tbuckley/cabot-search huggingface dataset:
BIOM-44.18F-DOPA-PET THRESHOLDS FOR BOTH NEWLY DIAGNOSED AND RECURRENT ASTROCYTOMA USING PATHOLOGICAL GROUPING OF SPATIALLY CORRELATED BIOPSIES
Authors: Deanna Pafundi, Ian Parney, Terry Burns, Caterina Giannini, Aditya Raghunathan, Christopher Hunt, Katharine Dooley, Brian Kabat, Val Lowe, Timothy Kaufmann, Jonathan Morris, Mark Zakhary, Michael Grams, Maasa Seaburg, William Breen, Jann Sarkaria, Derek Johnson, Nadia Laack, Debra Brinkmann
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioma radiotherapy planning requires accurate tumor delineation. While T1- contrast-enhanced-MRI (T1-CE-MRI) is the standard, due to blood-brain-barrier breakdown dependencies, T1-CE-MRI fails to reflect the extent of glioma. Studies using amino acid PET tracers report glioma uptake up to 3cm-4cm beyond T1-CE. In this study, amino acid tracer 18F-fluoro-dihydroxyphenylalanine (18F-DOPA) uptake was correlated with histopathological features to determine tumor thresholds. METHODS Using registered 18F-DOPA-PET and T1-CE-MRI images in the Stealth Neuronavigation system targeting concordant and discordant regions, 181 stereotactic biopsy samples (newly-diagnosed=74; recurrent=107) were obtained from 59 enrolled astrocytoma patients across two prospective phase II clinical trials between 2010-2019. An experienced neuropathologist reviewed each sample with hematoxylin and eosin stain and assigned an alphanumeric score: mitotic activity (0=no tumor; 1=no mitosis; 2=few/scattered mitosis; 3=frequent mitosis) and cellular density (A=&amp;lt;25%; B=25%-50%; C=50%-75%; D=&amp;gt;75%). Samples assigned 1C-1D, 2B-2D, or 3A-3D were categorized as histopathological high-score (aggressive disease), remaining samples as low-score. Relative mean (rFDOPA_mean) tumor-to-background uptake ratios were computed for 5mm uniformly expanded volumes from each Stealth biopsy coordinate using the crescent and wedge normalization methods. Relative uptake was compared overall and separately within newly-diagnosed/recurrent disease subgroups. An optimal rFDOPA_mean threshold to delineate high- from low-score was determined using the maximal Youden index of ROC curves. RESULTS Overall, high-score samples (n=116) had higher median (IQR) rFDOPA_mean uptake than low-score samples (n=65): high-score rFDOPA:mean=1.70(1.16-2.26), low-score rFDOPA:mean=1.16(0.83-1.49), Kruskal-Wallis p&amp;lt;0.001. The uptake difference between high- vs. low-score samples was observed within newly-diagnosed and recurrent subgroups, but was only significant for newly-diagnosed (p&amp;lt;0.001). For newly-diagnosed, an rFDOPA:mean=1.49 cutoff between high- and low-score groups shows 69% accuracy, 63% sensitivity, 80% specificity (AUC=0.782). Using the wedge normalization method, rFDOPA_mean values were 0.2 higher than crescent method values. CONCLUSIONS This work presents histologically verified 18F-DOPA-PET thresholds for aggressive disease in newly-diagnosed astrocytoma patients. Separate thresholds will need to be determined for recurrent glioma patients.
RADT-15. THE ROLE OF STEREOTACTIC RADIOSURGERY IN WHO GRADE II MENINGIOMAS: RESULTS FROM A LARGE EUROPEAN MULTICENTER STUDY
Authors: A Santacroce, C Tuleasca, R Liščák, A Kollova, E Motti, C Lindquist, M Radatz, J Frischer, B Lippitz, R Martínez Álvarez, B Sandvei Skeie, A Nicolato, M Longhi, F Unger, I Sabin, T Mindermann, O Bundschuh, G A Horstmann, A T C van Eck, M Nakamura, H -J Steiger, C Ewelt, S Zafy Alsofy, M Lewitz, J Régis, A Muacevic, T Hofmann, F Ehret, P Picozzi, S Faedo, A Franzini, S Masaranov, Tobias Greve
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND This study evaluates the outcomes of WHO grade II meningiomas treated with stereotactic radiosurgery (SRS) using a large, multi-institutional European database. We aim to investigate the long-term tumor control rate and morbidity associated with SRS. METHODS Data from 355 consecutive patients treated between 1992 and 2022 at 16 European radiosurgery centers were retrospectively analyzed. After excluding 40 patients due to loss to follow-up, results from 315 patients were included. Clinical and imaging data were independently collected by each center and uniformly entered into a multicenter database. RESULTS The median age of patients was 56 years, with 54% being female. The median follow-up duration was 46.3 ± 36.9 months. Tumors had prior surgical treatment and biopsy in 99% and 1% of cases, respectively. Tumors received previous radiotherapy or SRS in 27.4% of cases. SRS was performed due to local progression in 89.6% of cases, residual tumor in 6.4%, and distant progression in 4.0%. SRS characteristics included a median target volume of 5.1 cm³ and a median margin dose of 16 Gy (53.5% isodose). The 3-year local control rate was 72.0%, with a progression-free survival rate of 66.6% and an overall survival rate of 89.7%. Transient and permanent morbidity rates were 6.4% and 3.5%, respectively. Multivariate analysis identified previous radiotherapy and age as significant factors influencing these outcomes. CONCLUSIONS This study is the largest to date on SRS in WHO grade II meningiomas. Our data shows that SRS is a viable and safe treatment option for residual and recurrent WHO grade II meningiomas
DDDR-34. A SYSTEMS MEDICINE PLATFORM FOR INDIVIDUALIZED TREATMENT OF GLIOBLASTOMA
Authors: Erlend Skaga, Pourya Naderi, Skarphedinn Halldorsson, Cecilie J Sandberg, Winston Hide, Einar O Vik-Mo
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is an aggressive brain cancer characterized by complex intertumoral heterogeneity. Yet, no methods have successfully stratified patients for effective individualized treatments. We aimed to use a systems medicine approach to individualize treatments for patients. From 27 patients undergoing surgery for either a newly diagnosed or a progressive glioblastoma, we collected biopsies and cultured the cells as spheroids. Drug sensitivity testing for &amp;gt;500 drugs from the FDA-approved oncology collection was performed. Drug efficacy was quantified using a modified area under the dose-response curve (Drug Sensitivity Score, DSS), and individualized by normalizing the DSS to the drug response in bone marrow cells from healthy donors (selective DSS, sDSS). All samples were assayed by WES, WGS, and RNA-sequencing. We found that glioblastomas can be stratified into three DSS groups. These were associated with expression of genes both known (e.g. ALDH1A1), and not known (e.g. VRK2) to be linked to drug resistance. By unsupervised clustering of sDSS, we found a robust patient stratification primarily driven by drug sensitivity to four groups of targets: i) EGFR, ii) FGFR/PDGFR/VEGFR, iii) MDM2 and iv) MEK/ERK. We found differentially expressed genes (N = 20-90 genes, varying by group) between the responders and non-responders in each group. We explored differential pathway activity between the responders and non-responders in each group to correlate drug responses to transcriptional networks to inform underlying disease mechanisms. The transcriptional networks further provide a molecular basis for drug predictions for additional treatment prioritizations. We conclude that our platform can stratify glioblastomas into subgroups, inform the underlying biology of drug sensitivity, and prioritize treatments for patients. Clinical utility is currently under evaluation in a formal trial.
TMET-33. INVESTIGATING THE ROLE OF CHEMERIN SIGNALING IN GLIOBLASTOMA
Authors: Brianna Dessa, Dazhi Wang, Scott Welford
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma multiforme (GBM) is one of the most common and lethal primary brain tumors in adults. Despite clinical efforts, patient prognosis remains poor with a median survival of approximately 14 months. Thus, identification of novel treatment avenues is needed. Metabolic rewiring is a hallmark of cancer and lipid homeostasis has an increasingly appreciated role in cancer cell survival. It has been shown that the disruption of lipid metabolic balance can lead to lipotoxicity, creating a new avenue in GBM treatment. Therefore, identifying methods to disrupt said lipid metabolic balance in GBM could provide a needed foothold. Previous studies from the lab have identified chemerin, a multifunctional adipokine encoded by the retinoic acid receptor responder 2 (RARRES2) gene, as an important and targetable lipid metabolism modulator in Clear cell renal cell carcinoma (ccRCC). Chemerin has also been implicated in the mesenchymal-phenotype promoting network between GBM cells and tumor-associated macrophages. Given similarities in GBM and ccRCC lipid metabolism and the existing role of chemerin in the tumor immune microenvironment in GBM, we hypothesize that chemerin drives GBM development by regulating lipid metabolism in addition to immune cell trafficking. This study aims to investigate the role and therapeutic opportunities of altered lipid metabolism in GBM by examining chemerin and its receptors (CMKLR1 and GPR1). Immunocompetent GBM mouse models generated through CRISPR-in utero electroporation (IUE) show that mice bearing RARRES2, CMKLR1, and GPR1 knockout tumors have prolonged survival. In addition, in vitro molecular inhibition of CMKLR1 in both human and murine GBM cell lines results in cell death. Ongoing studies involving in vitro CRISPR knockouts of RARRES2, CMKLR1, and GPR1 aim to elucidate the mechanisms by which in vivo inhibition of chemerin signaling results in slower tumor progression.
IMMU-62. INVIGORATING EFFECTOR IMMUNE CELLS WITH HIGHLY SELECTIVE IL-2R AGONISTS AND POTENTIAL SYNERGY WITH TUMOR TARGETING THERAPEUTICS FOR TREATMENT OF GLIOBLASTOMAS
Authors: Minh D To, Aanchal Sharma, Nina Merchant, Jiali Liu, Christopher A Chamberlain, Yasmin Morris, Varshaa Anantharam, Shahida Sheraz, Mansi Shah, Gerasimos Mastrokalos, Steve Pollard, Lewis Thorne, Paul Brennan, Fahar Merchant, Felipe Galvez-Cancino, Sergio A Quezada
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is an aggressive brain tumor with a median overall survival (mOS) of 14 months. Treatment options are limited with no new approved therapies over the past 3 decades and no standard of care for a majority of patients (&amp;gt; 90%) who experience recurrence. GBM has a highly immune suppressive tumor microenvironment (TME) comprising of myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) that are capable of suppressing the activity of anti-cancer CD8+ T and NK cells. We have engineered highly selective IL-2 superkines (IL-2SK) that preferentially expand and activate CD8+ T and NK cells with limited effects on immune suppressive regulatory T cells (i.e., Tregs). MDNA11 is an IL-2SK -albumin fusion protein designed to increase half-life and promote tumor accumulation. MDNA223 is a bi-functional anti-PD1-IL-2SK designed to stimulate effector immune cells while preventing immune exhaustion. MDNA11 and MDNA223 extended survival of mice harboring orthotopic GBM tumors with accompanying increase in CD8+ T and NK cells within the TME. When patient-derived GBM tumor explants were treated with MDNA11 and MDNA223 ex vivo, there was clear evidence of activation among resident CD8+ T cells characterized by increased levels of intra-cellular Granzyme B responsible for tumor cell killing. There was also increased release of soluble Fas ligand and granulysin, consistent with an activated anti-tumor immune response within the TME. Ongoing studies include in depth immune profiling to further understand the mechanism of MDNA11 and MDNA223 in GBM as well as to test potential synergy with tumor targeting therapeutics and other treatment modalities capable of eliciting immunogenic cell death.
TMET-31. OXIDATIVE STRESS INDUCED PROTEIN AGGREGATION VIA GGCT PRODUCED PYROGLUTAMIC ACID IN DRUG RESISTANT GLIOBLASTOMA
Authors: Deanna Tiek, Xiao Song, Runxin Wu, Xiaozhou Yu, Rebeca Iglesia, Bo Hu, Shiyuan Cheng
Journal: Neuro-Oncology (2024)

Abstract Drug resistance is a major barrier to cancer therapies and remains poorly understood. Recently, non-mutational mechanisms of drug resistance have been proposed where a more plastic metabolic response can play a major role. Here, we show that upon drug resistance, glioblastoma (GBM) cells have increased oxidative stress, mitochondria function, and protein aggregation. Gamma (y)-glutamylcyclotranserase (GGCT), an enzyme in the y-glutamyl cycle for glutathione production, located on chromosome 7 which is commonly amplified in GBM is also increased upon resistance. We further observe that the byproduct of GGCT – pyroglutamic acid – can bind aggregating proteins and that genetic and pharmacological inhibition of GGCT prevents protein aggregation. Finally, we found increased protein aggregation, GGCT expression, and pyroglutamic acid staining in recurrent GBM patient samples, as well as adjacent normal brain. These findings suggest a new pathway for protein aggregation within drug resistant brain cancer that should be further studied in other brain disorders.
TMIC-03. CARD9 BLOCKADE OFFERS A NEW OPPORTUNITY TO REPROGRAM TUMOR-ASSOCIATED MACROPHAGES IN GLIOBLASTOMA
Authors: Juliana Hofstatter Azambuja, Saigopalakrishna Yerneni, Lisa Maurer, Hannah Crentsil, Gabriela Debom, Linda Klei, Mei Smyers, Chaim Sneiderman, Kristina Schwab, Rajesh Acharya, Yijen Lin Wu, Prasanna Ekambaram, Dong Hu, Pete Gough, Kevin Foley, John Bertin, Ari Melnick, Gary Kohanbash, Riyue Bao, Peter Lucas, Linda McAllister-Lucas
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM), one of the deadliest primary tumors of the central nervous system, is characterized by a highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages and microglia (TAMs) are a dominant population of immune cells in the GBM TME and substantially contribute to immunosuppression, tumor progression, and treatment resistance. Elucidating the molecular mechanisms underlying TAM behavior is crucial to the development of effective immuno-therapeutic strategies for treating GBM. The adaptor protein, Caspase Recruitment Domain-containing protein 9 (CARD9) is primarily expressed in myeloid cells and its activation triggers assembly of the CARD9-BCL10-MALT1 (CBM) complex, which then promotes activation of NF-κB and/or MAPK pathways. The aim of this study was to investigate the role of the CBM complex in the GBM TME and assess its potential as a therapeutic target. METHODS/RESULTS In silico analyses revealed that GBM tumors demonstrate increased CARD9 and MALT1 expression in comparison to non-tumor brain tissue, with CARD9 expressed only within the myeloid compartment. Using co-culture, scratch wound, and transwell assays, we found that GBM tumor cells induce macrophage M2 polarization and migration via a mechanism that is dependent on CARD9/MALT1 signaling within macrophages. scRNA-Seq and flow-cytometric analysis of orthotopic syngeneic immunocompetent GBM tumor models revealed that the GBM TME is dominated by macrophages. Disruption of MALT1 protease activity within the TME leads to reduced tumor infiltration by immunosuppressive TAMs, remodeling of TAMs toward an immunoreactive anti-tumor phenotype, and improved survival of GBM-bearing mice. Additionally, we found that tumor growth was abrogated when GBM-bearing mice were treated with either a MALT1-protease inhibitor or a CARD9 inhibitor. CONCLUSIONS Our study suggests that blockade of the CARD9-MALT1 signaling axis impairs GBM-induced macrophage recruitment and M2 polarization and inhibits tumor progression. These findings nominate the CARD9-MALT1 signaling axis as a new target for TAM-directed immunotherapy for the treatment of GBM.
CNSC-59. EPIGENETIC POTENTIATION OF ANTI-TUMOR IMMUNE RESPONSES USING VIRAL MIMICRY IN GLIOMAS
Authors: Jay Chandar, Deepa Seetharam, Jelisah Desgraves, Christian Ramsoomair, Jesus Castro, Anna Hudson, Vaidya Govindarajan, Yong Zhang, Adam Sonabend, Mynor Mendez Valdez, Dragan Maric, Vasundara Govindarajan, Sarah Rivas, Victor Lu, Alexandra Alvarado, Ritika Tiwari, Nima Sharifi, Catherine DeMarino, Kory Johnson, Macarena De La Fuente, Ruham Alsiekh Nasany, Teresa Noviello, Michael Ivan, Ricardo Komotar, Antonio Iavarone, Avindra Nath, John Heiss, Michele Ceccarelli, Katherine Chiappinelli, Maria Figueroa, Defne Bayik, Ashish Shah
Journal: Neuro-Oncology (2024)

Abstract Clinical trials using immune checkpoint inhibition(ICI) have traditionally failed in glioblastoma (GBM). Viral mimicry, which augments anti-tumor immune responses and sensitizes response to immunotherapy in other cancers, involves the epigenetic activation of endogenous retroelements (REs). REs are silenced via the HUSH complex and H3K9me3. This process is mediated by ZNF638. We aimed to elucidate the role of viral mimicry in enhancing ICI through epigenetic reprogramming of the HUSH complex. We demonstrated that RE expression among 48 superfamilies inversely correlated with ZNF638 expression in gliomas, based on data from 71 newly-diagnosed GBMs. Using transcriptional deconvolution, we showed ZNF638 negatively correlates with innate antiviral immune response signatures(TLR3)(RTLR3=-0.300,pTLR3=0.00006). We validated these in-silico results in pure glioma cell lines, patient-derived GBM neurospheres, and syngeneic murine models. ZNF638 knockdown induced intracellular RE-mediated dsRNA signaling cascades via RIG-I and TLR3. This knockdown significantly increased PD-L1 expression(p&amp;lt;0.001), reduced H3K9 trimethylation, and enhanced cytoplasmic dsRNA accumulation in glioma cell lines. In patient-derived GBM neurospheres, ZNF638 knockdown upregulated immune and antiviral programs. Additionally, knockdown resulted in upregulation of several endogenous repeat elements (Alu, LTR). Single-cell RNA sequencing showed ZNF638 clustering in neural progenitor-like and oligodendrocyte-like cells, with increased retroelement expression in low ZNF638 cells. Tumors with lower ZNF638 expression showed increased CD8+ populations. Bulk RNA sequencing deconvolution revealed that ZNF638 is linked to reduced CD8 and DC infiltration in gliomas (RCD8=-0.202,RDC=-0.198;pCD8=8.79E-06,pDC=1.34E-05). In immunocompetent mice, ZNF638 KO and PD-L1 inhibition significantly improved survival (mOS &amp;gt;50 days, p&amp;lt;0.0001) and reduced tumor volume (p&amp;lt;0.001). Analysis of cohorts from multiple cancer types treated with anti-PD1 therapy demonstrated that ZNF638 expression predicts therapeutic response and overall survival. Our findings suggest that epigenetic reprogramming through HUSH inhibition may potentiate immunotherapy for GBM.
EPCO-57. INTEGRATED ANALYSIS OF BULK AND SINGLE-CELL RNA SEQUENCING DATA OF PRIMARY AND METASTATIC PEDIATRIC MEDULLOBLASTOMA
Authors: Ana Isabel Castillo Orozco, Geoffroy Danieau, Niusha Khazaei, Masoumeh Aghababazadeh, Marjan Khatami, Livia Garzia
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma (MB) is a highly aggressive and the most common brain tumor in childhood. MB presents a high intertumoral heterogeneity, with at least four molecular subgroups identified (SHH, WNT, Group 3, and Group 4). Metastatic MB, or Leptomeningeal Disease (LMD), is predominantly found in the MB Group 3 type. Although LMD represents a main clinical challenge, its molecular mechanisms remain poorly characterized. Recent research has shown that primary and MB metastasis diverge dramatically. Our work has focused on establishing therapy naïve Group 3 Patient-Derived Xenografts models of primary and metastatic Medulloblastoma to conduct transcriptomic profiling at the bulk and single-nuclei RNAseq levels to identify genetic drivers/pathways that sustain leptomeningeal disease compartment. Our results show various signaling pathways enriched across LMD models, such as MYC targets, unfolded protein response, and fatty acid metabolism. Using single-sample GSEA analysis (ssGSEA) and deconvolution approaches, we have also identified that our PDXes models retain neoplastic subpopulations previously identified in MB single-cell sequencing studies. Similarly, we have identified slight differences in cell subpopulation proportions between primary and leptomeningeal compartments. Our single-nuclei studies have confirmed these results and differentially expressed genes previously found in bulk RNAseq analyses. These results suggest the presence of cell populations enriched in the metastatic compartment with an aberrant transcription phenotype and adaptations in fatty acid metabolism to survive the leptomeningeal space. In conclusion, our work supports the notion that primary and LMD retain subpopulation clusters present in MB Group 3 tumors with different proportions in the metastatic compartment shown by bulkRNAseq deconvolution and single nuclei RNA analysis. We also show that primary and LMD are transcriptionally different, with various enriched pathways in the metastatic compartment and shared among LMD Group 3 PDX models. Through these approaches, we aim to elucidate the genetic dependencies of metastatic Medulloblastoma that will help for targeted therapies.
SURG-09. IMPACT OF RESPONSIVE NEUROSTIMULATION IN PATIENTS WITH MESIAL TEMPORAL EPILEPSY: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Ayesha Ayesha, Mohammed Raake, Paweł Łajczak, Yasmin Silva, Aisha Rizwan Ahmed, Rabbia Jabbar, Eshita Sharma, Mir Wajid Majeed, Walter Fagundes
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain-responsive neurostimulation, known as the RNS therapy, proves to be a safe and effective adjuvant therapy in decreasing seizure frequency among medically refractory adults with partial-onset seizures who are either seizure-prone post-surgery or are not eligible candidates for surgery. Nevertheless, previous publications have not presented outcomes specifically on subjects with Mesial temporal lobe epilepsy (MTLE). This meta-analysis aims to evaluate the effectiveness of RNS therapy in patients with medically refractory MTLE. METHODS A comprehensive search was conducted across the PubMed, Cochrane, and Scopus databases for studies evaluating the impact of RNS on seizure frequency in patients with mesial temporal epilepsy. Relevant studies published up to March 2024 were included. The statistical analysis assessed the mean seizure reduction, responder rate, and seizure freedom. RESULTS We applied a random-effects model to data from 7 cohort studies with 207 patients, which revealed a significant mean reduction in seizures among individuals who received RNS therapy (68.76%, 95%CI=57.16-80.37%, p-value&amp;lt;0.01). A sub-analysis of 5 studies involving 164 patients demonstrated a substantial response rate (67%, 95%CI= 47-88%, p-value&amp;lt;0.01). Furthermore, an analysis of 4 studies comprising 154 patients indicated a considerable proportion of patients achieved seizure freedom after treatment (Proportion=0.29, 95%CI=0.03-0.55, p-value=0.03). Notably, there was moderate to high heterogeneity across the studies. CONCLUSION This single-arm meta-analysis demonstrates that responsive neurostimulation could be an effective therapeutic option for patients with MTLE, significantly reducing seizure frequency and a high proportion of patients achieving seizure freedom. Further research, including randomized controlled trials with control groups, larger sample sizes, and longer follow-up periods, is warranted to validate these results and optimize patient outcomes. Keywords: neurostimulation; mesial temporal epilepsy; systematic review; meta-analysis.