tbuckley/cabot-search huggingface dataset:
Abstract LB358: Single cell RNA sequencing of cerebrospinal fluid lymphocytes in CARv3 TEAM E treated glioblastoma patients
Authors: Christopher Mount, Demi Gerovasilis, Sophia Kovatsis, Jun Zhong, Md Raihan Chowdhury, Maxx King, William T. Curry, Elizabeth R. Gerstner, Kathleen M. Gallagher, Bryan D. Choi, Mario Suva, Marcela V. Maus
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) is a devastating primary brain tumor of adults with few treatment options. While there has been long-standing interest in engaging the immune system to combat this disease, monoclonal antibody therapies – including checkpoint modulating agents – have yet to result in widespread clinically meaningful outcomes. By contrast, adoptive cell therapies including chimeric antigen receptor (CAR)-T cell therapies have demonstrated promising early indications of efficacy in select GBM patients. However, heterogeneity of target molecule expression remains a significant barrier to long-term disease control. In a recent report, a first-in-human trial of CARv3-TEAM-E T cells engineered to target the epidermal growth factor receptor variant III tumor-specific antigen (EGFRvIII) as well as wild-type EGFR through secretion of a T-cell-engaging antibody molecule (TEAM) showed preliminary evidence of CAR activity. We now report the results of single cell RNA-sequencing (scRNA seq) of lymphocytes isolated from the cerebrospinal fluid (CSF) of CARv3-TEAM-E treated GBM patients. Longitudinal CSF sampling in these patients was performed via an Ommaya reservoir. Sampled cells were interrogated by scRNA Seq. We demonstrate the ability to detect transduced CARv3-TEAM-E expressing T cells in the CSF from these patients. Unsupervised analysis revealed evidence of the expression of cytotoxic effector gene expression programs, which we explore over the course of longitudinal sampling in this initial cohort. Additionally, we compare expression signatures in the CSF-sampled T cells to those present in the CARv3-TEAM-E infusion products. Taken together, our findings offer insight into the longitudinal dynamics of T cell gene expression programs in the setting of this first-in-human trial of CARv3-TEAM-E T cells in GBM patients. Citation Format: Christopher Mount, Demi Gerovasilis, Sophia Kovatsis, Jun Zhong, Md Raihan Chowdhury, Maxx King, William T. Curry, Elizabeth R. Gerstner, Kathleen M. Gallagher, Bryan D. Choi, Mario Suva, Marcela V. Maus. Single cell RNA sequencing of cerebrospinal fluid lymphocytes in CARv3 TEAM E treated glioblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB358.
Abstract SY27-02: Exploring the significance of somatic mtDNA mutations in the context of acute leukemia
Authors: Mondira Kundu
Journal: Cancer Research (2025)

Abstract Somatic mitochondrial DNA (mtDNA) mutations are commonly observed in tumors, yet their functional role in pediatric cancers remains largely unexplored. The unique biology of mtDNA—including its heteroplasmic nature, where mutant and wild-type mtDNA coexist—poses challenges in understanding its contribution to disease progression. To address this, we utilized an integrative approach combining bulk whole-genome sequencing, single-cell analysis, and experimental modeling. Analysis of 637 matched tumor and germline samples from the Pediatric Cancer Genome Project revealed an enrichment of functional-impact mtDNA variants in specific pediatric leukemia subtypes. Single-cell sequencing of diagnostic leukemia samples demonstrated that somatic mtDNA mutations can emerge early in leukemogenesis and undergo positive selection, achieving intermediate heteroplasmy—a "sweet spot" balancing mitochondrial dysfunction and cellular fitness. Systems biology analyses linked these heteroplasmic mutations to functional heterogeneity and metabolic adaptability within leukemic cells. To directly investigate the role of mtDNA mutations in leukemogenesis, we studied hematopoietic progenitor cells (HPCs) with varying mtDNA mutation burdens using wild-type, heterozygous, and homozygous mtDNA mutator mice (Polg D257A). Heterozygous Polg HPCs exhibited a higher incidence of spontaneous leukemogenesis and supported oncogene-driven transformation, whereas homozygous Polg HPCs showed impaired leukemogenesis due to disrupted glucose metabolism and pyruvate dehydrogenase inhibition. These findings highlight the role of intermediate heteroplasmy in balancing mitochondrial dysfunction and cellular fitness, enabling leukemic cells to maintain metabolic adaptability. Targeting this balance may uncover novel therapeutic strategies to disrupt the metabolic plasticity driving pediatric leukemia progression. Citation Format: Mondira Kundu. Exploring the significance of somatic mtDNA mutations in the context of acute leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY27-02.
Abstract LB177: Visualization and targeting of CD133+ cancer stem cells in MASLD-related hepatocellular carcinoma
Authors: Yasi Pan, Xiang Zhang, Chi Chun Wong, Huarong Chen, Kai Yuan, Jun Yu
Journal: Cancer Research (2025)

Abstract Metabolic dysfunction-associated steatotic liver disease related hepatocellular carcinoma (MASLD-HCC) is an emerging malignancy. However, the identity and function of cancer stem cells (CSCs) in MASLD-HCC are largely unclear. Here, we aim to investigate the function, mechanism, and targeted therapy of CSCs in MASLD-HCC. Intravital genetic lineage tracing in mice demonstrated that CD133+ cells from high-fat high cholesterol diet (HFHC)-induced MASLD-HCC possess the characteristics of CSCs, including superior self-renewal capacity in vitro and tumorigenicity in vivo compared to CD133- counterparts. ScRNA-seq of CD133+ progenies revealed their clonal expansion into multiple lineages during tumor progression, highlighting the role of CD133+ CSCs in contributing to cellular plasticity in MASLD-HCC. Further, we showed that CD133 functionally drives CSC phenotypes in MASLD-HCC and that hepatocyte-specific Cd133 overexpression in mice accelerated MASLD-HCC formation driven by diethylnitrosamine plus choline-deficient, high-fat (CDHF) diet. Mechanistically, CD133 interacts with myosin heavy chain 9 (MYH9) to promote the stabilization of active β-catenin, thereby propagating Wnt/β-catenin signaling critical for CSC phenotypes as well as pro-tumorigenic potential. Accordingly, MYH9 knockdown abrogated the induction of Wnt/β-catenin by CD133. In terms of translational relevance, targeted ablation of CD133+ cells using a selective diphtheria toxin receptor system (DTRlslCd133-CreER) in mice sensitizes MASLD-HCC to multikinase inhibitors (Sorafenib and Lenvatinib). Moreover, targeting of CD133 by nanoparticle-siRNA in combination with Sorafenib synergized to induce regression of tumors in subcutaneous and orthotopic MASLD-HCC. In summary, our results indicate that CD133+ CSCs potentiate MASLD-HCC by activating Wnt/β-catenin signaling through MYH9 and is a therapeutic target, especially in combination with multikinase inhibitors. Citation Format: Yasi Pan, Xiang Zhang, Chi Chun Wong, Huarong Chen, Kai Yuan, Jun Yu. Visualization and targeting of CD133+ cancer stem cells in MASLD-related hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB177.
Abstract SY42-01: Targeting fluidic force sensing mechanism to treat brain tumor metastasis
Authors: Xi Huang
Journal: Cancer Research (2025)

Abstract Biofluid flow generates fluid shear stress (FSS), a mechanical force widely present in tissue microenvironment. How brain tumor growth alters the conduit of biofluid, thereby impacting FSS-regulated cancer progression is unknown. Medulloblastoma (MB), the most common pediatric malignant brain tumor, frequently obstructs the 4th ventricle and infiltrates the cerebrospinal fluid (CSF) conduit. Dissemination of MB cells into the CSF initiates metastasis within the central nervous system. By simulating CSF flow based on magnetic resonance imaging of MB patients, we discovered that FSS is elevated at the cervicomedullary junction. FSS promotes MB metastasis in mice and zebrafish. Mechanistically, FSS promotes cell behaviors conducive to metastatic escape and survival within the nutrient-deprived CSF: FSS weakens cell-substrate adhesion, increases motility, cell clustering, and plasma membrane localization of glucose transporter 1 (GLUT1) to enhance glucose uptake. FSS is perceived by mechanosensitive ion channel PIEZO2, which drives actomyosin contractility-dependent GLUT1 recruitment at the plasma membrane. Genetic targeting of PIEZO2 or pharmacologic inhibition of GLUT1 mitigates metastasis. Collectively, these findings define a targetable FSS-activated mechano-metastatic cascade for the treatment of MB metastasis. Citation Format: Xi Huang. Targeting fluidic force sensing mechanism to treat brain tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY42-01.
Abstract LB188: YF550 is a potent and selective inhibitor of KIF18A, specifically targeting CIN+ cancer cells
Authors: Yaolin Wang, Rongfeng Liu, Hong Yang, Yong Luo, Younong Yu, Jifang Weng, Yan Weng, Hong Mei, David Dai
Journal: Cancer Research (2025)

Abstract Chromosomal instability (CIN+) characterizes a continuous mitotic dysfunction leading to karyotypic abnormalities and aneuploidy, commonly observed in various human cancers, including ovarian, triple-negative breast (TNBC), and head-and-neck tumors, with significant implications for tumor progression and prognosis. KIF18A, a mitotic kinesin motor protein essential for chromosome alignment during cell division, is critical for the proliferation of CIN+ cells but dispensable in near-diploid cells. Inhibition of KIF18A results in mitotic delays, multipolar spindle formation, and elevated cell death in CIN+ tumor cells. YF550 is a highly selective and potent inhibitor in KIF18A inhibitor and CIN+ cellular proliferation assays, as well as in phospho-Histone H3 mitotic marker evaluation. YF550 exhibits exceptional selectivity for KIF18A over related protein Eg5 and several other proteins. In contrast to the Eg5 inhibitor Ispinesib, YF550 does not inhibit normal PBMC proliferation. Notably, the cellular potency of YF550 correlates with the aneuploidy score of CIN+ cancer cells, which may serve as a potential biomarker for patient stratification. YF550 has demonstrated synergistic effects when combined with various agents, including Olaparib (PARP inhibitor), PF-07104091 (CDK2 inhibitor), Elimusertib (ATR inhibitor), Volasertib (PLK1 inhibitor), and MMAE, in cellular proliferation assays. In the OVCAR3 ovarian cancer xenograft model, YF550 has shown superior efficacy compared to KIF18A inhibitor AMG650 at a 5 mg/kg dose, with no significant impact on body weight. Furthermore, YF550 induced tumor regression in both the OVCAR8 ovarian and JIMT-1 HER2 positive breast cancer xenograft models. YF550 exhibits superior ADME and PK property suitable for clinical development for CIN+ cancers with high aneuploidy score and has the potential for combination therapy with PD-1/L1 antibodies, PARP1 inhibitors, and MMAE based ADC. Citation Format: Yaolin Wang, Rongfeng Liu, Hong Yang, Yong Luo, Younong Yu, Jifang Weng, Yan Weng, Hong Mei, David Dai. YF550 is a potent and selective inhibitor of KIF18A, specifically targeting CIN+ cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB188.
Abstract LB174: REST-USP37 axis controls GLI1 levels in sonic hedgehog medulloblastoma cells
Authors: Ashutosh Singh, Donghang Cheng, Lei Guo, Amanda Haltom, Tara Dobson, Veena Rajaram, Lin Xu, Vidya Gopalakrishnan
Journal: Cancer Research (2025)

Abstract Background: Medulloblastoma (MB), the most common pediatric cerebellar tumor, has a 5-year survival rate of approximately 70-80%. About 30% of MBs are driven by Sonic Hedgehog (SHH) signaling mutations in PTCH1, SMO, and SUFU. RE1-Silencing Transcription factor (REST), a transcriptional repressor, plays a crucial role in SHH-MB progression. Previously, we have shown that elevated REST in SHH-MBs is linked to poor outcomes, and it controls SHH pathway by causing epigenetic loss of Ptch1 haploinsufficiency. This study explores REST's role in regulating SHH pathway effectors GLI1 and GLI2. Methods: Transcriptomic data was analyzed from publicly available RNA-seq and scRNA-seq datasets. Histological analysis of patient tumors and -derived xenografts, along with biochemical studies of SHH-MB cell lines, provided insights into REST-driven regulation of GLI in this MB subgroup. Summary: The scRNA-seq data of high- and low-REST SHH-MB patient tumors demonstrated an increase in cycling cerebellar granule progenitor cells (GNPs) in the context of REST elevation, which was associated with decreased GLI1 and increased GLI2 expression. Interestingly, we found that USP37-a REST target gene product and a deubiquitylase, controls GLI1 stability. USP37 decline in REST-high SHH-MBs reduces GLI1 levels, although cells are maintained in a proliferative state. GLI1 is also known to activate its own gene expression. So, we attribute the maintenance of cell proliferation under high REST conditions to the loss of stabilization of p27, a cyclin-dependent kinase inhibitor that is required for terminal cell cycle exit and initiation of terminal neurogenesis. A potential role for a compensatory increase in GLI2 levels in maintaining SHH pathway activity and cell proliferation cannot be excluded at this time. Consistent with this effect of REST on SHH signaling activity, GLI inhibitors reduce the growth of SHH-MB cells in vitro. Conclusion: In summary, our work has uncovered a novel REST-USP37-GLI1 axis in controlling SHH pathway activity in SHH-MBs. Our findings may have therapeutic implications for patients with SHH-MBs with REST elevation. Citation Format: Ashutosh Singh, Donghang Cheng, Lei Guo, Amanda Haltom, Tara Dobson, Veena Rajaram, Lin Xu, Vidya Gopalakrishnan. REST-USP37 axis controls GLI1 levels in sonic hedgehog medulloblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB174.
Abstract LB256: Circulating methylated <i>GCM2</i> and <i>TMEM240</i> as novel biomarkers for dynamic monitoring of breast cancer progression and treatment response
Authors: Chin-sheng Hung, Hsieh-Tsung Shen, Ruo-Kai Lin
Journal: Cancer Research (2025)

Abstract Background Breast cancer remains a leading cause of cancer-related deaths, with 20-30% of early-stage cases progressing to metastasis. Current biomarkers, such as CA15-3 and CEA, are limited in detecting metastases, necessitating improved diagnostic tools. This study develops and validates a blood test using methylated GCM2 and TMEM240 for monitoring breast cancer progression, treatment response, tumor burden, and clinical parameters. Methods A prospective study in Taiwan (396 patients) and a retrospective cohort from Western populations (134 samples) were analyzed. cfDNA was extracted, bisulfite-converted, and GCM2 and TMEM240 methylation levels were measured using QMSP. Monte Carlo cross-validation (1,000 iterations) was performed to assess sensitivity, specificity, and accuracy. Methylation changes were further evaluated for correlations with treatment response, tumor burden, and clinical parameters. Results In the training set (n = 166, 13.3% recurrence/metastasis), biomarker cut-offs were established. Validation in an independent cohort (n = 325, 20% recurrence/metastasis) demonstrated significantly improved diagnostic performance compared to CA15-3 and CEA, with an accuracy of 95.1%, sensitivity of 89.4%, specificity of 96.5%, PPV of 86.8%, and NPV of 97.3%. Monte Carlo analysis of the training data yielded an average sensitivity of 95.7%, specificity of 90.3%, and accuracy of 91.5%, while validation data achieved sensitivity of 92.8%, specificity of 89.5%, and accuracy of 90.3% across 1,000 replicates.Critically, methylation levels of GCM2 and TMEM240 demonstrated high utility for monitoring treatment response and tumor burden. Decreased methylation levels were observed in patients responding favorably to treatment, signifying therapeutic success, whereas increased methylation levels were strongly associated with cancer progression, including recurrence and pre-metastatic events. Positive methylation levels were also significantly associated with advanced-stage disease (P &amp;lt; 0.001), larger tumor size (P = 0.002), and distant metastasis (P &amp;lt; 0.001). Conclusions The detection of methylated GCM2 and TMEM240 in plasma offers a highly accurate and noninvasive approach for monitoring breast cancer progression. The ability to dynamically track treatment response and tumor burden further underscores the clinical value of this novel biomarker assay in enhancing patient management and outcomes. Citation Format: Chin-sheng Hung, Hsieh-Tsung Shen, Ruo-Kai Lin. Circulating methylated GCM2 and TMEM240 as novel biomarkers for dynamic monitoring of breast cancer progression and treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB256.
Abstract LB346: Single-cell transcriptomic analysis of exosome-related genes in triple-negative breast cancer
Authors: Yuan Zhang
Journal: Cancer Research (2025)

Abstract Background: Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with limited targeted therapeutic options. Exosomes, small membrane vesicles secreted by cells, play a crucial role in intercellular communication and material exchange. However, the role of exosome-related genes (ERGs) in TNBC remains unclear. Methods: We utilized single-cell RNA sequencing (scRNA-seq) from 10 TNBC samples and Weighted Gene Co-expression Network Analysis (WGCNA) to identify exosome-related genes and establish a prognostic model. The study’s methodology allows for an in-depth analysis of cellular heterogeneity within the tumor microenvironment and its impact on patient prognosis. Results: Our analysis identified 31,140 cells from TNBC samples, categorized into nine cell types, with epithelial cells exhibiting the highest exosome activity. A total of 232 differentially expressed genes (DEGs) related to exosome activity were identified, with 19 prognostic genes selected through univariate Cox regression, leading to the construction of an exosome-related gene signature (ERGS). Low ERGS scores correlated with poorer clinical outcomes, higher immune infiltrates, and immune-related pathways. Furthermore, we identified notable differences in biological functions and mutation profiles between the two ERGS groups. Additionally, the low ERGS score group exhibited lower tumor immune dysfunction and exclusion (TIDE) scores, immunophenoscore (IPS), and higher immune checkpoint expression, suggesting better immunotherapy outcomes. Conclusions: The findings indicate that the ERGS can effectively predict the prognosis and immunotherapy response of TNBC patients, highlighting its clinical relevance and potential as a biomarker for guiding treatment decisions. Citation Format: Yuan Zhang. Single-cell transcriptomic analysis of exosome-related genes in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB346.
Abstract LB165: Evaluating U5 snRNP200-targeting CAR-T therapy for acute myeloid leukemia: A novel multiplex immunoassay for analyte discrimination in mouse models
Authors: Anthony J. Saporita, Takeshi Fujino, Tina Raeber, Sarah Yoo, Brooke Gilliam, Shane Curran, Rick Wiese, Omar Abdel-Wahab, Anthony F. Daniyan
Journal: Cancer Research (2025)

Abstract Multiplex immunoassay kits are essential for profiling immunomodulatory proteins, including cytokines, chemokines, and growth factors in humans and animal models. Humanized mice, engineered to express human genes or incorporate human cells, allow for the study of human immune responses and vaccine efficacy. The ability to distinguish human and mouse homologues in the same sample is valuable for researchers. A novel multiplex immunoassay was developed containing both mouse-specific and human-specific antibody pairs, utilizing a rigorous screening protocol specifically designed for the selection of effective human and mouse-specific capture antibodies. Specificity was confirmed by testing individual recombinant proteins, ensuring that mouse serum and plasma samples were detected exclusively by mouse-analyte capture beads, while human-analyte capture beads showed no reactivity. Using this novel multiplex immunoassay, we evaluated the safety and efficacy of IL-18 secreting CAR-T cells targeting U5 snRNP200, a ribonucleoprotein that is specifically expressed on the surface of AML cells in a syngeneic mouse model. Firstly, IL-18 secreting CAR-T-cells in the recipient mice showed both prolonged survival and marked proliferative ability. Cytokine profiling of serum collected 14 days post-transplant revealed elevated levels of murine IL-18, IFN-gamma, CXCL9, and CXCL10 while corresponding human cytokines remained undetected, confirming mouse specificity and validation of our model. This dataset establishes a baseline for future humanized mouse experiments, demonstrating the kit's utility in validating mouse models before transitioning to human applications. Citation Format: Anthony J. Saporita, Takeshi Fujino, Tina Raeber, Sarah Yoo, Brooke Gilliam, Shane Curran, Rick Wiese, Omar Abdel-Wahab, Anthony F. Daniyan. Evaluating U5 snRNP200-targeting CAR-T therapy for acute myeloid leukemia: A novel multiplex immunoassay for analyte discrimination in mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB165.