Fonkem, Ekokobe

Abstract Diffuse midline glioma (DMG) is a universally fatal pediatric brainstem cancer. Outside of clinical trials, palliative radiotherapy (RT) remains the only approved treatment, with a median overall survival (OS) of <12 months. The brain-penetrant oral therapy dordaviprone (ONC201) has demonstrated early clinical efficacy by activating the overexpressed mitochondrial protease ClpP, inducing mitochondrial dysfunction. Our previous studies identified that dordaviprone triggers compensatory energy production via the PI3K/mTOR pathway to avoid cell death. To overcome this adaptation, we combined dordaviprone with the brain-penetrant pan-PI3K/mTOR inhibitor paxalisib, showing synergistic anti-tumor effects across multiple immunocompromised patient-derived xenograft models. These results led to the international Phase II clinical trial (PNOC022/NCT05009992), where >20% of patients enrolled pre-radiation achieved survival beyond 2 years. However, approximately 20% of patients experienced immune-related toxicities-mucositis, colitis, and skin reactions, likely driven by paxalisib’s pan-PI3K inhibition, as PIK3CG (p110γ) and PIK3CD (p110δ) are enriched in hematopoietic cells. In contrast, PIK3CA (p110α) is a known genetic dependency in DMG. We hypothesized that the brain-penetrant, p110α-selective inhibitor GCT-007 could maintain therapeutic efficacy while reducing immune toxicity. DMG patient-derived cell lines showed comparable sensitivity to paxalisib and GCT-007 (mean IC50: 0.659 μM vs. 0.775 μM, respectively). Unbiased proteomic profiling in two DMG lines treated with GCT-007 identified robust downregulation of PI3K/AKT/mTOR signaling, confirmed via immunoblotting. Pathway enrichment further showed upregulation of oxidative phosphorylation, reinforcing the rationale for synergistic combination with dordaviprone. In aggressive immunocompetent syngeneic models, GCT-007 significantly extended overall survival (median 53 vs. 40 days, p=0.0001). When combined with dordaviprone, enzastaurin, or immune checkpoint inhibitors (ICI), GCT-007 increased survival in immune-competent DMG models by an average of 53% to 77% compared to vehicle (p=0.001), with 25% of mice in the GCT-007 + ICI cohort achieving long-term survival. Ongoing spatial profiling of the tumor immune microenvironment and organ-toxicity screening is underway to support translation.

Abstract Background Central nervous system (CNS) tumors are a significant cause of morbidity and mortality in sub-Saharan Africa (SSA). To date, no large-scale efforts have focused on brain tumor genetics within this region. This study aimed to assess and map the current neuro-oncology capacity in SSA, including workforce availability and existing services for brain tumor registries and biobanks. The results represent the final analysis representing respondents from 70 healthcare institutions. Methods This cross-sectional study utilized an online survey to collect data from healthcare professionals involved in CNS tumor care across SSA through the Society for Neuro-Oncology SSA (SNOSSA). The survey gathered information on the availability of neuro-oncology practitioners, neuropathology and molecular diagnostic capacity, brain tumor management, cancer registries, and biobanking of specimens. Purposive sampling was used to identify participants, with the questionnaire provided in English, French, and Swahili. Results A total of 145 respondents from 22 countries and 70 healthcare institutions participated. Among the 70 institutions, neurosurgery was available in 89%, anatomic pathology in 74%, and medical oncology in 71%. For radiologic evaluation, 64% of institutions reported having both CT and MRI, while 17% had CT only. Molecular testing through IHC or NGS was available in 46% of institutions. Multidisciplinary tumor boards for CNS cases were present in 86% of institutions. General cancer registries were available in 66% of institutions, while 29% had brain tumor-specific registries, and 10% maintained brain tumor biorepositories. Conclusion This study provides a comprehensive summary of the neuro-oncology capacity in SSA. Next steps are to reach out to institutions who have registries and determine what data are being collected, with the hopes of defining a set of common elements to expand registry efforts across SSA. Similarly, to reach out to institutions that have ongoing brain tumor biobanks and CT/MRI capacity to determine what infrastructure exists.

AbstractAbstract Background Central nervous system (CNS) tumors are a significant cause of morbidity and mortality in Sub-Saharan Africa (SSA). This project aimed to assess and map out the current neuro-oncology capacity in SSA, brain tumor registries, and biobanks. Methods This cross-sectional study utilized an online survey to gather data from healthcare professionals involved in CNS tumor care across SSA through the Society for Neuro-Oncology SSA (SNOSSA). The survey captured information on the availability of neuro-oncology practitioners, neuropathology, molecular diagnostics, cancer registries, and biobanking. Results A total of 145 respondents representing 70 healthcare institutions across 22 countries participated. Of the 70 institutions, specialties included neurosurgery (89%, 62/70), anatomic pathology (74%, 52/70), and medical oncology (71%, 50/70). For radiologic evaluation, 64% (45/70) of responding institutions reported having both CT and MRI. Access to molecular testing through immunohistochemistry or next-generation sequencing was available in 46% (32/70) of responding institutions. Multidisciplinary tumor boards were available for CNS cases in 86% (60/70) of responding institutions. Brain tumor-specific registries were available in 29% (20/70) of responding institutions, and 10% (7/70) maintained brain tumor biorepositories. Conclusion This study demonstrates that SSA has substantial potential in neuro-oncology care practice capacity and facilities. The most significant gaps were in neuropathology and molecular testing, which makes widespread implementation of the WHO 2021 diagnosis challenging. Understanding the prevalence of CNS tumor subtypes in SSA is difficult due to the low number of brain tumor registries and biobanks.

Abstract Background Brain tumors represent a significant global health challenge, with rising incidence and mortality impacting individuals worldwide and contributing to cancer-related morbidity and mortality. In Africa, this burden is exacerbated by limited access to advanced diagnostics, treatment options, and multidisciplinary care, compounded by the absence of standardized cancer registration and tumor biobanking. The introduction of molecular diagnostics, as outlined in the 2021 World Health Organization central nervous system (CNS) tumor classification, adds complexity to brain tumor management, particularly in regions with scarce resources. Methods To address these issues, the Brain Tumor Consortium for Africa (BTCA) was established in 2023, bringing together experts to improve CNS tumor diagnosis, patient care, and research. The initial project, conducted via an electronic questionnaire, aimed to assess neuro-oncology capacity across Sub-Saharan Africa. Results The study revealed significant gaps, with a limited number of institutions incorporating molecular subtyping into their diagnostic algorithms. The consortium’s efforts focus on enhancing local data use, informing public policy, and promoting collaboration to advance neuro-oncology practices in Africa. By fostering a network enlisting the expertise of collaborators in the fields of neurosurgery, neurology, neuropathology, anatomic pathology, and medical and radiation oncology, the BTCA seeks to improve brain tumor management through better diagnostics, infrastructure, and policy advocacy. Future directions include expanding molecular diagnostic capabilities, standardizing brain tumor biobanking, enhancing data collection, and advocating for improved brain tumor care in national health agendas. Conclusions The BTCA represents a pioneering model of collaboration and innovation in addressing the unique challenges of brain tumor care in Africa.

Abstract Brain tumors constitute significant morbidity and mortality in sub-Saharan Africa (SSA). There is no previous large-scale effort focusing on brain tumor genetics in SSA. This project aims to map out the current neuro-oncology capacity in terms of workforce and available services in SSA. This is an ongoing online survey among a cross section of neuro-oncology practitioners spread across SSA countries to capture information on the distribution, number of available neuro-oncology care practitioners, capacity for neuropathology and molecular diagnosis, management of brain tumors, cancer registration, and tumor biobanking. The survey was disseminated by the Society for Neuro-oncology in SSA (SNOSSA). There were 83 respondents representing 15 countries and 52 health institutions: 46 tertiary, 4 secondary, 1 private and 1 other. Here, we present data on the 52 institutions. The prevalence of specialties was 87% neurosurgery, 75% anatomic pathology, 69% medical oncology, 64% neurology, 60% radiation oncology, and 39% neuropathology. For radiologic evaluation, 81% of institutions were reported to have both CT and MRI, 17% CT only, and one institution neither. For molecular testing, 46% have access to IHC or NGS testing, whereas 52% were reported to have neither. A neuro-oncology tumor board was reported at 58% of institutions. A general cancer registry is available in 64% of institutions, 31% have a brain tumor specific registry and 10% have a brain tumor biorepository. This study shows that SSA has substantial potential in neuro-oncology care practice capacity and facilities. Most significant gaps remain in areas such as neuropathology and molecular testing, which makes widespread implementation of the WHO 2021 diagnosis challenging. Understanding the prevalence of CNS tumor subtypes is also difficult due to low number of brain tumor registries and biobanks in SSA. The present findings reveal strategic opportunities, especially in neuropathology, tumor registries, biobanks, and infrastructure for IHC and NGS in SSA.

Abstract INTRODUCTION Brain tumors constitute significant morbidity and mortality in sub-Saharan Africa (SSA). Improvements in neuro-oncology practice and research have seen increased diagnosis of brain tumors. However, to our knowledge, there have been no previous projects on brain tumor genetics in SSA. To understand the feasibility of developing brain tumor biobanking and registries, this project aims to start by mapping out the current neuro-oncology capacity in terms of workforce and available services. METHODOLOGY We will conduct a descriptive questionnaire-based online survey among a cross section of neuro-oncology practitioners spread across SSA countries. The dissemination of the survey questionnaire will be facilitated by the Society for Neuro-oncology in SSA (SNOSSA). The Google designed questionnaire will capture information on the distribution, and number of available neuro-oncology care practitioners, capacity for brain tumor diagnosis and management, cancer registration, tumor biobanking, and research. CLINICAL IMPACT AND CONCLUSION This study will generate robust data from SSA, which can be used to improve future research and promote advocacy towards brain tumor diagnosis and management. This work will also serve as a pilot study for subsequent research that will focus on the development of brain tumor-specific registries and biorepositories in SSA.

Abstract Background The optimal diagnosis and management of patients with brain tumors currently uses the 2021 WHO integrated diagnosis of histomorphologic and molecular features. However, neuro-oncology practice in resource-limited settings usually relies solely on histomorphology. This study aimed to classify glioma cases diagnosed in the Department of Anatomic and Molecular Pathology, Lagos University Teaching Hospital, using the 2021 WHO CNS tumor classification. Methods Fifty-six brain tumors from 55 patients diagnosed with glioma between 2013 and 2021 were reevaluated for morphologic diagnosis. Molecular features were determined from formalin-fixed paraffin-embedded (FFPE) tissue using immunohistochemistry (IHC) for IDH1-R132H, ATRX, BRAF-V600E, p53, Ki67, and H3-K27M, OncoScan chromosomal microarray for copy number, targeted next generation sequencing for mutation and fusion and methylation array profiling. Results Of 55 central nervous system tumors, 3 were excluded from histomorphologic reevaluation for not being of glial or neuroepithelial origin. Of the remaining 52 patients, the median age was 20.5 years (range: 1 to 60 years), 38(73%) were males and 14(27%) were females. Seventy-one percent of the gliomas evaluated provided adequate DNA from archival FFPE tissue blocks. After applying the 2021 WHO diagnostic criteria the initial morphologic diagnosis changed for 35% (18/52) of cases. Diagnoses of 5 (9.6%) gliomas were upgraded, and 7 (14%) were downgraded. Conclusions This study shows that the incorporation of molecular testing can considerably improve brain tumor diagnoses in Nigeria. Furthermore, this study highlights the diagnostic challenges in resource-limited settings and what is at stake in the global disparities of brain tumor diagnosis.

Abstract BACKGROUND The diagnosis and management of patients with brain tumors currently uses WHO defined morphologic and molecular features. However, neuro-oncology practice in low resource settings relies on histomorphology. This study aims to reclassify glioma cases diagnosed in the Department of Anatomic and Molecular Pathology Lagos University Teaching Hospital using the 2021 WHO classification. METHODS Fifty-six cases of glioma diagnosed between 2013 to 2021 were evaluated. Morphologic diagnosis was reassessed. Five-micron sections were obtained for immunohistochemistry (IHC), and genetic testing (DNA and RNA); after manual macrodissection for tumor enrichment using 10μm sections. IHC for IDH1-R132H, ATRX, BRAFV600E, P53,Ki67, and H3K27M and OncoScan chromosomal microarray analysis were performed. NGS mutation/fusion analysis and EPIC methylation array profiling are in progress. RESULTS Of 56 cases evaluated, median age was 22 years (range=1-60 years); 71% were males. The initial morphologic diagnosis include 21 pilocytic astrocytoma, 11 glioblastoma, 9 ependymoma, 7 diffuse astrocytoma, 3 anaplastic astrocytoma, 2 high-grade gliomas, 1 oligodendroglioma, 1 diffuse midline glioma, and 1 pleomorphic xanthoastrocytoma (PXA). Histomorphologic re-evaluation revealed discordant diagnosis in 29% (16/56) of cases. Of the 56 cases, 73% (41/56) had usable DNA yield and 38% (21/56) had DNA yield of ≥ 750ng. Chromosomal microarray analysis was completed for 50% (28/56) cases. The revised 2021 WHO diagnosis were: 5 glioblastoma, IDH-wildtype, 5 pilocytic astrocytoma, 4 glioma NEC, 3 posterior fossa ependymoma, group B, 3 PXAs, 3 astrocytoma, IDH-mutant, 2 pediatric low-grade glioma, 2 supratentorial ependymoma, ZFTA fusion-positive, 1 posterior fossa ependymoma, group A. In 71% (20/28) of cases, diagnosis was revised using the 2021 WHO criteria. CONCLUSION Most cases had usable DNA yield. Overall, hsitologic re-evaluation and molecular testing based on the 2021 WHO classification guidelines refined the diagnosis in 48% (27/56) of cases.

Abstract INTRODUCTION Brain tumors constitute significant morbidity and mortality in sub-Saharan Africa (SSA). Improvements in neuro-oncology practice and research have seen increased diagnosis of brain tumors. However, to our knowledge, there have been no previous projects on brain tumor genetics in SSA. To understand the feasibility of developing brain tumor biobanking and registries, this project aims to start by mapping out the current neuro-oncology capacity in terms of workforce and available services. METHODOLOGY We will conduct a descriptive questionnaire-based online survey among a cross section of neuro-oncology practitioners spread across SSA countries. The dissemination of the survey questionnaire will be facilitated by the Society for Neuro-oncology in SSA (SNOSSA). The Google designed questionnaire will capture information on the distribution, and number of available neuro-oncology care practitioners, capacity for brain tumor diagnosis and management, cancer registration, tumor biobanking, and research. CLINICAL IMPACT AND CONCLUSION This study will generate robust data from SSA, which can be used to improve future research and promote advocacy towards brain tumor diagnosis and management. This work will also serve as a pilot study for subsequent research that will focus on the development of brain tumor-specific registries and biorepositories in SSA.

Abstract BACKGROUND The diagnosis and management of patients with brain tumors currently uses WHO defined morphologic and molecular features. However, neuro-oncology practice in low resource settings relies solely on histomorphology. This study aims to reclassify glioma cases diagnosed in the Department of Anatomic and Molecular Pathology Lagos University Teaching Hospital using the WHO 2021 classification. METHODS Fifty-six cases of glioma diagnosed between 2013 to 2021 were evaluated. Morphologic diagnosis was reassessed. Five-micron sections were obtained for immunohistochemistry (IHC), and genetic testing (DNA and RNA) after manual macrodissection for tumor enrichment used 10-µm sections. IHC for IDH1-R132H, ATRX, BRAF-V600E, p53, Ki67 and H3-K27M and Oncoscan chromosomal microarray analysis were performed. NGS mutation/fusion analysis and EPIC methylation array profiling are in progress. RESULTS Of the 56 cases evaluated, median age was 22 years (range, 1-60); 71% were male. The initial morphologic diagnoses included 21 pilocytic astrocytoma, 11 glioblastoma, 9 ependymoma, 7 diffuse astrocytoma, 3 anaplastic astrocytoma, 2 high-grade gliomas, 1 oligodendroglioma, 1 diffuse midline glioma, and 1 pleomorphic xanthoastrocytoma (PXA). Histomorphologic re-evaluation revealed discordant diagnosis in 29% (16/56) of cases. Of the 56 cases, 73% (41/56) had usable DNA yield and 38% (21/56) had DNA yield of ≥750ng. Chromosomal microarray analysis was completed for 50% (28/56) cases. The revised WHO 2021 diagnosis was: 5 glioblastoma IDH-wildtype, 5 pilocytic astrocytoma, 4 glioma NEC, 3 posterior fossa ependymoma, group B, 3 PXA, 3 astrocytoma IDH-mutant, 2 pediatric low-grade gliomas, 2 supratentorial ependymoma, ZFTA fusion-positive, 1 posterior fossa ependymoma, group A. In 71% (20/28) of cases with molecular testing, diagnosis was revised using WHO 2021 criteria. CONCLUSION Most cases had usable DNA. Overall, histologic re-evaluation and molecular based on the WHO 2021 criteria refined the diagnosis in 48% (27/56) of cases.