waszak

• Haas-Kogan, Daphne A.; Aboian, Mariam S.; Minturn, Jane E.; Leary, Sarah E S; Abdelbaki, Mohamed S. & Goldman, Stewart [Vis alle 20 forfattere av denne artikkelen] (2023). Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial. Journal of Clinical Oncology. ISSN 0732-183X. 42(4), s. 441–451. doi: 10.1200/JCO.23.01838. Fulltekst i vitenarkiv Vis sammendrag

  Purpose The PNOC001 phase II single-arm trial sought to estimate progression-free survival (PFS) associated with everolimus therapy for progressive/recurrent pediatric low-grade glioma (pLGG) on the basis of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway activation as measured by phosphorylated-ribosomal protein S6 and to identify prognostic and predictive biomarkers. Patients and Methods Patients, age 3-21 years, with progressive/recurrent pLGG received everolimus orally, 5 mg/m2 once daily. Frequency of driver gene alterations was compared among independent pLGG cohorts of newly diagnosed and progressive/recurrent patients. PFS at 6 months (primary end point) and median PFS (secondary end point) were estimated for association with everolimus therapy. Results Between 2012 and 2019, 65 subjects with progressive/recurrent pLGG (median age, 9.6 years; range, 3.0-19.9; 46% female) were enrolled, with a median follow-up of 57.5 months. The 6-month PFS was 67.4% (95% CI, 60.0 to 80.0) and median PFS was 11.1 months (95% CI, 7.6 to 19.8). Hypertriglyceridemia was the most common grade ≥3 adverse event. PI3K/AKT/mTOR pathway activation did not correlate with clinical outcomes (6-month PFS, active 68.4% v nonactive 63.3%; median PFS, active 11.2 months v nonactive 11.1 months; P = .80). Rare/novel KIAA1549::BRAF fusion breakpoints were most frequent in supratentorial midline pilocytic astrocytomas, in patients with progressive/recurrent disease, and correlated with poor clinical outcomes (median PFS, rare/novel KIAA1549::BRAF fusion breakpoints 6.1 months v common KIAA1549::BRAF fusion breakpoints 16.7 months; P < .05). Multivariate analysis confirmed their independent risk factor status for disease progression in PNOC001 and other, independent cohorts. Additionally, rare pathogenic germline variants in homologous recombination genes were identified in 6.8% of PNOC001 patients. Conclusion Everolimus is a well-tolerated therapy for progressive/recurrent pLGGs. Rare/novel KIAA1549::BRAF fusion breakpoints may define biomarkers for progressive disease and should be assessed in future clinical trials.

• Messinger, Dana; Harris, Micah K; Cummings, Jessica R; Chase, Thomas; Yang, Tao & Sweha, Stefan R [Vis alle 38 forfattere av denne artikkelen] (2022). Therapeutic targeting of prenatal pontine ID1 signaling in diffuse midline glioma. Neuro-Oncology. ISSN 1522-8517. doi: 10.1093/neuonc/noac141. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis and limited understanding of the mechanism behind tumor invasion. Previous reports demonstrate upregulation of the protein ID1 with H3K27M and ACVR1 mutations in DMG, but this has not been confirmed in human tumors or therapeutically targeted. Methods Whole exome, RNA, and ChIP-sequencing was performed on the ID1 locus in DMG tissue. Scratch-assay migration and transwell invasion assays of cultured cells were performed following shRNA-mediated ID1-knockdown. In vitro and in vivo genetic and pharmacologic [cannabidiol (CBD)] inhibition of ID1 on DMG tumor growth was assessed. Patient-reported CBD dosing information was collected. Results Increased ID1 expression in human DMG and in utero electroporation (IUE) murine tumors is associated with H3K27M mutation and brainstem location. ChIP-sequencing indicates ID1 regulatory regions are epigenetically active in human H3K27M-DMG tumors and prenatal pontine cells. Higher ID1-expressing astrocyte-like DMG cells share a transcriptional program with oligo/astrocyte-precursor cells (OAPCs) from the developing human brain and demonstrate upregulation of the migration regulatory protein SPARCL1. Genetic and pharmacologic (CBD) suppression of ID1 decreases tumor cell invasion/migration and tumor growth in H3.3/H3.1K27M PPK-IUE and human DIPGXIIIP* in vivo models of pHGG. The effect of CBD on cell proliferation appears to be non-ID1 mediated. Finally, we collected patient-reported CBD treatment data, finding that a clinical trial to standardize dosing may be beneficial. Conclusions H3K27M-mediated re-activation of ID1 in DMG results in a SPARCL1+ migratory transcriptional program that is therapeutically targetable with CBD.

• Waszak, Sebastian Martin (2022). Copy-number dosage regulates telomere maintenance and disease-associated pathways in neuroblastoma. BioRxiv. ISSN 0362-4331. doi: 10.1101/2022.08.16.504100. Fulltekst i vitenarkiv
• Kratz, Christian P.; Smirnov, Dmitrii; Autry, Robert; Jäger, Natalie; Waszak, Sebastian Martin & Großhennig, Anika [Vis alle 13 forfattere av denne artikkelen] (2022). Heterozygous BRCA1 and BRCA2 and Mismatch Repair Gene Pathogenic Variants in Children and Adolescents With Cancer. Journal of the National Cancer Institute. ISSN 0027-8874. 114(11), s. 1523–1532. doi: 10.1093/jnci/djac151. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background Genetic predisposition is has been identified as a cause of cancer, yet little is known about the role of adult cancer predisposition syndromes in childhood cancer. We examined the extent to which heterozygous pathogenic germline variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, MSH2, MSH6, MLH1, and PMS2 contribute to cancer risk in children and adolescents. Methods We conducted a meta-analysis of 11 studies that incorporated comprehensive germline testing for children and adolescents with cancer. ClinVar pathogenic or likely pathogenic variants (PVs) in genes of interest were compared with 2 control groups. Results were validated in a cohort of mainly European patients and controls. We employed the Proxy External Controls Association Test to account for different pipelines. Results Among 3975 children and adolescents with cancer, statistically significant associations with cancer risk were observed for PVs in BRCA1 and 2 (26 PVs vs 63 PVs among 27 501 controls, odds ratio = 2.78, 95% confidence interval = 1.69 to 4.45; P &amp;lt; .001) and mismatch repair genes (19 PVs vs 14 PVs among 27 501 controls, odds ratio = 7.33, 95% confidence interval = 3.64 to 14.82; P &amp;lt;.001). Associations were seen in brain and other solid tumors but not in hematologic neoplasms. We confirmed similar findings in 1664 pediatric cancer patients primarily of European descent. Conclusion These data suggest that heterozygous PVs in BRCA1 and 2 and mismatch repair genes contribute with reduced penetrance to cancer risk in children and adolescents. No changes to predictive genetic testing and surveillance recommendations are required.

• Waszak, Sebastian Martin (2022). Mutation-Attention (MuAt): deep representation learning of somatic mutations for tumour typing and subtyping. BioRxiv. ISSN 0362-4331. doi: 10.1101/2022.03.15.483816. Fulltekst i vitenarkiv
• Llamazares-Prada, Maria; Espinet, Elisa; Mijosek, Vedrana; Schwartz, Uwe; Lutsik, Pavlo & Tamas, Raluca [Vis alle 27 forfattere av denne artikkelen] (2021). Versatile workflow for cell type–resolved transcriptional and epigenetic profiles from cryopreserved human lung. JCI Insight. doi: 10.1172/jci.insight.140443. Fulltekst i vitenarkiv Vis sammendrag

  Complexity of lung microenvironment and changes in cellular composition during disease make it exceptionally hard to understand molecular mechanisms driving development of chronic lung diseases. Although recent advances in cell type–resolved approaches hold great promise for studying complex diseases, their implementation relies on local access to fresh tissue, as traditional tissue storage methods do not allow viable cell isolation. To overcome these hurdles, we developed a versatile workflow that allows storage of lung tissue with high viability, permits thorough sample quality check before cell isolation, and befits sequencing-based profiling. We demonstrate that cryopreservation enables isolation of multiple cell types from both healthy and diseased lungs. Basal cells from cryopreserved airways retain their differentiation ability, indicating that cellular identity is not altered by cryopreservation. Importantly, using RNA sequencing and EPIC Array, we show that gene expression and DNA methylation signatures are preserved upon cryopreservation, emphasizing the suitability of our workflow for omics profiling of lung cells. Moreover, we obtained high-quality single-cell RNA-sequencing data of cells from cryopreserved human lungs, demonstrating that cryopreservation empowers single-cell approaches. Overall, thanks to its simplicity, our workflow is well suited for prospective tissue collection by academic collaborators and biobanks, opening worldwide access to viable human tissue.

• Waszak, Sebastian Martin (2020). Germline Elongator mutations in Sonic Hedgehog medulloblastoma. Nature. ISSN 0028-0836. doi: 10.1038/s41586-020-2164-5. Fulltekst i vitenarkiv
• Waszak, Sebastian Martin (2020). Pan-cancer analysis of whole genomes. Nature. ISSN 0028-0836. doi: 10.1038/s41586-020-1969-6. Fulltekst i vitenarkiv
• Waszak, Sebastian Martin (2020). Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma. Journal of Clinical Oncology. ISSN 0732-183X. doi: 10.1200/JCO.19.00577. Fulltekst i vitenarkiv
• Bonner, Erin R; Waszak, Sebastian Martin; Grotzer, Michael A; Mueller, Sabine & Nazarian, Javad (2020). Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells. Neuro-Oncology. ISSN 1522-8517. doi: 10.1093/neuonc/noaa283. Fulltekst i vitenarkiv Vis sammendrag

  ONC201 is the first member of the imipridone family of anticancer drugs to enter the clinic for the treatment of diverse solid and hematologic cancers. A subset of pediatric and adult patients with highly aggressive brain tumors has shown remarkable clinical responses to ONC201, and recently, the more potent derivative ONC206 entered clinical trials as a single agent for the treatment of CNS cancers. Despite the emerging clinical interest in the utility of imipridones, their exact molecular mechanisms are not fully described. In fact, the existing literature points to multiple pathways (e.g. TRAIL signaling, dopamine receptor antagonism, and mitochondrial metabolism) as putative drug targets. We have performed a comprehensive literature review and highlighted mitochondrial metabolism as the major target of imipridones. In support of this, we performed a meta-analysis of an ONC201 screen across 539 human cancer cell lines and showed that the mitochondrial protease ClpP is the most significant predictive biomarker of response to treatment. Herein, we summarize the main findings on the anticancer mechanisms of this potent class of drugs, provide clarity on their role, and identify clinically relevant predictive biomarkers of response.

• Waszak, Sebastian Martin (2018). Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. The Lancet Oncology. ISSN 1470-2045. doi: 10.1016/S1470-2045(18)30242-0. Fulltekst i vitenarkiv

Se alle arbeider i NVA

• Banono, Nancy Saana; Gawel, Kinga Aurelia; Mäki-Marttunen, Tuomo; Ent, Wietske van der; Kukula-Koch, Wirginia & Fyhn, Marianne [Vis alle 10 forfattere av denne artikkelen] (2023). Novel zebrafish model for studying neurodevelopment in Timothy syndrome. Fulltekst i vitenarkiv
• Kriener, Birgit & Waszak, Sebastian Martin (2023). A deep learning approach to infer somatic alterations in glioma using digital tissue slides. Fulltekst i vitenarkiv
• Waszak, Sebastian Martin (2022). Mapping the genetic and cellular origin of DIPG/DMG in clinical trials. Fulltekst i vitenarkiv
• Waszak, Sebastian Martin (2022). Reconstructing the past, predicting the future: mapping the genetic and cellular origin of brain tumors. Fulltekst i vitenarkiv
• Kriener, Birgit & Waszak, Sebastian Martin (2022). Digital pathology in neuro-oncology: Towards deep learning-based prediction of clinically-actionable genomic alterations from histopathological images. Fulltekst i vitenarkiv
• Kriener, Birgit; Mueller, Sabine & Waszak, Sebastian Martin (2022). Digital pathology in neuro-oncology: deep learning-based prediction of clinically-actionable genomic alterations from histopathological images. Fulltekst i vitenarkiv
• Mottl, Sophie; Sill, Martin; Northcott, Paul A.; Jäger, Natalie; Pfister, Stefan M & Waszak, Sebastian Martin (2022). Parent-of-origin-specific genetic predisposition to medulloblastoma. Fulltekst i vitenarkiv
• Waszak, Sebastian Martin (2022). Genetic origin and somatic evolution of childhood medulloblastoma. Fulltekst i vitenarkiv
• Waszak, Sebastian Martin (2022). Reconstructing the past, predicting the future: using somatic genomes to identify the cellular origin of childhood cancers. Fulltekst i vitenarkiv
• Waszak, Sebastian Martin (2022). Genetic Origin and Somatic Evolution of Childhood Medulloblastoma. Fulltekst i vitenarkiv
• Waszak, Sebastian Martin (2022). Genetic origin and somatic evolution of childhood brain tumors. Fulltekst i vitenarkiv
• Waszak, Sebastian Martin (2022). Reconstructing the past and predicting the future: novel methods to map the genetic and cellular origin of brain tumors. Fulltekst i vitenarkiv

Se alle arbeider i NVA