tbuckley/cabot-search huggingface dataset:
Abstract A012 Unravelling the role of METTL1 in Myc driven pediatric cancers using CRISPR Cas13d
Authors: Pei Y. Liu, Steven He, Chelsea Mayoh, Alice Salib, Antoine De Weck, Paul G. Ekert
Journal: Cancer Research (2024)

Abstract METTL1 is an RNA methyltransferase which catalyzes N7-methylguanosine (m7G) methylation on various RNAs, particularly on tRNAs. METTL1 has been reported to be amplified and/or overexpressed and high expression correlates with poor patient prognosis in different types of adult cancers. Our ZERO Childhood Cancer Program focuses on identifying and validating potential new drug targets and developing novel therapies for clinical use. ZERO has sequenced the whole genome and transcriptome in over 500 high-risk pediatric tumors and found that METTL1 gene copy number and gene expression are significantly higher in a subset of high-grade glioma, neuroblastoma, diffuse midline glioma and fusion positive rhabdomyosarcoma. Analysis of the publicly available SEQC microarray dataset showed that high METTL1 expression correlates with poor outcomes in MYCN amplified neuroblastoma patients. We validated the functional roles of METTL1 gene amplification and overexpression in a few pediatric cancer cell line models using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) Cas13d knockdown system, in dual lentiviral constructs. We found that knocking down METTL1 significantly decreased METTL1 amplified neuroblastoma and rhabdomyosarcoma cell viability and colony formation but not in METTL1 non-amplified neuroblastoma and rhabdomyosarcoma cells. Gene Set Enrichment Analysis from RNA sequencing data revealed that knocking down METTL1 resulted in a decrease in Myc target gene expression, and an increased in apoptosis, interferon alpha response and p53 pathway hallmarks. Western blot analysis confirmed that knocking down METTL1 led to a decrease in the MCL-1 antiapoptotic protein expression and an increase in the proapoptotic protein expression such as cleaved PARP and caspase 3. Taken together, our data demonstrate that METTL1 is a potential therapeutic target in METTL1 amplified pediatric cancers. Citation Format: Pei Y. Liu, Steven He, Chelsea Mayoh, Alice Salib, Antoine De Weck, Paul G. Ekert. Unravelling the role of METTL1 in Myc driven pediatric cancers using CRISPR Cas13d [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A012.
Abstract A005 <i>TP53</i> variant clusters stratify the Li-Fraumeni spectrum and reveal an osteosarcoma-prone subgroup
Authors: Nicholas W. Fischer, Brianne Laverty, Noa Alon, Emilie Montellier, Pierre Hainaut, Kara N. Maxwell, Christian P. Kratz, David Malkin
Journal: Cancer Research (2024)

Abstract Li-Fraumeni syndrome (LFS) has recently been redefined as a ‘spectrum’ cancer predisposition disorder to reflect its broad phenotypic heterogeneity. The wide functional gradient associated with different TP53 variants is thought to contribute to LFS heterogeneity, although it is still poorly understood and there is an unmet clinical need for risk stratification strategies. Leveraging p53 mutagenesis datasets, we performed an unsupervised cluster analysis that revealed five TP53 variant clusters with unique structural and functional consequences. Classifying variant carriers according to these clusters stratified cancer onset and survival using discovery and validation cohorts, and exposed important clinical characteristics to consider for patient management. In particular, we identified a subgroup of monomeric TP53 variant carriers prone to osteosarcoma, along with a cluster associated with less “LFS-like” phenotypes enriched in carriers with no history of cancer. Our classification of TP53 variants demonstrates the existence of a wide TP53-heritable cancer susceptibility spectrum and provides a new framework to delineate carriers toward personalized patient care. Citation Format: Nicholas W. Fischer, Brianne Laverty, Noa Alon, Emilie Montellier, Pierre Hainaut, Kara N. Maxwell, Christian P. Kratz, David Malkin. TP53 variant clusters stratify the Li-Fraumeni spectrum and reveal an osteosarcoma-prone subgroup [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A005.
Abstract A047 Synergy between polarized dendritic cells, radiation and PD-1 blockade in effective treatment of rhabdomyosarcoma
Authors: Ajay Gupta, Eoghan Connors, Michael Moser, Bryan Gillard, Katie Kokolus, Per Basse, Pawel Kalinski
Journal: Cancer Research (2024)

Abstract Introduction: Clinical effectiveness of immune checkpoint inhibitor (ICI) therapy depends on tumor-infiltrating cytotoxic T lymphocytes (CTLs) resulting in the need for new tools to convert “cold” tumors which lack CTLs, into CTL-infiltrated “hot” tumors. Radiation therapy (RT) is known to modulate the solid tumor microenvironment (TME) and induce a systemic immune response via enhanced tumor antigen release, production of type I interferons (IFN), intratumoral attraction and activation of DCs, and enhanced tumor recognition by natural killer (NK) cells. Thus, local irradiation of a tumor can be advantageous for both the local treatment of a tumor as well as the prevention of distant metastases. Since previous studies have shown that RT can synergize with ICI and that IL-12 producing DCs administered intratumorally also impart a clinical advantage with ICI, we tested if ST-αDC1s, a DC type designed to produce high levels of IL-12 and CTL-attracting chemokines, can enhance the combination of RT plus anti-PD-1 therapy of mouse rhabdomyosarcoma. Methods: Mice (10-15 mice per group) were inoculated with syngeneic orthotopic (gastrocnemius) M3-9-M rhabdomyosarcoma. At day 13, when tumors reached ∼200 mm3, animals started RT with single fraction of 6 Gy (225 peak kVp) using the Precision X-Rad 320 irradiator. Four doses of anti-PD-1 treatment were given on days 13, 15, 18, and 20. ST-αDC1s were given intratumorally either early (Day 13) or late (Day 20). Surviving animals were challenged with 2.5x higher number of cancer cells on day 90-100 and followed for evidence of tumor recurrence. Results: Anti-PD1 treatment alone was not effective. Control groups receiving PBS injection or anti-PD-1 alone had no survivors at day 90, with most animals succumbing to tumors within 4 weeks. RT alone improved the outcomes, yielding 15% of day-90 survivors (2/13 animals). RT plus anti-PD-1 treatment increased the fraction of survivors to 54% (7/13 animals) , while RT plus anti-PD-1 and early ST-αDC1 treatment resulted in 70% of survivors (7/10 animals). Late ST-αDC1 treatment did not enhance the survival beyond the RT plus anti-PD1 combination. The correlative studies and rechallenge studies will be presented. Citation Format: Ajay Gupta, Eoghan Connors, Michael Moser, Bryan Gillard, Katie Kokolus, Per Basse, Pawel Kalinski. Synergy between polarized dendritic cells, radiation and PD-1 blockade in effective treatment of rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A047.
Abstract IA016: Mapping microglia – tumor crosstalk in pediatric brain cancer
Authors: Florent Ginhoux, Claudia Pasqualini
Journal: Cancer Research (2024)

Abstract The management of diffuse midline gliomas (DMG) is one of the greatest challenges in the field of pediatric oncology. Available treatments do not improve the poor survival rates, and preclinical research is struggling to find new targets that could have the potential to revolutionize the therapeutic approach. In most of the current preclinical tools, microglia and macrophages are not taken into account, despite being the most abundant immune players in the brain tumor microenvironment. To address this issue, we established neural organoids and macrophages (iMacs) from induced pluripotent stem cells (iPSC) derived from pediatric patients treated for DMG ("autologous immuno-organoids"). We have reprogrammed fibroblasts into iPSC from 9 children with DMG and generated autologous immuno-organoids for 4 of them. These "avatars" provide a unique preclinical model to which tumor cells from the same patient can be added, enabling us to better understand the crosstalk between the tumor and its immunological microenvironment, and to evaluate new immunotherapies. In particular, we show here that iMacs decrease tumor proliferation and tumor cell-invasion capability in neural organoids, with such effect reduced upon iMac depletion using CSF1R inhibitor treatment. Genes/signaling pathways identified by multi-omics analysis and validated at proteomic level show a reciprocal reprogramming of tumor cells and iMacs over time. Altogther, our approach reveals an unique tumor macrophage crosstalk that will be targeted by tailored immunotherapies or gene modification to validate their impact on tumor progression. Citation Format: Florent Ginhoux, Claudia Pasqualini. Mapping microglia – tumor crosstalk in pediatric brain cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr IA016.
Abstract A015 FGF8 promotes non-canonical KRAS/MAPK pathway in favorable histology Wilms' tumor
Authors: Yongdong Su, Katie T. Skinner, Garrett W. Cooper, Sumin Kang, Hong Yin, Jason T. Yustein, Andrew L. Hong
Journal: Cancer Research (2024)

Abstract Favorable Histology Wilms tumor (FHWT) is the most common pediatric kidney cancer and those with relapsed FHWT continue to have poor prognoses. A challenge in the field of FHWT research is the lack of faithful preclinical in vitro models for both primary and relapsed tumors. This prevents us from understanding the biology of FHWT and introducing new targeted therapies into FHWT clinical trials. We recently established 10 FHWT cell lines, including one from a relapsed case, which faithfully recapitulated the genome and transcriptome of the primary tumor. However, challenges persist in maintaining the long-term growth of these cell lines, limiting our insight into the functional study of FHWT. Through comparison of the transcriptome of the FHWT primary tumor samples to their respective cell lines, we identified upregulation of fibroblast growth factor 8 (FGF8) expression in primary tumors. We then performed functional genomics to study the role of FGF8 in FHWT. We found that the splice variants, FGF8b or FGF8f, are required for the maintenance of FHWT cells. Re-introducing these two splice variants using either exogenous addition or endogenous overexpression led to increased viability and passaging of FHWT cell line models by an average of 100% and 30%, respectively. Further, we found that overexpressing FGF8b or FGF8f led to increased clonogenicity and invasion in vitro and led to tumor formation in vivo. Our mechanistic studies suggest that FGF8 drives a stemness and proliferation program through a non-canonical KRAS/MAPK pathway: FGF8b and FGF8f overexpression activates MEK1/2 without activating Erk1/2 while still promoting ETV1 and ETV4, leading to increased cell proliferation. Abrogation of MAPK pathway in vitro using MEK inhibitors led to decreased viability in cells overexpressing FGF8b and FGF8f. Together, our study highlights the oncogenic effect of FGF8 in FHWT and links FHWT to an unexpected non-canonical MAPK pathway. Citation Format: Yongdong Su, Katie T. Skinner, Garrett W. Cooper, Sumin Kang, Hong Yin, Jason T. Yustein, Andrew L. Hong. FGF8 promotes non-canonical KRAS/MAPK pathway in favorable histology Wilms' tumor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A015.
Protein kinase R is highly expressed in dermatomyositis and promotes interferon-beta-induced muscle damage
Authors: Guoyong Zhang, Lining Zhang, Dandan Zhao, Xiaoyu Liu, Wei Li, Chuanzhu Yan, Tingjun Dai
Journal: Annals of the Rheumatic Diseases (2024)

Dermatomyositis (DM) has been consistently linked to the type I interferon (IFN-I) pathway. However, the precise pathogenesis remains incompletely elucidated. We aimed to explore potential molecular mechanisms and identify promising therapeutic targets in DM. We employed bioinformatics analysis to investigate molecular signatures, aiming to shed light on the pathogenesis of DM. The expression of protein kinase R (PKR) in DM muscle tissues was determined by real-time quantitative PCR, western blot and immunohistochemistry (IHC) analysis. We then assessed the sensitivity and specificity of sarcoplasmic PKR expression by IHC in a consecutive DM cohort and other diseases in this retrospective study. Furthermore, IFN-β was used to stimulate myoblasts and myotubes, and the relationship between PKR and IFN-β-induced pathogenic molecules was investigated in vitro. Bioinformatics analysis indicated two primary pathological processes: viral infection and the IFN-I signalling pathway. We subsequently verified that PKR was notably expressed in the cytoplasm of myofibers in DM patients. The sensitivity and specificity of sarcoplasmic PKR expression in DM were 84.6% and 97.6%, respectively. In vitro studies revealed that IFN-β upregulates the expression of PKR, along with several molecules associated with DM muscle damage. Conversely, inhibiting PKR has been shown to downregulate IFN-β-induced pathogenic molecules in both myoblasts and myotubes. We observed that PKR exhibits specific expression in the cytoplasm of DM muscle and inhibiting PKR ameliorates IFN-β-induced muscle damage in vitro. These findings provide insights into the diagnostic and therapeutic roles of PKR in DM.
Abstract A066 Acquired resistance to temozolomide in the Th-<i>MYCN</i> mouse as a clinically-relevant platform to evaluate novel therapeutic strategies against high-risk neuroblastoma
Authors: Evon Poon, Tong Liang, Giuseppe Barone, Barbara M. Costa, Sara Heuss, Simon P. Robinson, Charles Lin, Paul Workman, Yann Jamin, Louis Chesler
Journal: Cancer Research (2024)

Abstract Advances in preclinical models that recapitulate chemorefractory and relapsed disease are needed to better predict the efficacy of an expanding and promising armamentarium of drug candidates being tested in early-phase pediatric clinical trials. Here, we used longitudinal magnetic resonance imaging to design an individualized, dose-escalating treatment regimen that induces evolution of neuroblastoma in the Th-MYCN genetically-engineered mouse model, concomitant with the acquisition of resistance to temozolomide, a standard chemotherapy used in treatment of refractory, relapsed neuroblastoma patients within European early-phase clinical trials. MRI longitudinally identified the development of intra-tumoral heterogeneity. Molecular profiling of expanding, treatment-refractory regions identified prominent up-regulation of the nor-adrenergic core regulatory signature and deregulation of the CDK2 pathway. Treatment with a CDK2/9 inhibitor led to significant response and an overall survival benefit in temozolomide-resistant Th-MYCN tumors and allografts generated from these resistant tumours. These findings demonstrate the utility of genetically-engineered mouse models as platforms to dissect the evolution of chemoresistance in neuroblastoma and they provide a mechanistic rationale to support the evaluation of CDK2/9 in ongoing paediatric phase I studies of chemotherapy combined with temozolomide in relapsed, treatment refractory neuroblastoma patients. Citation Format: Evon Poon, Tong Liang, Giuseppe Barone, Barbara M. Costa, Sara Heuss, Simon P. Robinson, Charles Lin, Paul Workman, Yann Jamin, Louis Chesler. Acquired resistance to temozolomide in the Th-MYCN mouse as a clinically-relevant platform to evaluate novel therapeutic strategies against high-risk neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A066.
Abstract A022 Characterizing the cell of origin of Ewing sarcoma
Authors: Elena Vasileva, Claire Arata, Gage Crump, James Amatruda
Journal: Cancer Research (2024)

Abstract Ewing sarcoma (ES) is a malignant bone and soft tissue tumor that affects children, adolescents, and young adults. ES is characterized by the presence of a driver fusion oncogene, most frequently EWSR1-FLI1. The cell of origin of Ewing sarcoma and the mechanisms of EWSR1-FLI1-driven cell transformation are the subjects of long-standing debates, largely due to the absence of a representative mouse model. Previous reports have suggested that bone-marrow mesenchyme or/and neural crest cells may serve as potential cells of origin for Ewing sarcoma. These hypotheses have never been tested in vivo, as the EWSR1-FLI1 fusion causes severe developmental toxicity in most cell types. To address these questions, we developed a stable model enabling controlled expression of the human EWSR1-FLI1 oncofusion specifically in neural crest cells. Using this model, we demonstrated that expression of human EWSR1-FLI1 oncofusion in neural crest cells can lead to their transformation and the development of tumors in vivo. Here we applied innovative single-cell transcriptomic, genetic, and high-resolution imaging approaches to characterize cells giving rise to EWSR1-FLI1 driven tumors in zebrafish model of Ewing sarcoma. EWSR1-FLI1 hindered the normal differentiation of neural crest cells into glial and neuronal lineages. Instead, EWSR1-FLI1 strongly reprogrammed neural crest cells by upregulating the expression of mesodermal regulators, including the key mesodermal regulator tbxta (Brachyury or T) transcription factor. tbxta/TBXT expression was maintained in subset of zebrafish and human Ewing sarcomas. Our model provides a mechanism by which a neural crest cell population can be transformed to Ewing sarcoma, a malignancy with predominant mesenchymal features. Taken together, these findings shed light on the cellular and molecular mechanisms underlying Ewing sarcoma development and provide valuable insights into its pathogenesis. Citation Format: Elena Vasileva, Claire Arata, Gage Crump, James Amatruda. Characterizing the cell of origin of Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A022.
Abstract B042: Socioeconomic and racial disparities in pediatric cancer outcomes in the Ghanaian health sector: Challenges and strategies for equitable care
Authors: Mavis Agyapomaa
Journal: Cancer Research (2024)

Abstract Objectives This study aims to investigate the socioeconomic and racial disparities in pediatric cancer outcomes within the Ghanaian health sector. The objectives are to identify the specific challenges faced by different socioeconomic and racial groups, assess the impact of these disparities on diagnosis and treatment outcomes, and propose strategies for achieving more equitable care for pediatric cancer patients in Ghana. Methods A mixed-methods approach was employed, combining quantitative analysis of patient data from national cancer registries and hospitals with qualitative interviews of healthcare providers and affected families. The quantitative component focused on variables such as socioeconomic status, race, stage of cancer at diagnosis, treatment received, and survival rates. The qualitative component explored personal experiences, barriers to care, and perceptions of the healthcare system. Data were collected from multiple regions to ensure a representative sample of the diverse population in Ghana. Results The study found significant disparities in pediatric cancer outcomes based on socioeconomic status and race. Children from lower socioeconomic backgrounds and minority racial groups were more likely to be diagnosed at later stages and had lower survival rates compared to their higher-income and majority-race counterparts. Key challenges identified included limited access to specialized oncology care, financial barriers, inadequate health insurance coverage, and cultural beliefs affecting treatment-seeking behavior. Additionally, there was a shortage of trained healthcare professionals and insufficient infrastructure in rural areas. Conclusion Socioeconomic and racial disparities significantly impact pediatric cancer outcomes in Ghana. Addressing these disparities requires a multifaceted approach, including policy interventions to improve healthcare access and affordability, targeted outreach programs to educate communities, and investment in healthcare infrastructure and workforce training. Implementing these strategies can promote more equitable care and improve survival rates for all pediatric cancer patients in Ghana. Collaboration between government, healthcare providers, and non-governmental organizations is essential to overcome these challenges and ensure that every child has the opportunity for a healthy future. Citation Format: Mavis Agyapomaa. Socioeconomic and racial disparities in pediatric cancer outcomes in the Ghanaian health sector: Challenges and strategies for equitable care [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B042.