Cancer research最新文献

{"title":"Abstract A018-PR014: B7-H3-CAR T cells expressing 41BB ligand for pediatric solid tumors: Preliminary results of a phase 1 study","authors":"Rebecca Epperly, Teresa Santiago, Selene Koo, Lindsay Talbot, Elaine Harstead, Jennifer Wallace, Alexandra Boyd, Jennyfer Bran, Timothy Lockey, Catherine Willis, Faizan Malik, Ying Li, Leigh Poston, Sarah Schell, Polly Adams, Manjul Rana, Scott Perry, Jean-Yves Metais, Deanna Langfitt, Salem Akel, Frank Fazio, Renee Madden, Esther Obeng, Ali Suliman, M Paulina Velasquez, Amr Qudeimat, Caitlin Zebley, Senthil Bhoopalan, Akshay Sharma, Aimee C Talleur, Swati Naik, Brandon M Triplett, Michael Frett, Vinod Maller, Andrew Smith, Michael Bishop, Sara Federico, Alberto Pappo, Andrew Davidoff, Cheng Cheng, Beth McCarville, Stephen Gottschalk, Chris DeRenzo","doi":"10.1158/1538-7445.pediatric25-a018-pr014","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-a018-pr014","url":null,"abstract":"In this phase 1 dose escalation study (3CAR; NCT04897321) we are evaluating the safety and antitumor activity of a B7-H3-targeted chimeric antigen receptor (B7-H3-CAR) T cell strategy for pediatric patients with relapsed/refractory (r/r) solid tumors. These patients have poor outcomes despite multimodal therapy and need novel therapeutic approaches. B7-H3 is an immunomodulatory protein broadly expressed in solid tumors, with limited expression in healthy tissues, making it an attractive target for immunotherapy. We developed B7-H3-CAR T cells with a CD28.ζ signaling domain, which express 41BB ligand (41BBL) on the cell surface to provide additional costimulation. B7-H3-CAR T cells were generated from CD4+/CD8+ selected autologous apheresis products using a lentiviral vector encoding both the B7-H3-CAR and 41BBL. In this study we are evaluating a single systemic infusion of B7-H3-CAR T cells following fludarabine/cyclophosphamide lymphodepletion in pediatric patients with r/r solid tumors. B7-H3 expression was confirmed by immunohistochemistry on previously obtained tissues using a CLIA-approved assay, with an H-score ≥ 100 considered positive. Evaluated dose levels (DLs) include 3x105 (DL1), 1x106 (DL2), 3x106 (DL3), 1x107 (DL4), and 3x107 (DL5) CAR+ cells/kg. We have enrolled 23 participants for T cell collection, all of whom had successful B7-H3-CAR T cell products manufactured. As of July 2025, 16 participants received B7-H3-CAR T cells (DL1: n=4, DL2: n=3, DL3: n=3, DL4: n=5, DL5: n=1). The median age was 15.1 years (range 4.8-21.3), and participants had a range of solid tumor diagnoses (osteosarcoma n=4, rhabdomyosarcoma n=3, Ewing sarcoma n=2, hepatoblastoma n=2, other soft tissue sarcomas n=5) with a median H-score of 173 (range 110-250). No dose-limiting toxicities were observed among 15 evaluable participants. Nine participants experienced cytokine release syndrome (grade 1: n=7, grade 2: n=2), characterized by early onset fevers starting within 12 hours post-infusion. No participants experienced neurotoxicity. Ten participants underwent tumor biopsy 2 weeks post-infusion. Post-treatment B7-H3 expression was retained in seven of eight quantifiable specimens (median H-score 190, range 30-220). Two participants had local inflammation at superficial tumor sites, with accompanying necrosis on post-treatment biopsies. Imaging-based disease response at 4-6 weeks post-infusion included: 8 stable disease, 7 progressive disease, and 1 not evaluable due to excisional biopsy of a solitary target lesion. B7-H3-CAR T cells were detected in the peripheral blood by qPCR consistently starting with DL2 and were also detected in the peritoneal fluid of a participant with sarcomatosis. B7-H3-CAR T cells can be safely infused in pediatric patients with r/r solid tumors with evidence of homing to tumor sites and antitumor activity. Enrollment is ongoing to establish a recommended CAR T cell dose for further evaluation. Citation Format: Rebecca Epperly, Teres","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"2 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140992","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 A048: Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy","authors":"Helen S Mueller","doi":"10.1158/1538-7445.pediatric25-a048","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-a048","url":null,"abstract":"Essential epigenetic dependencies have become evident in many cancers. Based on functional antagonism between BAF/SWI/SNF and PRC2 in SMARCB1-deficient sarcomas, we and colleagues recently completed the clinical trial of the EZH2 inhibitor tazemetostat, leading to its FDA approval. However, the principles of tumor response to epigenetic therapy in general, and tazemetostat in particular, remain unknown. First, using functional genomics of patient tumors and diverse experimental models, we define molecular mechanisms of tazemetostat resistance in SMARCB1-deficient sarcomas and rhabdoid tumors. We found distinct classes of acquired mutations that converge on the RB1/E2F axis and decouple EZH2-dependent differentiation and cell cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest despite EZH2 inhibition, and suggests a general mechanism for effective EZH2 therapy. We provide prospective biomarkers for therapy stratification, including the cell cycle-regulated PRICKLE1 gene. To circumvent tazemetostat resistance and improve response in vitro and in vivo we develop the rational combination of tazemetostat with barasertib, to target the downstream cell cycle kinase AURKB. Second, through transcriptomic inference of SMARCB1-deficient tumor cells, we predicted ATR as a target to overcome resistance to EZH2 inhibition. We found that EZH2 inhibition induces DNA damage, at least in part via upregulation of the transposase-derived PGBD5 nuclease. Finally, we establish a second rational combination strategy for increased anti-tumor efficacy between tazemetostat and the ATR inhibitor, elimusertib, by leveraging the synthetic lethal interaction with PGBD5-dependent DNA damage repair signaling via ATR. Thus, the epigenetic therapy, EZH2 inhibition, induces a targetable collateral vulnerability through activation of the PGBD5-ATR axis. This establishes a mechanistically rational combination strategy for targeting EZH2 and ATR in SMARCB1-deficient cancers based on an EZH2-PGBD5-ATR synthetic lethal axis and is immediately translatable to clinical trials for patients with these aggressive malignancies. Citation Format: Helen S Mueller. Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr A048.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"100 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140993","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 B006: Tissue-specific mutational outcomes underlying the late effects of anthracyclines on tumours, blood, and heart","authors":"Mathepan Jeya Mahendralingam, Mehdi Layeghifard, Burçak Otlu, Timmy Wen, Yael Babichev, Syed Kashif Daud, Shreya Gramolini, Rebecca Gladdy, Anita Villani, Seema Mital, Filio Billia, Adam Shlien","doi":"10.1158/1538-7445.pediatric25-b006","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-b006","url":null,"abstract":"Motivation: Anthracyclines, a cornerstone chemotherapy, disproportionately contributes to several late effects burdening survivors of cancer, including cancer relapse, therapy-related blood cancers, and fatal cardiotoxicity. Despite decades of clinical use, the mechanisms underlying these late effects – particularly how anthracyclines damage the genome of various tissues (tumours, blood, and heart) – remain poorly understood. Methods: We assembled a cohort of untreated or anthracycline-treated tumour, blood, and heart samples. Tumours and blood were leveraged from childhood cancer patients enrolled in the SickKids Cancer Sequencing Program. Heart samples were obtained from cancer survivors who received anthracyclines and later developed severe cardiotoxicity that required a heart transplant. We sequenced the DNA of each tissue type to identify anthracycline-induced somatic mutations. Results: Our initial results revealed minimal genome-wide mutational differences between anthracycline-treated versus untreated samples across all tissue types. We hypothesized that anthracyclines may instead alter the topography, rather than burden, of somatic mutations. Indeed, we found that anthracycline-treated tissues had a strong enrichment of somatic mutations in open chromatin of their respective cell of origin. Anthracycline-treated tumours had a unique enrichment of single nucleotide variants, especially C>T mutations, in promoters and introns. Open chromatin promoter regions demonstrated a unique enrichment for C[C>T]G mutations, reminiscent of a thiopurine signature seen in relapsed acute lymphoblastic leukemia. To validate these findings, we generated and sequenced doxorubicin resistant cancer cell lines, which confirmed that anthracycline-induced somatic mutations preferentially occur in open chromatin regions. Despite the heart’s non-proliferative capacity, anthracycline-treated hearts had a significant enrichment of insertion-deletions in fetal cardiomyocyte open chromatin and non-B DNA regions. However, we did not find any exonic mutations in anthracycline-treated hearts, suggesting that disruption of the non-coding genome results in cardiotoxicity. Unexpectedly, we did not find any enrichment of somatic mutations in open chromatin regions for anthracycline-treated blood samples. Lastly, comparative analysis of the somatic mutational profiles of anthracycline-exposed hearts, tumours, and blood samples, we uncovered previously underappreciated tissue-specific mutational signatures. Significance: This study is the first to characterize the tissue-specific genomic consequences of anthracyclines on tumours, blood, and heart. We establish a foundation for developing tissue-specific mutational signatures as predictive biomarkers for the late effects. The early identification of high-risk patients will transform survivorship care, ensuring children with cancer do not merely survive their diagnosis – they thrive beyond it. Citation Format: Math","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"37 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140937","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 A021: Standardized Oncogenic Classification Guidance of Critical Diagnostic and Therapeutic markers in pediatric cancers: NTRK fusions","authors":"Jason Saliba, Shivani Golem, Arpad Danos, Laura B Corson, Morteza Seifi, Jan Clement Santiago, Emma G Sullivan, Scott Myrand, Elan Hahn, Valentina Nardi, Theodore W Laetsch, Marilyn M Li, Obi L Griffith, Malachi Griffith, Gordana Raca, Larissa V Furtado, Angshumoy Roy, Alanna J Church","doi":"10.1158/1538-7445.pediatric25-a021","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-a021","url":null,"abstract":"Gene fusions involving neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, & NTRK3) are well-established oncogenic drivers and serve as critical diagnostic and therapeutic markers in pediatric hematologic malignancies and solid tumors. The accurate and consistent interpretation of their clinical significance is a high priority given FDA approval of TRK inhibitors; however, this remains challenging due to the rapid pace of fusion discovery, the diversity of fusion partners and tumor types, inconsistent and incomplete reporting of fusion data elements, and the lack of standardized fusion-specific classification guidelines. The Clinical Genome Resource (ClinGen) NTRK Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) is addressing these challenges and creating a publicly available resource of high-quality clinically significant NTRK fusion classifications in the Clinical Interpretation of Variants in Cancer (CIViC; civicdb.org) knowledgebase to support patient care. ClinGen SC-VCEPs follow a rigorous 4-step process to reach approval status. Following the definition of scope and membership recruitment (Step 1), standardized guidance was created to determine the oncogenicity of NTRK fusions (Step 2). This guidance was piloted on 12 NTRK fusions ranging from rare to common (Step 3). After incorporating modifications to the classification guidelines directly influenced by the pilot, we established protocols for prioritizing NTRK fusions for classification (Step 4). The NTRK SC-VCEP created the first-ever standardized guidance to classify the oncogenicity of NTRK fusions through the systematic compilation, review, and discussion of fundamental fusion element annotations. The NTRK fusion-specific oncogenicity guidelines classify NTRK fusions as Oncogenic, Likely Oncogenic, Fusion of Unknown Significance (FUS), or Benign based on Fusion Structure (orientation/breakpoints/reading frame), Cancer Association (number of unique cases), Clinical Validity (targeted inhibitor response), and Functional Status (pathway activation or expression). Over 190 evidence items from 93 publications have been curated into CIViC, with over 20% tagged with Human Phenotype Ontology age of onset terms as part of our pediatric dataset. For the pilot, 12 Oncogenic classifications (6 Oncogenic, 1 Likely Oncogenic, 2 FUS, 3 Benign) were created along with 5 diagnostic and 12 therapeutic response classifications. We established sustained protocols to direct our ongoing coordinated team effort to evaluate the 90-plus NTRK fusions we’ve identified from public databases and private member laboratory lists and to maintain their up-to-date record in CIViC with broader distribution in ClinVar. Completing the ClinGen 4-step approval process assures access, accuracy, and transparency of the variant-level evidence, assessment process, and classifications of the NTRK SC-VCEP. As the first SC-VCEP to navigate this process, the work of the NTRK SC-VCEP provides the blueprin","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"28 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140939","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 A014: Understanding the transcriptional heterogeneity of pediatric low-grade gliomas and its implication for tumor pathophysiology","authors":"Michelle Boisvert, Ashwyn Perera, Alexandra L. Condurat, John Jeang, Jessica W. Tsai, Dana Novikov, Kevin Zhou, Madison Chacon, Jeromy DiGiacomo, Rushil Kumbhani, Dayle Wang, Michael D. Taylor, Jordan R. Hansford, Louise Ludlow, Nada Jabado, Keith L. Ligon, Rameen Beroukhim, Pratiti Bandopadhayay, David T.W. Jones","doi":"10.1158/1538-7445.pediatric25-a014","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-a014","url":null,"abstract":"Pediatric low-grade gliomas (pLGGs) are the most frequent brain tumors in children and comprise a heterogeneous group of tumors with different locations, histologic subtypes, ages at presentation, and clinical behavior. Tumors frequently respond to treatment with chemotherapy or radiation therapy, but they can regrow after a period of quiescence, requiring further therapy. Thus, a deeper understanding of the molecular processes involved in these tumors is required to develop therapeutic strategies that are effective against their disease mechanisms. To better understand the cellular behaviors of this heterogenous group of tumors, we have employed single-cell and single-nuclei RNA sequencing technologies to analyze a large-scale dataset (>250,000 cells) of pLGGs. Analysis of this data identified a heterogenous population of cell types and cell states, detecting mature and progenitor-like astrocytes and oligodendrocytes, as well as cells exhibiting senescence or cycling programs. Moreover, we identify a significant immune infiltrate, comprised primarily of microglia. In addition to heterogeneity within pLGG tumors, heterogeneity between LGG subtypes represents another layer that stratifies pLGG biology. We performed a compositional analysis of the cell types present in these tumors and compared transcription signatures and gene expression programs across shared cellular populations of histologically and genetically distinct pLGGs. Finally, we optimized our integration and batch correction analyses by using external 293T cells as spike in controls during our single-cell and single-nuclei data generation steps to determine the most suitable method for batch-effect removal. Our analysis of human pLGGs at the single-cell and single-nuclei resolution provides critical insight into the heterogenous biological activities that constitute these tumors. Citation Format: Michelle Boisvert, Ashwyn Perera, Alexandra L. Condurat, John Jeang, Jessica W. Tsai, Dana Novikov, Kevin Zhou, Madison Chacon, Jeromy DiGiacomo, Rushil Kumbhani, Dayle Wang, Michael D. Taylor, Jordan R. Hansford, Louise Ludlow, Nada Jabado, Keith L. Ligon, Rameen Beroukhim, Pratiti Bandopadhayay, David T.W. Jones. Understanding the transcriptional heterogeneity of pediatric low-grade gliomas and its implication for tumor pathophysiology [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr A014.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"193 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140934","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 B039: Exploring the early genetic determinants of tumor risk in Li-Fraumeni Syndrome","authors":"Laura Raiti, Tanvi Anandampillai, Anita Villani, Adam Shlien, David Malkin, Yiming Wang","doi":"10.1158/1538-7445.pediatric25-b039","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-b039","url":null,"abstract":"Background Li-Fraumeni Syndrome (LFS), caused by germline pathogenic variants in the TP53 tumor suppressor gene, is a highly penetrant cancer predisposition syndrome with lifetime cancer risk approaching 100%. Surveillance protocols have led to improved survival, and it is optimal to identify patients before tumor development. LFS exhibits broad phenotypic heterogeneity in age of onset and tumor subtype, likely related to other germline genetic/epigenetic variants and early acquired somatic variants. We have previously shown that loss of heterozygosity (LOH) and mutant TP53 copy gain arise years before tumor diagnosis (Light N, 2023). Hypothesis TP53 LOH and other somatic cancer driver mutations arise prenatally, with further clonal evolution after birth, and dictate the postnatal tumor risk in LFS. Aims Explore prenatal cancer driver mutations and their postnatal clonal evolution to define tumor risk in LFS. Methods We have recruited 20 children with LFS and collected their clinical history. Their archived Newborn Screening Dried Blood Spots (DBS), and those from 5 healthy controls, will be sequenced (leukocyte genomic DNA and cell-free DNA) using a deep, comprehensive cancer gene panel (905 genes) and Whole Genome Sequencing. Sequencing data will be analyzed using our established bioinformatic pipeline. We will focus on TP53 LOH and established cancer driver mutations seen in tumors associated with LFS, accompanied by global mutational landscape analysis. These findings will be compared to sequencing data from matched postnatal germline and tumor samples, accessible through our previous genomic studies. Results 25 participants have been enrolled in our study: 5 controls and 20 children with LFS, of which 65% (13/20) are female. 55% (11/20) have had a prior malignancy, one each of osteosarcoma, CNS sarcoma, and low grade glioma, two each of acute lymphoblastic leukemia, rhabdomyosarcoma and adrenocortical carcinoma, and four with astrocytoma. 15% (3/20) have a history of two prior malignancies. 35% (7/20) have had paired tumor/germline sequencing through the KiCS (Kids Cancer Sequencing) Program or the SickKids LFS registry. DNA extraction is currently underway for the first 10 DBS samples from patients with LFS, followed by DNA sequencing and analysis. Impact The data will provide critical insights into the prenatal origin of cancer and the unique clonal evolution related to cancer development. Our study has the potential to impact surveillance practices and discover new links between prenatally acquired mutations and pediatric cancers, which may reveal novel approaches for early therapeutic interception and prevention. Citation Format: Laura Raiti, Tanvi Anandampillai, Anita Villani, Adam Shlien, David Malkin, Yiming Wang. Exploring the early genetic determinants of tumor risk in Li-Fraumeni Syndrome [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Brea","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"11 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141154","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 A031: A combined degrader-antisense therapeutic for fibrolamellar carcinoma","authors":"Mahsa Shirani, Ronaldo Shaquille Bowie, Michael Tomasini, Denise Ng, Ruth Hook, Barbara Lyons, Philip Coffino, Sanford Simon","doi":"10.1158/1538-7445.pediatric25-a031","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-a031","url":null,"abstract":"Introduction: Many pediatric cancers, are driven by fusion oncoproteins. Since each fusion partner originates from a native protein with essential functions, it is important but difficult to selectively target fusion oncoproteins while sparing native components. FLC is a usually lethal primary liver tumor of adolescents and young adults driven by an oncogenic fusion between the first exon of DNAJB1, a heat shock protein, to the bulk of the coding region of PRKACA, the catalytic subunit of protein kinase A (PKA), forming DNAJB1::PRKACA. Since the active sites of the DNAJB1::PRKACA and native PRKACA are structurally indistinguishable, designing inhibitors specific to the fusion protein is challenging. Currently, there is no accepted therapy for FLC. Brief summary: We present a new therapeutic strategy that is applicable to other Fusion Oncoprotein-driven Malignancies. We designed a single molecule that encodes both a degrader to eliminate the oncoprotein and an antisense to eliminate the mRNA encoding the oncoprotein. Results: The degrader is based on a peptide that binds exclusively to PRKACA or DNAJB1::PRKACA, expressed as a fusion to an E3 ligase. The peptide-E3 selectively eliminates just the fusion oncoprotein without affecting the native kinase. This design allows the choice of E3 that is optimized for the tumor and location of the oncoprotein. This degrader is sufficient not only to eliminate the fusion oncoprotein but to eliminate patient tumors growing in mice, with no detectable effects on the physiology of the mouse or the healthy liver. This degrader was delivered as an mRNA. This empowered using the same mRNA to then encode an siRNA against the oncoprotein. Together the degrader-antisense combo more rapidly and completely eliminated the fusion oncoprotein and, together, greatly reduce the opportunities for mutational escape. Conclusion: This combined approach can be adopted to any target mutant protein driving other pediatric tumors. Citation Format: Mahsa Shirani, Ronaldo Shaquille Bowie, Michael Tomasini, Denise Ng, Ruth Hook, Barbara Lyons, Philip Coffino, Sanford Simon. A combined degrader-antisense therapeutic for fibrolamellar carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr A031.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"42 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140988","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 B017: Precision Nanotherapy for the Treatment of Progressive Neuroblastoma","authors":"Loganayaki Periyasamy, Poorvi Subramanian, Sheeja Aravindan, Afsana Parveen Jahir Hussain, Natarajan Aravindan","doi":"10.1158/1538-7445.pediatric25-b017","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-b017","url":null,"abstract":"Deadly progressive neuroblastoma (pNB) that defy current clinical therapy is a devastating pediatric malignancy with frequent relapses and negligible <2% long-term survival. Appropriately, global efforts are in place to identify new and effective molecular-targeted maintenance therapies. Owing to our recent findings on the function of Retinal Degeneration 3 (RD3) in NB pathogenesis, particularly in therapy resistance and disease evolution, we aimed to develop and characterize RD3-targeted therapeutic strategy for pNB. Herein, we archived novel targeted therapeutic deliverables and assessed their efficacy in treating clinical therapy defying pNB, as well evaluated their safety profiles. Five unique RD3 peptides were synthesized, labeled, capped, and assessed for their cellular homing capacities. NB targeted (GD2) RD3-peptide loaded immunoliposomes (RD3Þ[GD2]IL) were constructed and characterized for size distribution (NT Analyzer NS300), encapsulation efficacy (absorbance) and structural integrity (TEM). Xenografts developed in athymic nude mice with pNB cells derived from retroperitoneum (CHLA-20) were treated with plain liposomes or RD3Þ[GD2]IL 1 through 5 (i.v. 5mM) 3 days/week for 4 weeks were assessed for tumor regression, differentiation, and normal tissue toxicity if any. All RD3Þ[GD2]IL formulations demonstrated significant anti-tumor efficacy compared to controls. Micromorphological analysis indicated no defined toxicity in health tissues and major organs. Relatively, RD3Þ[GD2]IL-3 displayed high efficacy with substantial reduction in tumor volume . Histopathology revealed that tumors treated with RD3Þ[GD2]IL-3 exhibited a well-differentiated phenotype in the residual tumor, in stark contrast to the poorly differentiated morphology observed in control groups. Together, the results present a novel, targeted nano therapy that effectively suppresses pNB growth and restores differentiation. RD3Þ[GD2]IL-3 demonstrates the ability to both inhibit pNB progression and promote tumor cell dedifferentiation, the two critical challenges in the treatment of resistant/refractory disease. When integrated with existing intensive multi-modal clinical therapies, RD3Þ[GD2]IL-3 holds the potential to redefine the therapeutic landscape and deliver desirable clinical benefit in a setting where options are currently not available. Funding: This work was funded by the DoD-CA-210339, OCAST-HR19-045, NIH P20GM103639 to Dr. Aravindan and NCI-P30 CA225520, OK-TSET-R23-03 and NIGMS P30GM154635 awarded to the OU Health SCC. Citation Format: Loganayaki Periyasamy, Poorvi Subramanian, Sheeja Aravindan, Afsana Parveen Jahir Hussain, Natarajan Aravindan. Precision Nanotherapy for the Treatment of Progressive Neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"4 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140995","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 B005: Evaluation of TP53 expression in pediatric b-cell acute lymphoblastic leukemia and its correlations with clinicopathological profiles","authors":"HASIB THONDIKODAN, AMITA TREHAN, PRATEEK BHATIA, PARMINDER KAUR, MINU SINGH","doi":"10.1158/1538-7445.pediatric25-b005","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-b005","url":null,"abstract":"Evaluation Of TP53 Expression in Pediatric B- Cell Acute Lymphoblastic Leukemia And Its Correlation With Clinicopathological Profiles Authors: Hasib Tk, Parminder Kaur, Prateek Bhatia, Amita Trehan, Minu SinghAffiliation: Advanced pediatric Centre, Postgraduate Institute of Medical Education and Research (PGIMER) , Chandigarh , India. Background: TP53 is a tumor suppressor gene which impacts tumor progression and prognosis in various cancers. TP53 isoforms regulate key processes like cell cycle arrest, apoptosis, and DNA repair. Elevated TP53 expression in B-cell ALL correlates with poor outcomes, making it a potential prognostic marker and therapeutic target. This study aimed at to evaluate the expression of TP53 isoforms and its correlation with clinicopathological profiles in pediatric B-cell ALL patients. Materials and methods: One hundred pediatric B-cell ALL patients (≤12 years) and 20 age matched healthy controls were enrolled for this study. Expression of TP53 full-length and isoform Delta40TP53, Delta133TP53, TP53Beta expressions was checked using qRT-PCR. Fold change was calculated using 2- DDCt method. The expression of isoforms was correlated with various clinical parameters such as risk stratification, blast count, molecular cytogenetics etc. Results: The median age of the patients was 5 years with male: female ratio of 1.2:1. 52% patients had high expression of TP53 full gene expression with the maximum fold change of 9.99-fold. Isoform Delta40TP53, Delta133TP53 and TP53Beta was overexpressed in 17%, 53% and 6% of the patients respectively. Delta133TP53 showed significant association with presence of ETV6::RUNX1 (p=0.047) which is associated with standard risk. The presence of KMT2A::AF4 which is linked with poor prognosis was also associated with TP53Beta expression (p=0.043). However, we could not find significant association between expression of TP53 isoforms and other clinical parameters such as age, gender, TLC, MRD, or progressive disease etc. in pediatric ALL patients. Conclusions: Our study has shown that the expression of full length TP53 and its isoforms is dysregulated in Pediatric B-ALL patients. These findings suggest that Delta133TP53 could be further explored as a potential biomarker for standard risk, whileTP53Beta might serve as an indicator of poor risk in ALL, warranting further investigation in larger cohorts. Citation Format: HASIB THONDIKODAN, AMITA TREHAN, PRATEEK BHATIA, PARMINDER KAUR, MINU SINGH. Evaluation of TP53 expression in pediatric b-cell acute lymphoblastic leukemia and its correlations with clinicopathological profiles [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr B005.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"24 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140998","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 IA001: Targeting chromatin modulators with therapeutic degraders","authors":"Gromek Smolen","doi":"10.1158/1538-7445.pediatric25-ia001","DOIUrl":"https://doi.org/10.1158/1538-7445.pediatric25-ia001","url":null,"abstract":"E1A binding protein (EP300) is a histone acetyltransferase, which modifies chromatin and drives the expression of oncogenes critical in several hematological malignancies and solid tumors. Current pharmacological inhibitors targeting EP300 are not very selective and result in adverse effects, such as thrombocytopenia. Therefore, the development of agents that selectively target EP300 is of high interest as it has the potential to broaden the therapeutic window. Using the targeted degradation approach, we have developed a potent and selective heterobifunctional degrader of EP300 with biological activity in multiple hematological malignancies, including diffuse large B-cell lymphoma, multiple myeloma, and follicular lymphoma. We observed excellent translation of in vitro sensitivities to profound efficacies in a series of xenograft-based in vivo studies. Importantly, an investigational safety study was performed in mice at efficacious doses, and no thrombocytopenia was observed. To further investigate the therapeutic potential of this novel class of agents, we also demonstrated synergistic effects of EP300 degraders with several standard-of-care agents (such as IMiDs, dexamethasone, and venetoclax) in several tumor indications. Collectively, leveraging targeted protein degradation to achieve selective EP300 degradation shows promise to be a well-tolerated and effective treatment strategy for multiple hematological malignancies. Citation Format: Gromek Smolen. Targeting chromatin modulators with therapeutic degraders [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2): nr IA001.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"11 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140872","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}