Deciphering cellular interaction between malignant and normal brain cells in pediatric high-grade gliomas
Hematology, Oncology
Final Report Abstract
Pediatric high-grade gliomas (pHGGs) are a group of aggressive brain tumors and the leading cause of cancer-related death in children. pHGGs encompass clinically and biologically distinct subtypes characterized by specific anatomical localizations and typical ages of occurrence. In recent years, immense progress has been achieved in deciphering oncogenic alterations in pHGG. However, efforts to translate these findings into effective therapeutic options have not yet been successful. Previous single-cell RNA sequencing studies have revealed transcriptionally and functionally distinct malignant cell states within individual tumors of certain pHGG subtypes, such as H3K27-altered diffuse midline gliomas. Building on these recent findings, I hypothesized that, in addition to known genomic alterations, other factors may influence the growth and recurrence of pHGG. These factors include: (1) transcriptional differences of malignant cells within a single tumor (intratumoral heterogeneity) and across different tumors of distinct molecular pHGG subtypes (intertumoral heterogeneity); (2) unique developmental origins reflected in the developmental hierarchies of malignant cell states within pHGG subtypes; (3) the spatial composition and global structure of malignant cells within the tumor; and (4) interactions between malignant cells and normal cells in the tumor microenvironment. The aims of this project were (I) to decipher the transcriptional intra- and intertumoral heterogeneity and spatial landscape across pHGGs, including cell-cell interactions between malignant and non-malignant cells, and to (II) develop novel treatments targeting these transcriptional programs. In the first part of the project, I performed an in-depth single-nucleus and spatial transcriptomic characterization of pHGG leveraging an extensive cohort of 79 pHGG samples. I identified common and subtype-specific patterns of disease plasticity, characterized by distinct transcriptional programs and developmental hierarchies as well as unique spatial niches, with communicating malignant and normal cells of the tumor microenvironment, across pHGG subtypes. In the second part of the project, I aimed at therapeutically targeting these newly characterized transcriptional programs in pHGG. Using our genomic and single cell transcriptomic data sets, I identified an oncogenic receptor tyrosine kinase, PDGFRA, as a potential therapeutic target in pHGG. In a translational approach, I demonstrated that the PDGFRA inhibitor avapritinib exhibits in vitro and in vivo activity in patient-derived HGG models, effective blood-brain barrier penetration in mice and humans, and radiographic and clinical response in a subset of pHGG patients. Overall, this project provides a comprehensive landscape of the transcriptional heterogeneity of malignant and normal cells in pHGG and elucidates how these findings can be translated into novel targeted treatments for patients with this lethal disease.
Publications
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Abstract 5719: Clinical response to the PDGFRα inhibitor avapritinib in high-grade glioma patients. Cancer Research, 83(7_Supplement), 5719-5719.
Mayr, Lisa; Trissal, Maria; Schwark, Kallen; Labelle, Jenna; Groves, Andrew; Furtner-Srajer, Julia; Supko, Jeffrey; Weiler-Wichtl, Liesa; Hack, Olivia; Rozowsky, Jacob; Marques, Joana G.; Pandatharatna, Eshini; Leiss, Ulrike; Rosenmayr, Verena; Dubois, Frank; Greenwald, Noah F.; Madlener, Sibylle; Guntner, Armin S.; Pálová, Hana ... & Filbin, Mariella
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Clinical response to the PDGFRA/KIT inhibitor avapritinib in pediatric and young adult high-grade glioma patients with H3K27M or PDGFRA genomic alterations. SNO Pediatric Neuro-Oncology Conference 2023, Washington DC, USA
Trissal M., Mayr L., Schwark K., Neyazi S., LaBelle J., Kong S., Furtner J., Weiler-Wichtl L. ... & Filbin, M.G.
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DIPG-28. IDENTIFICATION AND TARGETING OF METABOLIC VULNERABILITIES IN COMBINATION WITH PDGFRA-INHIBITION IN DIFFUSE MIDLINE GLIOMA. Neuro-Oncology, 25(Supplement_1), i19-i19.
Neyazi, Sina; Gowda, Pruthvi S.; Trissal, Maria; Fonticella, Jay-Miguel; Portero, Erika P.; Haley-Read, John-Paul; Anderson, Emily P.; Danial, Nika N. & Filbin, Mariella G.
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DIPG-14. METABOLIC REPROGRAMMING AS A RESISTANCE MECHANISM IN DIFFUSE MIDLINE GLIOMA. Neuro-Oncology, 26(Supplement_4), 0-0.
Neyazi, Sina; Gowda, Pruthvi; Frederico, Stephen C.; Nguyen, Cuong M.; Trissal, Maria C.; Portero, Erika P.; Haley-Read, John-Paul; Anderson, Emily P.; Thomas, Craig J.; Danial, Nika N. & Filbin, Mariella G.
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GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant. Cancer Cell, 42(9), 1528-1548.e17.
Liu, Ilon; Alencastro, Veiga Cruzeiro Gustavo; Bjerke, Lynn; Rogers, Rebecca F.; Grabovska, Yura; Beck, Alexander; Mackay, Alan; Barron, Tara; Hack, Olivia A.; Quezada, Michael A.; Molinari, Valeria; Shaw, McKenzie L.; Perez-Somarriba, Marta; Temelso, Sara; Raynaud, Florence; Ruddle, Ruth; Panditharatna, Eshini; Englinger, Bernhard; Mire, Hafsa M. ... & Filbin, Mariella G.
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Single-cell multidimensional profiling of tumor cell heterogeneity in supratentorial ependymomas. openRxiv.
Jeong, Daeun; Danielli, Sara G.; Maaß, Kendra K.; Ghasemi, David R.; Tetzlaff, Svenja K.; Reyhan, Ekin; Oliveira, de Biagi-Junior Carlos Alberto; Neyazi, Sina; Nascimento, Andrezza; Haase, Rebecca; Lo, Cascio Costanza; Englinger, Bernhard; Jiang, Li; Nguyen, Cuong M.; Baumgartner, Alicia-Christina; Castellani, Sophia; Rozowsky, Jacob S.; Hack, Olivia A.; Shaw, McKenzie L. ... & Filbin, Mariella G.
