Morgan Adams Foundation

MYC-driven medulloblastoma (MB) is a highly aggressive brain tumor with poor prognosis and limited treatment options. Through CRISPR-Cas9 screening, we identify the Mediator-associated kinase CDK8 as a critical regulator of MYC-driven MB. Both genetic loss and pharmacological inhibition of CDK8 impair MB tumor growth. Moreover, we find that CDK8 cooperates with MYC to sustain the MYC-mediated translational program, as CDK8 depletion induces pronounced transcriptional changes in translation-associated gene sets, reduces ribosome biogenesis, and impairs protein synthesis. Mechanistically, CDK8 regulates the occupancy of RNA polymerase II at specific chromatin loci, facilitating epigenetic alterations that promote the transcription of ribosomal genes. Furthermore, combined inhibition of CDK8 and mTOR synergistically enhances therapeutic efficacy in vivo, leading to more pronounced tumor growth suppression. Overall, our findings establish a functional link between CDK8-mediated transcriptional regulation and mRNA translation, suggesting a promising therapeutic approach targeting protein synthesis for MYC-driven MB.

Diffuse hemispheric glioma H3 G34-mutant is primarily diagnosed in adolescents/young adults. While molecular diagnostics have improved, cellular mechanisms that drive tumor progression and therapy resistance are poorly understood. Combining previous published studies with findings from the 2024 NIH G34-mutant symposium aid in summarizing translational and clinical updates on disease development, cellular repair processes, and the immune microenvironment. This collective work is meant to outline opportunities for treatment and prolonged survival.

Abstract Background Adamantinomatous craniopharyngioma (ACP) comprises 5-11% of pediatric intracranial tumors and is associated with poor quality of life. In general, cancer outcome studies indicate that females have higher survival rates and better treatment responses than males. Leading theories focus on sex-related genetic/molecular differences versus sex hormone differences as primary contributors to the different outcomes. Here, we investigated sex-associated differences in survival and functional outcomes of prepubescent patients with ACP, aiming to study the role of biological sex in the absence of hormonal effects. Methods Sixty-four patients diagnosed with ACP under 7 years of age were retrospectively identified from the Advancing Treatment for Pediatric Craniopharyngioma (ATPC) and the Children’s Hospital Colorado databases. A Cox regression model was used to evaluate time to recurrence/progression. A linear regression model was used to evaluate functional outcomes compared to pre-treatment baseline using a modified Craniopharyngioma Clinical Status Scale (CCSS). Patient age and length of follow-up were included as covariates. Results We found that sex is a statistically significant predictor of disease progression (p = 0.0183, power = 0.999), with males demonstrating a 57.4% lower risk of progression (95% CI [13.5%, 79.0%]). In contrast, patient age and follow-up duration did not significantly affect the hazard of progression. There was no statistically significant difference in neurological, visual, pituitary, or hypothalamic functional outcomes between males and females. Conclusions Our study finds that in prepubescent ACP patients, males have a lower risk of disease progression than females, although the functional outcomes are equivalent. With an underdeveloped hypothalamic-pituitary-­gonadal axis in prepubertal patients, the observed sex difference is likely attributed to factors such as genetic and molecular differences other than hormonal effects. This study highlights the need to identify variables impacting ACP disease course and advocates for personalized treatment strategies to improve patient outcomes and quality of life.

Abstract Pediatric central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with survival outcomes significantly influenced by racial, ethnic, and socioeconomic disparities. These disparities may arise from delayed diagnosis, unequal access to care, and challenges in navigating complex treatment decisions, including clinical trial enrollment. To better understand the patient and family perspective at the beginning of their journey, we performed a qualitative study to explore their experience from symptom onset through treatment initiation, focusing on diagnosis, treatment discussions, and decision-making processes. We conducted semi-structured interviews with a diverse cohort of 17 families during diagnosis or early treatment; 13 completed a follow-up interview later in treatment. We examined the emotional and logistical challenges encountered during diagnosis and treatment planning. Our findings reveal the profound emotional toll of diagnosis, characterized by uncertainty, shock, and urgency. Families reported difficulties understanding complex medical information and accessing advanced treatment options, including clinical trials. Decisions about treatment were shaped by perceptions of therapeutic efficacy, anticipated side effects, and the resources available to support care. The study underscores differences in families’ perceptions of care, with variations in barriers and obstacles influenced by individual circumstances. These disparities shaped the types of support families sought from their care teams, highlighting the necessity of personalized communication and tailored resources to meet diverse needs. By centering patient and family experiences, this study contributes a nuanced understanding of disparities in pediatric CNS tumor care, emphasizing the need for targeted interventions to improve access to innovative treatments, support informed decision making, and enhance communication. Future research should incorporate quantitative methods, including surveys and clinical trial enrollment analysis, to validate findings and guide the development of scalable solutions. Addressing the structural and informational barriers identified can reduce disparities and improve the experiences of families navigating pediatric CNS tumor care.

Pediatric low‐grade gliomas (pLGG) comprise 35% of all brain tumors. Despite favorable survival, patients experience significant morbidity from disease and treatments. A deeper understanding of pLGG biology is essential to identify novel, more effective, and less toxic therapies. We utilized single‐cell RNA sequencing (scRNA‐seq), spatial transcriptomics, and cytokine analyses to characterize and understand tumor and immune cell heterogeneity of pilocytic astrocytoma (PA) and ganglioglioma (GG). scRNA‐seq revealed tumor and immune cells within the tumor microenvironment (TME). Tumor cell subsets include both progenitor and mature cell populations. Immune cells included myeloid and lymphocytic cells. There was a significant difference between the prevalence of two major myeloid subclusters between PA and GG. Bulk and single‐cell cytokine analyses evaluated the immune cell signaling cascade with distinct immune phenotypes among tumor samples. KIAA1549‐BRAF tumors appeared more immunogenic, secreting higher levels of immune cell activators and chemokines, compared to BRAF V600E tumors. Spatial transcriptomics revealed the differential gene expression of these chemokines and their location within the TME. A multi‐pronged analysis demonstrated the complexity of the PA and GG TME and differences between genetic drivers that may influence their response to immunotherapy. Further investigation of immune cell infiltration and tumor‐immune interactions is warranted.

Medulloblastoma is the most common malignant brain tumor of childhood. The highest-risk tumors are driven by recurrent Myc amplifications (Myc-MB) and experience poorer outcomes despite intensive multimodal therapy. The Myc transcription factor defines core regulatory circuitry for these tumors and acts to broadly amplify downstream pro-survival transcriptional programs. Therapeutic targeting of Myc directly has proven elusive, but inhibiting transcriptional cofactors may present an indirect means of drugging the oncogenic transcriptional circuitry sustaining Myc-MB. Independent CRISPR-Cas9 screens were pooled to identify conserved dependencies in Myc-MB. We performed chromatin conformation capture (Hi-C) from primary patient Myc-MB samples to map enhancer-promoter interactions. We then treated in vitro and xenograft models with CDK9/7 inhibitors to evaluate effect on Myc-driven programs and tumor growth. Eight CRISPR-Cas9 screens performed across three independent labs identify CDK9 as a conserved dependency in Myc-MB. Myc-MB cells are susceptible to CDK9 inhibition, which is synergistic with concurrent inhibition of CDK7. Inhibition of transcriptional CDKs disrupts enhancer-promoter activity in Myc-MB and downregulates Myc-driven transcriptional programs, exerting potent anti-tumor effect. Our findings identify CDK9 inhibition as a translationally promising strategy for the treatment of Myc-MB. CDK9 is an intrinsic dependency in Myc-driven medulloblastomaDual CDK9/7 inhibition disrupts Myc-driven transcriptional circuitryCDK9 inhibitors should be developed as pharmaceutical agents for Myc-MB. Medulloblastoma is the most common malignant brain tumor of childhood, and outcomes for high-risk subgroups remain unsatisfactory despite intensive multimodal therapy. In this study, we pool multiple independent CRISPR-Cas9 screens to identify transcriptional cofactors such as CDK9 as conserved dependencies in Myc-MB. Using Hi-C from primary patient samples, we map Myc enhancer-promoter interactions and show that they can be disrupted using inhibition of transcriptional CDKs. CDK9 inhibitor treatment depletes Myc-driven transcriptional programs, leading to potent anti-tumor effect in vitro and prolongation of xenograft survival in vivo . With a large number of CDK9 inhibitory compounds now in clinical development, this study highlights the opportunity for clinical translation of these for children diagnosed with Myc-MB.

Abstract Central nervous system (CNS) tumors with either BCOR internal tandem duplication (BCOR ITD) or gene fusions involving BCOR/BCORL1 (BCOR FUS) are recognized as tumor types with characteristic molecular and clinical features but lacking clear therapeutic guidance. In an extensive international effort, we compiled a retrospective cohort of 229 (148 BCOR ITD, 81 BCOR FUS) unique cases via molecular profiling of CNS tumors. By analyzing DNA methylation patterns of 220 tumors we confirmed distinct epigenetic profiles of BCOR ITD versus BCOR FUS. The majority (91 percent) of BCOR FUS primary tumors was localized in the supratentorial region whereas BCOR ITD were localized across all anatomical CNS compartments. Median patient age at diagnosis was 20 years for BCOR FUS and 4 years for BCOR ITD. Metastatic disease was rare in BCOR FUS patients but more common in BCOR ITD tumors where 10 percent presented with metastatic disease and one third showed CNS or (rarely) extra-CNS metastasis in the course of disease. This was also reflected in clinical outcome as 5-year overall survival (OS) was 89 percent in BCOR FUS but 61 percent in BCOR ITD. In contrast, 5-year progression-free survival (PFS) was comparable reaching 27 percent in BCOR FUS and 30 percent in BCOR ITD. Integrating treatment details we found a trend towards benefit of gross-total resection on OS (BCOR FUS, n=18, p<0.08; BCOR ITD, n=67, p<0.12) but not for PFS (BCOR FUS, n=16, p<0.33; BCOR ITD, n=64, p<0.59). Radiotherapy was associated with improved PFS (BCOR FUS, n=18, p<0.01; BCOR ITD, n=70, p<0.001) and OS (BCOR FUS, n=20, p<0.01; BCOR ITD, n=73, p<0.001). Further in-depth analyses of clinical outcome parameters (primary metastatic disease, radiotherapy approach, chemotherapy type, patient age) are currently ongoing. In summary, we provide first robust annotation of CNS BCOR tumor types, clinical outcomes and therapy.

In 2019 the University of Technology Sydney developed a research project to assess the variety of students’ state of mind in their first year. The context was implementing transition pedagogy and determining if it was possible to visually map the range of student responses to transition from high school to university. The aim was to be in a better position to anticipate transition challenges for our students. The methodology involved asking first year students across all faculties to express their experience of their first year at university in a drawing, accompanied by a Likert scale self-assessment with an optional text reflection. The data gathered comprised over 550 drawings. Further, we documented and compared a range of examples of this type of research in other institutions. We noticed images common to all the different research projects appeared. The question we asked ourselves was whether it is possible to develop a taxonomy of images which could be relied upon in subsequent iterations of the exercise. We wanted to know whether we could create categories of symbols or images which could be objectively understood. The key outcomes were despite common use of images in these projects there are challenges in creating such a taxonomy. Interpretation is subjective and a classification system might be observer constructed, and not reflect the subject’s true intention. While our own data included the Likert scale and the opportunity to add text to the response, the triangulation is only apparently helpful in determining meaning because the difficulties remained. The added information does not overcome the inherent subjectivity of interpretation. The importance of this paper is it is an admission the exercise does not establish an ability to develop a definitive taxonomy. Instead, it cautions against an attempt at a taxonomy because it risks being ultimately unfaithful to the data.

In a cohort of patients who were treated with resection and adjuvant radiotherapy (RT) for adamantinomatous craniopharyngioma (ACP), the authors aimed to determine whether gross tumor volume (GTV) at the initiation of RT was associated with the risk of progressive disease (PD) following treatment. Pediatric and adolescent patients who received surgery and RT for ACP at a single institution from 1998 to 2021 were identified. Univariable Cox regression analyses (UVAs) were performed to assess the association between pre-RT GTV and PD after RT. Multivariable analyses (MVAs) were used to control for potential confounders. Two different endpoints were used to define PD. The first definition was based on radiographic tumor growth, with or without progression of clinical symptoms. The second definition was the requirement for an additional tumor-directed intervention following the completion of RT. Forty-eight patients were eligible for inclusion. The median age at diagnosis was 7.9 years (range 2.1-17.4 years). All patients were treated with surgery and RT with a median dose of 52.2 Gy (range 45-55.8 Gy) and median GTV of 9.86 cm3 (range 0.7-117.7 cm3). After a median follow-up of 66.4 months, 8 patients experienced PD based on both definitions. The 5-year event-free survival rate was 85.4% (95% CI 74.1%-98.3%). On both UVA and MVA, GTV was significantly associated with an increased likelihood of PD (UVA: HR 1.02, 95% CI 1.00-1.04, p = 0.02; MVA: HR 1.10, 95% CI 1.02-1.19, p = 0.01). However, after exclusion of a single outlier with a GTV of 117.7 cm3 prior to RT (remainder of the cohort: range 0.7-37.3 cm3), a second analysis identified no significant association between GTV and PD (UVA: HR 1.03, 95% CI 0.96-1.10, p = 0.4; MVA: HR 1.06, 95% CI 0.96-1.17, p = 0.24). The authors conclude that for most children and adolescents with ACP, the GTV at the initiation of RT is not associated with the risk of PD. This finding may influence surgical practice, because it suggests that aggressive tumor debulking for the purpose of improving the efficacy of RT may not be necessary. In the case of giant tumors, however, novel strategies may be needed for tumor control.