Browsing by Author "Burket, Noah"

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    Combinatorial Inhibition of Epigenetic Regulators to Treat Glioblastoma
    (2022-07-29) Burket, Noah; Koenig, Jenna; Saratsis, Amanda
    Glioblastoma (GBM) is a deadly primary brain cancer that affects 12,000 patients in the US annually with a median survival time of 15 months. Temozolomide is the standard-of-care chemotherapy for GBM; however, many tumors are resistant, necessitating the expansion of therapeutic options. EZH2 and JMJD3 are two proteins responsible for epigenetic regulation of the genome via histone methylation, with EZH2 also affecting non-histone targets. Prior studies showed that inhibition of these proteins decreased cell counts and induced radiosensitivity in GBM cells. Thus, we investigated combined use of EZH2 inhibitor, EPZ6438, and JMJD3 inhibitor, GSK-J4, in the treatment of temozolomide-resistant GBM10 cells. Non-irradiated cells were treated with both drugs singly and combined, and counted at 24-, 48-, and 72-hour intervals. Irradiated cells were pre-treated with each drug and combination therapy for three days, irradiated, and then counted at 24-, 48-, and 72-hour intervals. Western blot was used to investigate dsDNA damage biomarker y-H2AX, gene-silencing modification H3K27me3, tumor suppressor p53, EZH2, and JMJD3 expression in non-irradiated and irradiated cells following drug treatment. Single EPZ-6438 and GSK-J4 treatments reduced cell counts with increasing concentration and time. GSK-J4 appears to reduce cell counts more than EPZ-6438 alone, and combinatorial use reduces this further. Western blot reveals increased H3K27me3 expression with GSK-J4 treatment following radiation, but not with EPZ-6438. y-H2AX expression is increased after EPZ-6438 treatment but is not further increased with radiation. Meanwhile, GSK-J4 increased y-H2AX, but only after irradiation. Reduced cell counts following treatment with GSK-J4 may be due to its effects on gene silencing from inhibition of H3K27 demethylation. Additionally, increased dsDNA breaks seen in EPZ-6438 and GSK-J4 supports their roles in radiosensitizing GBM cells. This study highlights the importance of further investigation into GSK-J4 and EPZ-6438 combination therapy in temozolomide-resistant GBM tumors.
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    LIN28B and Let-7 in Diffuse Midline Glioma: A Review
    (MDPI, 2023-06-19) Knowles, Truman; Huang, Tina; Qi, Jin; An, Shejuan; Burket, Noah; Cooper, Scott; Nazarian, Javad; Saratsis, Amanda M.; Neurological Surgery, School of Medicine
    Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. DMGs are driven by histone-tail-mutation-mediated epigenetic dysregulation and partner mutations in genes controlling proliferation and migration. One result of this epigenetic and genetic landscape is the overexpression of LIN28B RNA binding protein. In other systems, LIN28B has been shown to prevent let-7 microRNA biogenesis; however, let-7, when available, faithfully suppresses tumorigenic pathways and induces cellular maturation by preventing the translation of numerous oncogenes. Here, we review the current literature on LIN28A/B and the let-7 family and describe their role in gliomagenesis. Future research is then recommended, with a focus on the mechanisms of LIN28B overexpression and localization in DMG.
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    NCOG-25. Single-Institution Series of Spinal Ependymoma in Children With NF2-Related Schwannomatosis
    (Oxford University Press, 2023-11-10) Burket, Noah; Koenig, Jenna; Tailor, Jignesh; Neurological Surgery, School of Medicine
    NF2-related schwannomatosis (NrS) is a tumor predisposition syndrome that results in the development of multiple central nervous system tumors, including spinal ependymomas (SP-EPN). SP-EPN are intramedullary tumors that are slow growing but can displace critical nerve pathways in the spinal cord, resulting in motor and sensory deficits that contribute to patient morbidity. Although surgery is the mainstay of treatment, it can also result in high morbidity, resection of sporadic SP-EPN is often curative; however, SP-EPN in NrS patients will often regrow, possibly resulting in additional surgeries and a lifetime of deficits, especially impacting pediatric patients. Yet, natural history and clinical outcomes for pediatric NrS patients with SP-EPN have not been well described. We reviewed 27 pediatric NrS patient cases from 1993 to 2023 at our institution and identified 10 patients with a diagnosis of SP-EPN, with a range of 1-3 tumors present at patient diagnosis. Demographic, clinical, pathologic, and radiologic data were collected from electronic medical records. Median age of diagnosis of NrS was 12 years old (range: 5-17) and median time from NrS diagnosis to SP-EPN diagnosis was 31 days (range: -1-1636). 14 out of 16 (87.5%) initial tumors were in the cervical spine region, with C2 being the most frequently involved level. Two patients underwent resection of their tumors, with both experiencing progression of their disease and one developing paraplegia. The most common symptoms from SP-EPN were pain (30%), motor deficits (30%), and sensory deficits (30%). 40% of the patients had progressive disease at last follow up, with median time from diagnosis to progression of 3.33 years. Median time from SP-EPN to last follow-up was 4.08 years. This series showcases the burden of SP-EPN in pediatric NrS patients, emphasizing the need for further exploration into clinical outcomes and novel treatments for this debilitating condition.
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    Pituitary Adenoma and Social Determinants of Health: Tracing PAths to Better Outcomes
    (2024-09-28) Virtanen , Piiamaria S.; Obeng-Gyasi, Barnabas; Brown, Ethan D. L.; Colter, Austyn; Koenig, Jenna; Burket, Noah; Szilagyi, Halie; Williams, Greer; Halalmeh, Dia; Wang, Hannah S.; Tinkham, Shawn A.; Vetter, Cecelia J.; Richardson, Angela M.
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    Validation and next-generation update of a DNA methylation-based recurrence predictor for meningioma: A multicenter prospective study
    (Oxford University Press, 2025) Landry, Alexander P.; Wang, Justin Z.; Patil, Vikas; Gui, Chloe; Mamatjan, Yasin; Patel, Zeel; Yakubov, Rebecca; Kaloti, Ramneet; Habibi, Parnian; Wilson, Mark; Ajisebutu, Andrew; Ellenbogen, Yosef; Wei, Qingxia; Singh, Olivia; Sosa, Julio; Mansouri, Sheila; Wilson, Christopher; Cohen-Gadol, Aaron A.; Virtanen, Piiamaria; Burket, Noah; Blackwell, Matthew; Koenig, Jenna; Alfonso, Anthony; Davis, Joseph; Zaazoue, Mohamed A.; Tabatabai, Ghazaleh; Tatagiba, Marcos; Behling, Felix; Barnholtz-Sloan, Jill S.; Sloan, Andrew E.; Chotai, Silky; Chambless, Lola B.; Mansouri, Alireza; Ehret, Felix; Capper, David; Tsang, Derek S.; Aldape, Kenneth; Gao, Andrew; International Consortium on Meningiomas (ICOM); Nassiri, Farshad; Zadeh, Gelareh; Neurological Surgery, School of Medicine
    Background: We previously developed a DNA methylation-based risk predictor for meningioma, which has been used locally in a prospective fashion since its original publication. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation predictor compatible with newer methylation arrays. Methods: Genome-wide methylation profiles were generated with the Illumina EPICArray. The performance of our next-generation predictor was compared with our original model and standard-of-care 2021 WHO grade using time-dependent receiver operating characteristic curves. An nomogram was generated by incorporating our methylation predictor with WHO grade and the extent of resection. Results: A total of 1347 meningioma cases were utilized in the study, including 469 prospective cases from 3 institutions and an external cohort of 100 WHO grade 2 cases for model validation. Both the original and next-generation models significantly outperform the 2021 WHO grade in predicting early postoperative recurrence. Dichotomizing patients into grade-specific risk subgroups was predictive of outcomes within both WHO grades 1 and 2 tumors (P < .05), whereas all WHO grade 3 tumors were considered high-risk. Multivariable Cox regression demonstrated the benefit of adjuvant radiotherapy (RT) in high-risk cases specifically, reinforcing its informative role in clinical decision-making. Finally, our next-generation predictor contains nearly 10-fold fewer features than the original model, allowing for targeted arrays. Conclusions: This next-generation DNA methylation-based meningioma outcome predictor significantly outperforms the 2021 WHO grading in predicting time to recurrence. We make this available as a point-and-click tool that will improve prognostication, inform patient selection for RT, and allow for molecularly stratified clinical trials.