Cancer research最新文献

{"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}

{"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 < 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}

{"title":"Abstract B025: Elucidating the role of ZFTA-RELA in radiation resistance in ependymoma","authors":"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","doi":"10.1158/1538-7445.fusionpositive26-b025","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-b025","url":null,"abstract":"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.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"39 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 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<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}

{"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 >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","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}

{"title":"Abstract A013: Hi-C DNA Sequencing of Solid Tumors for Rearrangements and Fusions Detects Targetable Biomarkers Missed by RNA Sequencing","authors":"Alex Hastie","doi":"10.1158/1538-7445.fusionpositive26-a013","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-a013","url":null,"abstract":"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","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"38 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B031: The fibrolamellar carcinoma database","authors":"Daniel F. Guevara-Diaz, David Requena, Sanford M. Simon","doi":"10.1158/1538-7445.fusionpositive26-b031","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-b031","url":null,"abstract":"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.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"120 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A006: Transcriptomic landscape of fusion-driven CNS tumors for the design and validation of junction-specific antisense oligonucleotide-mediated targeting of fusion oncogenes","authors":"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","doi":"10.1158/1538-7445.fusionpositive26-a006","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-a006","url":null,"abstract":"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,","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"30 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A030: Detection of Clinically Actionable RNA Fusions Across Multiple Cancer Types Using Optimized cfRNA Extraction from Diverse Sample Matrices","authors":"Nafiseh Jafari, Yabin Lu, Jason Saenz, Carlos Hernandez, Daniel Cedeno, Cameron Van Dieren, Mayer Saidian","doi":"10.1158/1538-7445.fusionpositive26-a030","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-a030","url":null,"abstract":"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","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"38 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LT003: Fetal differentiation programs afford a protective barrier to NUP98 fusion-driven AML initiation","authors":"Jihye Yoon, Elisabeth Denby, Wei Yang, Run Zhang, Emily B. Casey, Riddhi M. Patel, Yanan Li, J. Michael White, Luis Batista, Jeffrey Magee","doi":"10.1158/1538-7445.fusionpositive26-lt003","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-lt003","url":null,"abstract":"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 ","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":"145962043","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}