基因组编辑引入了一个合作的flt3 -内部串联复制。表达nha9的少年和成年祖细胞可产生高外显率的AML，而胎儿和新生儿祖细胞则没有。这就提出了一个问题，为什么胎儿/新生儿祖细胞会抵抗转化，以及在婴儿NUP98r AML的情况下如何克服抵抗。为了了解胎儿/新生儿祖细胞抵抗转化的原因，我们对胎儿、幼年或成年诱导后表达nha9的祖细胞进行了单细胞RNA测序。在胚胎小鼠中，NHA9以牺牲自我更新的祖细胞为代价促进了红细胞的早熟分化，而在幼年或成年小鼠中则没有。红系偏倚需要一个功能性同源结构域。有趣的是，突变内在无序区（IDR）在体内被证明对造血祖细胞具有高度毒性，但在体外却没有，这再次反映了环境在融合蛋白功能中的重要性。胎儿NK表达也会引起红细胞早熟分化，但其影响不如NHA9严重。因此，NK突变可能比NHA9更有效地克服根深蒂固的胎儿转化障碍。这些结果表明，年龄极大地影响癌蛋白驱动白血病转化的能力，并且当婴儿NUP98r AML确实出现时，它必须克服反映胎儿/新生儿个体发生的转化障碍。引用格式：尹jihye， Elisabeth Denby，杨伟，张run， Emily B. Casey, Riddhi M. Patel, Yanan Li， J. Michael White, Luis Batista, Jeffrey Magee胎儿分化程序为NUP98融合驱动的AML启动提供了保护性屏障[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 LT003。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-pr002
Chinmay S. Sankhe, Delia Calderon, Cenny Taslim, Melissa Sammons, Lindsay Ryan, Amy C. Gross, Joanna Cyrta, Olivier Delattre, Ryan D. Roberts, Genevieve C. Kendall
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and has molecular features of immature skeletal muscle development. Spindle-cell RMS subtype in infant patients has been associated with the presence of chromosomal translocation event in the form of fusion-oncogenes. The most common fusion-oncogene in these patients is VGLL2::NCOA2, the fusion between vestigial-like family member 2 (VGLL2) and nuclear receptor coactivator 2 (NCOA2). Conventional chemotherapeutic approaches do not target the fusion-oncogene itself, are broadly toxic, and often impose lifelong adverse side effects that decrease the patient’s quality of life. Previous work from our lab has shown that the VGLL2::NCOA2 fusion is oncogenic in zebrafish and mouse allograft models, with tumors forming without requiring secondary mutations. Importantly, these tumors histologically and transcriptionally recapitulated the human disease. Understanding fusion-oncogene biology is critical to identifying novel molecular therapeutic targets to improve patient outcomes. Here, we implemented a structure-function-based strategy to define the requirements of each functional domain of VGLL2::NCOA2 in fusion-driven tumorigenesis. We hypothesize that the protein domains retained in the fusion-oncogene influence tumorigenic mechanisms. We generated deletions of the functional protein domain vestigial/Tondu (TDU) of VGLL2 and activating domains (AD1 and AD2) of NCOA2, both of which are retained in the fusion. We transfected C2C12 mouse myoblast cells with either the full-length VGLL2::NCOA2 fusion construct or the mutant domain deletion constructs. Using immunofluorescence staining and western blotting, we found that the VGLL2::NCOA2 fusion localized in the nucleus, whereas the single deletions of the TDU and AD1 domains resulted in decreased nuclear localization. C2C12 cells transfected with the full-length fusion readily formed colonies in soft agar; however, removing the TDU and AD1 domains suppressed colony formation. We complemented our in vitro studies with a mouse allograft approach. Mice injected with the C2C12 cells stably expressing VGLL2::NCOA2 with deletions of TDU and/or AD1 had a delayed tumor onset with more differentiated tumors compared to mice injected with the full-length fusion. Furthermore, bulk RNA-sequencing transcriptional analysis of transfected cells demonstrated that deletion of the TDU and AD1 domains resulted in an upregulation of skeletal muscle myogenesis gene sets, suggesting promotion of muscle differentiation compared to cells expressing the full-length fusion. Overall, our results indicate that VGLL2::NCOA2 is dependent on the TDU and AD1 domains for supporting tumorigenic activities and that targeting these domains or their interacting protein partners represents a potential therapeutic opportunity. Citation Format: Chinmay S. Sankhe, Delia Calderon, Cenny Taslim, Melissa Sammons, Lindsay Ryan, Amy C. Gross, Joanna Cyrta, Olivier Delattre, Ryan
横纹肌肉瘤（Rhabdomyosarcoma， RMS）是儿童最常见的软组织肉瘤，具有未成熟骨骼肌发育的分子特征。婴儿患者的梭形细胞RMS亚型与融合癌基因形式的染色体易位事件的存在有关。这些患者中最常见的融合癌基因是VGLL2::NCOA2，即退化样家族成员2 （VGLL2）和核受体辅激活因子2 （NCOA2）之间的融合。传统的化疗方法不针对融合癌基因本身，具有广泛的毒性，并且经常造成终生的不良副作用，降低患者的生活质量。我们实验室之前的工作表明，VGLL2::NCOA2融合在斑马鱼和小鼠同种异体移植模型中具有致癌作用，肿瘤形成不需要继发性突变。重要的是，这些肿瘤在组织学和转录上再现了人类疾病。了解融合癌基因生物学对于确定新的分子治疗靶点以改善患者预后至关重要。在这里，我们实施了一种基于结构-功能的策略来定义融合驱动肿瘤发生中VGLL2::NCOA2的每个功能域的需求。我们假设融合癌基因中保留的蛋白结构域影响致瘤机制。我们删除了VGLL2的功能蛋白结构域退化/通度（TDU）和NCOA2的激活结构域（AD1和AD2），这两个结构域在融合中都被保留。我们用全长VGLL2::NCOA2融合构建体或突变结构域缺失构建体转染C2C12小鼠成肌细胞。通过免疫荧光染色和western blotting，我们发现VGLL2::NCOA2融合在细胞核中定位，而TDU和AD1结构域的单一缺失导致核定位降低。全长融合后的C2C12细胞在软琼脂中容易形成菌落；然而，去除TDU和AD1结构域抑制了菌落的形成。我们用小鼠同种异体移植方法补充了我们的体外研究。与注射全长融合的小鼠相比，注射稳定表达VGLL2::NCOA2并缺失TDU和/或AD1的C2C12细胞的小鼠肿瘤发生延迟，肿瘤分化程度更高。此外，转染细胞的大量rna测序转录分析表明，TDU和AD1结构域的缺失导致骨骼肌肌生成基因集的上调，这表明与表达全长融合的细胞相比，TDU和AD1结构域的缺失促进了肌肉分化。总体而言，我们的研究结果表明，VGLL2::NCOA2依赖于TDU和AD1结构域来支持致瘤活性，靶向这些结构域或其相互作用的蛋白伙伴代表了潜在的治疗机会。引文格式：Chinmay S. Sankhe, Delia Calderon, Cenny Taslim, Melissa Sammons, Lindsay Ryan, Amy C. Gross, Joanna Cyrta, Olivier Delattre, Ryan D. Roberts, Genevieve C. Kendall。VGLL2::NCOA2在婴儿横纹肌肉瘤中的结构域特异性致癌功能[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 PR002。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a023
Miwa Tanaka, Takuro Nakamura
Prompt trafficking of growth factors and cytokines to the cytoplasmic membrane is essential to provide growth stimuli during cell-cell communication. Also, efficient trafficking of surface receptors is required for their renewal upon the binding with their specific ligands. The RAB27/SYTL/Myosin V/actin axis plays a central role in trafficking of cytoplasmic vesicles and surface receptors toward the plasma membrane. Abnormal enhancement of this pathway induces excessive intercellular signaling exchange in cancer, resulting in significant modifications of tumor microenvironment. Our previous study identified SYTL1, a binding partner of RAB27B, as a transcriptional target of MEIS1 that promotes homing and engraftment of leukemia stem cells in the hematopoietic niche by facilitating membrane trafficking of CXCR4 and FLT3. Alveolar soft part sarcoma (ASPS) is a rare neoplasm that affects adolescents and young adults with an invariable ASPSCR1::TFE3 (AT3) fusion. ASPS is characterized by the abundant vascular network forming the alveolus around tumor cell nests that causes the highly metastatic activity of the tumor. ChIP-seq analysis revealed that AT3 binding peaks are enriched at angiogenesis-associated enhancers, and inhibition of enhancer activity by the BRD4 inhibitor JQ1 suppressed angiogenesis and tumor growth in vivo. Subsequent in vivo epigenomic CRISPR/dCas9-KRAB screening identified RAB27A and SYTL2 as key molecules of angiogenesis in ASPS. Upregulation of the RAB27A/SYTL2 axis enhanced secretion of angiogenic factors including PDGFB, VWF, GPNMB, and ANGPTL2, promoting migration and proliferation of pericytes and endothelial cells to form the highly integrated vascular network characteristic of ASPS. A similar pathway activation is observed in translocation renal cell carcinoma (tRCC) harboring TFE3 rearrangements, generating a comparable vascular architecture. We have reconstructed vascular mimics in vitro using ASPS and tRCC cells in 3D microfluidic devices. We are currently exploring novel inhibitors targeting the protein-protein interaction (PPI) between RAB27A and SYTL2. To perform high throughput screening (HTS) of candidate inhibitors we constructed the cell-based Fluoppi and cell-free AlphaLISA systems. During our first HTS Compound A was identified as a specific inhibitor of RAB27A and SYTL2 PPI. This compound inhibited the secretion of pro-angiogenic factors and significantly suppressed angiogenesis and tumor growth in vivo. We are currently optimizing Compound A to enhance its PPI inhibitory activity and safety profile. Citation Format: Miwa Tanaka, Takuro Nakamura. ASPSCR1::TFE3 promotes angiogenesis via RAB27A/SYTL2 upregulation in alveolar soft part 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 A023.
生长因子和细胞因子的迅速运输到细胞质膜是在细胞间通讯过程中提供生长刺激所必需的。此外，表面受体的有效运输是它们在与特定配体结合时更新所必需的。RAB27/SYTL/Myosin V/actin轴在细胞质囊泡和表面受体向质膜的运输中起核心作用。该通路的异常增强可诱导肿瘤细胞间过度信号交换，导致肿瘤微环境发生显著改变。我们之前的研究发现RAB27B的结合伙伴SYTL1作为MEIS1的转录靶点，通过促进CXCR4和FLT3的膜运输，促进白血病干细胞在造血生态位的归巢和植入。肺泡软部肉瘤（Alveolar soft part sarcoma， ASPS）是一种罕见的肿瘤，多发于青少年和年轻人，伴有不变的ASPSCR1::TFE3 （AT3）融合。ASPS的特点是肿瘤细胞巢周围有丰富的血管网络形成肺泡，引起肿瘤的高度转移活性。ChIP-seq分析显示，AT3结合峰在血管生成相关增强子上富集，BRD4抑制剂JQ1抑制增强子活性可抑制体内血管生成和肿瘤生长。随后的体内表观基因组CRISPR/dCas9-KRAB筛选鉴定出RAB27A和SYTL2是ASPS血管生成的关键分子。RAB27A/SYTL2轴上调可增强PDGFB、VWF、GPNMB、ANGPTL2等血管生成因子的分泌，促进周细胞和内皮细胞的迁移和增殖，形成高度整合的血管网络。在易位性肾细胞癌（tRCC）中观察到类似的途径激活，其中包含TFE3重排，产生类似的血管结构。我们在体外用ASPS和tRCC细胞在三维微流体装置中重建了血管模拟物。我们目前正在探索针对RAB27A和SYTL2之间蛋白蛋白相互作用（PPI）的新型抑制剂。为了进行候选抑制剂的高通量筛选（HTS），我们构建了基于细胞的Fluoppi和无细胞的AlphaLISA系统。在我们的第一个HTS中，化合物A被确定为RAB27A和SYTL2 PPI的特异性抑制剂。该化合物抑制促血管生成因子的分泌，显著抑制体内血管生成和肿瘤生长。我们目前正在优化化合物A，以增强其PPI抑制活性和安全性。引用格式：Miwa Tanaka， Takuro Nakamura。ASPSCR1::TFE3通过上调RAB27A/SYTL2促进肺泡软组织肉瘤血管生成[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 A023。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-b026
Sean Misek, Anna Borgenvik, Daniel Christen, Gloria Kyrila, Alexander Zhang, Sarah Reel, Michelle Boisvert, Kelly Cai, Kevin Zhou, Elizabeth Gonzales, Lorena Lazo de la Vega, Timothy Ragnoni, Nicole Persky, Tanaz Abid, Esteban Miglietta, Sergey Vakhrushev, Michael Stumpe, Jacquelyn Jones, Seth Malinowski, Lobna Elsadek, Aaron Fultineer, Kira Tang, Antonio Maldera, Hyesung Jeon, Sangita Pal, Todd Golub, William Hahn, Eric Fischer, Jesse Boehm, Jörn Dengjel, Henrik Clausen, Nada Jabado, Till Milde, Anne Carpenter, Beth Cimini, Keith Ligon, Katherine Janeway, Michael Eck, David Root, David Jones, Timothy Phoenix, Rameen Beroukhim, Hiren Jitendra Joshi, Tilman Tilman, Adnan Halim, Pratiti Bandopadhayay
The most common fusion oncoprotein in the most common pediatric solid tumor, pediatric low-grade glioma (pLGG), is KIAA1549::BRAF. Although MAPK inhibitors show early promise, they often fail to achieve durable cures, highlighting the need to develop new therapeutics for KIAA1549::BRAF-driven tumors. In this study we leverage genome-scale anti-transformation CRISPR screens to uncover KIAA1549::BRAF-specific genetic vulnerabilities. Across all genes, POMT1 and POMT2, the two members of the heterodimeric Protein O-mannosyltransferase (POMT) complex emerge as the strongest KIAA1549::BRAF-specific dependencies. We demonstrate that KIAA1549 is a direct substrate of this complex, and that glycosylation of KIAA1549::BRAF by POMT is necessary for its maturation through the secretory pathway and subsequent oncogenic signaling. These data highlight for the first time a new route to directly target KIAA1549::BRAF independent of the MAPK pathway. This work also uncovered an unexpected and previously unrecognized role for KIAA1549 in driving KIAA1549::BRAF oncogenic signaling. The prevailing dogma has been that BRAF fusions exert their transforming activity through truncation and removal of N-terminal regulatory domains, thereby rendering the BRAF kinase domain constitutively active. We demonstrate that BRAF fusion partners, including KIAA1549, contain domains that facilitate membrane localization, thereby enhancing BRAF signaling. These findings challenge the traditional view of BRAF fusion biology and establish a role for fusion partners in shaping oncogenic potential. Citation Format: Sean Misek, Anna Borgenvik, Daniel Christen, Gloria Kyrila, Alexander Zhang, Sarah Reel, Michelle Boisvert, Kelly Cai, Kevin Zhou, Elizabeth Gonzales, Lorena Lazo de la Vega, Timothy Ragnoni, Nicole Persky, Tanaz Abid, Esteban Miglietta, Sergey Vakhrushev, Michael Stumpe, Jacquelyn Jones, Seth Malinowski, Lobna Elsadek, Aaron Fultineer, Kira Tang, Antonio Maldera, Hyesung Jeon, Sangita Pal, Todd Golub, William Hahn, Eric Fischer, Jesse Boehm, Jörn Dengjel, Henrik Clausen, Nada Jabado, Till Milde, Anne Carpenter, Beth Cimini, Keith Ligon, Katherine Janeway, Michael Eck, David Root, David Jones, Timothy Phoenix, Rameen Beroukhim, Hiren Jitendra Joshi, Tilman Tilman, Adnan Halim, Pratiti Bandopadhayay. O-mannosylation and protein maturation checkpoints represent therapeutic opportunities in BRAF fusion protein oncogenesis [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 B026.
在最常见的儿童实体肿瘤——儿童低级别胶质瘤（pLGG）中，最常见的融合癌蛋白是KIAA1549::BRAF。尽管MAPK抑制剂显示出早期的希望，但它们往往无法实现持久的治疗，这突出了开发新的治疗KIAA1549:: braf驱动肿瘤的方法的必要性。在这项研究中，我们利用基因组规模的抗转化CRISPR筛选来发现KIAA1549:: brf特异性遗传脆弱性。在所有基因中，异二聚体蛋白o -甘露糖基转移酶（POMT）复合体的两个成员POMT1和POMT2表现出最强的KIAA1549:: braf特异性依赖。我们证明KIAA1549是该复合物的直接底物，并且POMT对KIAA1549::BRAF的糖基化是其通过分泌途径成熟和随后的致癌信号传导所必需的。这些数据首次突出了独立于MAPK通路直接靶向KIAA1549::BRAF的新途径。这项工作还发现了KIAA1549在驱动KIAA1549::BRAF致癌信号传导中的一个意想不到的和以前未被认识到的作用。普遍的观点认为，BRAF融合通过截断和去除n端调控结构域来发挥其转化活性，从而使BRAF激酶结构域具有组成性活性。我们证明BRAF融合伙伴，包括KIAA1549，包含促进膜定位的结构域，从而增强BRAF信号传导。这些发现挑战了BRAF融合生物学的传统观点，并确立了融合伙伴在形成致癌潜能中的作用。引文格式:肖恩·米塞克、安娜·博尔根维克、丹尼尔·克里斯腾、格洛丽亚·基里拉、亚历山大·张、莎拉·里尔、米歇尔·布瓦维尔、凯利·蔡、凯文·周、伊丽莎白·冈萨雷斯、洛雷纳·拉佐·德拉·维加、蒂莫西·拉格诺尼、妮可·波斯基、塔娜·阿比德、埃斯特班·米格列塔、谢尔盖·瓦赫鲁舍夫、迈克尔·斯坦普、杰奎琳·琼斯、塞思·马林诺夫斯基、洛布娜·埃尔萨德克、亚伦·富尔廷纳、唐吉娜、安东尼奥·马尔德拉、全Hyesung、桑吉塔·帕尔、托德·戈拉布、威廉·哈恩、埃里克·菲舍尔、杰西·博姆、Jörn邓杰尔、亨里克·克劳森、纳达·贾巴多、Till Milde, Anne Carpenter, Beth Cimini, Keith Ligon, Katherine Janeway, Michael Eck, David Root, David Jones, Timothy Phoenix, Rameen Beroukhim, Hiren Jitendra Joshi, Tilman Tilman, Adnan Halim, Pratiti Bandopadhayay。o -甘露糖基化和蛋白质成熟检查点代表了BRAF融合蛋白肿瘤发生的治疗机会[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 B026。
{"title":"Abstract B026: O-mannosylation and protein maturation checkpoints represent therapeutic opportunities in BRAF fusion protein oncogenesis","authors":"Sean Misek, Anna Borgenvik, Daniel Christen, Gloria Kyrila, Alexander Zhang, Sarah Reel, Michelle Boisvert, Kelly Cai, Kevin Zhou, Elizabeth Gonzales, Lorena Lazo de la Vega, Timothy Ragnoni, Nicole Persky, Tanaz Abid, Esteban Miglietta, Sergey Vakhrushev, Michael Stumpe, Jacquelyn Jones, Seth Malinowski, Lobna Elsadek, Aaron Fultineer, Kira Tang, Antonio Maldera, Hyesung Jeon, Sangita Pal, Todd Golub, William Hahn, Eric Fischer, Jesse Boehm, Jörn Dengjel, Henrik Clausen, Nada Jabado, Till Milde, Anne Carpenter, Beth Cimini, Keith Ligon, Katherine Janeway, Michael Eck, David Root, David Jones, Timothy Phoenix, Rameen Beroukhim, Hiren Jitendra Joshi, Tilman Tilman, Adnan Halim, Pratiti Bandopadhayay","doi":"10.1158/1538-7445.fusionpositive26-b026","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-b026","url":null,"abstract":"The most common fusion oncoprotein in the most common pediatric solid tumor, pediatric low-grade glioma (pLGG), is KIAA1549::BRAF. Although MAPK inhibitors show early promise, they often fail to achieve durable cures, highlighting the need to develop new therapeutics for KIAA1549::BRAF-driven tumors. In this study we leverage genome-scale anti-transformation CRISPR screens to uncover KIAA1549::BRAF-specific genetic vulnerabilities. Across all genes, POMT1 and POMT2, the two members of the heterodimeric Protein O-mannosyltransferase (POMT) complex emerge as the strongest KIAA1549::BRAF-specific dependencies. We demonstrate that KIAA1549 is a direct substrate of this complex, and that glycosylation of KIAA1549::BRAF by POMT is necessary for its maturation through the secretory pathway and subsequent oncogenic signaling. These data highlight for the first time a new route to directly target KIAA1549::BRAF independent of the MAPK pathway. This work also uncovered an unexpected and previously unrecognized role for KIAA1549 in driving KIAA1549::BRAF oncogenic signaling. The prevailing dogma has been that BRAF fusions exert their transforming activity through truncation and removal of N-terminal regulatory domains, thereby rendering the BRAF kinase domain constitutively active. We demonstrate that BRAF fusion partners, including KIAA1549, contain domains that facilitate membrane localization, thereby enhancing BRAF signaling. These findings challenge the traditional view of BRAF fusion biology and establish a role for fusion partners in shaping oncogenic potential. Citation Format: Sean Misek, Anna Borgenvik, Daniel Christen, Gloria Kyrila, Alexander Zhang, Sarah Reel, Michelle Boisvert, Kelly Cai, Kevin Zhou, Elizabeth Gonzales, Lorena Lazo de la Vega, Timothy Ragnoni, Nicole Persky, Tanaz Abid, Esteban Miglietta, Sergey Vakhrushev, Michael Stumpe, Jacquelyn Jones, Seth Malinowski, Lobna Elsadek, Aaron Fultineer, Kira Tang, Antonio Maldera, Hyesung Jeon, Sangita Pal, Todd Golub, William Hahn, Eric Fischer, Jesse Boehm, Jörn Dengjel, Henrik Clausen, Nada Jabado, Till Milde, Anne Carpenter, Beth Cimini, Keith Ligon, Katherine Janeway, Michael Eck, David Root, David Jones, Timothy Phoenix, Rameen Beroukhim, Hiren Jitendra Joshi, Tilman Tilman, Adnan Halim, Pratiti Bandopadhayay. O-mannosylation and protein maturation checkpoints represent therapeutic opportunities in BRAF fusion protein oncogenesis [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 B026.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"53 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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