145 This work would not have been possible without the generous support from our funding organizations @alexslemonade.bsky.social al, Sontag Foundation, NIH, Chadtough, Pediatric Brain Tumor Foundation, Yuvaan Tiwari Foundation and many more!

14/ Most of all, we want to express our deepest gratitude to our patients and families who trusted us with their care and provided invaluable tumor samples. We will keep fighting for better therapies for you! 💛

13/ Massive thanks to the countless collaborators and supporters who helped along the way, we highly appreciate each one of you! My heartfelt gratitude especially goes to Mariella Filbin who has provided incredible mentorship, guidance, inspiration and support!

12/ I am deeply grateful to be part of this wonderful and fruitful collaboration between the labs of Mariella Filbin, Johannes Gojo and Carl Koschmann that enabled this work across @danafarber.bsky.social @bostonchildrens.bsky.social ns.bsky.social, @umich.edu and MedUni Wien.

11/ We hope that molecularly targeted and personalized treatments, such as avapritinib, will be at the forefront of novel therapeutic strategies for pHGG and DMG patients, complemented by other recently developed approaches like CAR-T cells @michellemonje.bsky.social and ONC201.

10/ Overall, our translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in pHGG and DMG with distinct PDGFRA alterations, a patient cohort that currently faces a dismal prognosis.

9/ Lastly, we aimed to identify genetic predictors of response to avapritinib and propose alternative receptor tyrosine kinase pathway upregulation as a resistance mechanism, as illustrated in an avapritinib resistant tumor lesion that developed a novel EGFR amplification.

8/ Our early data demonstrate that avapritinib monotherapy is well tolerated and results in radiographic response in 3/7 cases, with best responses observed in patients with tumors harboring PDGFRA amplification or exon 18 mutation.

7/ Through wonderful clinical collaborations around the globe, we treated eight pediatric and young adult pHGG patients with avapritinib as a compassionate use and report first safety and response data in this patient population.

6/ We furthermore revealed efficient brain penetrance and prolonged survival in three PDGFRA-altered DMG models in vivo following oral avapritinib treatment.

5/ Among a panel of 2nd and 3rd generation TKIs, we identified the FDA-approved PDGFRA/KIT inhibitor avapritinib as selective against PDGFRA and highly effective against PDGFRA-altered patient-derived pHGG and DMG models in vitro.

4/ We detected PDGFRA activating mutations and/or gene amplifications in ~15% of pHGG cases, with high-level PDGFRA amplifications frequently found on extrachromosomal DNA.

3/ PDGFRA has been suggested as a therapeutic target in pediatric high-grade glioma (pHGG) and H3K27M diffuse midline glioma (DMG) due to its frequent genomic alterations, high-expression in stem- OPC-like cells, and role as an essential driver in tumor formation in transgenic glioma mouse models.

2/ This study is the final result of an amazing team effort together with 🦋-less co-first authors Lisa Mayr, Maria Trissal, Kallen Schwark. The work with this team has been nothing but an immense pleasure. ❤️ A 🧵 of our key findings: