tbuckley/cabot-search huggingface dataset:
TMOD-19. GERMLINE<i>ELP1</i> DEFICIENCY SENSITIZES CEREBELLAR GRANULE NEURON PROGENITORS TO SHH MEDULLOBLASTOMA
Authors: Shiekh Tanveer Ahmad, Jesus Garcia-Lopez, Yiran Li, Jennifer Hadley, Leena Paul, Brian Gudenas, Melissa Batts, Taha Soliman, Aaron Pitre, Marija Kojic, Frederik Manz, Frederique Zindy, Alun Jones, Anand Mayasundari, Brandon Bianski, Christopher Tinkle, Abbas Shirinifard, Laura Janke Janke, Meifen Lu, Arzu Onar-Thomas, Stefan Pfister, Amar Gajjar, Suzanne Baker, Martine Roussel, Zoran Rankovic, Giles Robinson, Brent Orr, Brandon Wainwright, Lena Kutscher, Sebastian Waszak, Hong Lin, Paul Northcott
Journal: Neuro-Oncology (2024)

Abstract Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events observed in medulloblastoma (MB), accounting for 30% of the Sonic Hedgehog 3 subtype (SHH-3). Molecularly, ELP1-associated SHH-MBs acquire somatic PTCH1 mutations in &amp;gt;80% of cases, and universal loss-of-heterozygosity of the wild-type ELP1 and PTCH1 alleles through loss of chromosome-arm 9q, resulting in their biallelic inactivation. Notably, germline ELP1 LOF occurs mutually exclusive with somatic/germline TP53 mutations in the SHH-3 subtype, suggesting that genetic perturbation of either ELP1 or TP53 may promote similar downstream oncogenic consequences in cerebellar granule neuron progenitors (GNPs), the accepted cellular origin of SHH-MB. Despite these findings, the molecular, biochemical, and cellular mechanism(s) by which ELP1-deficiency provokes malignant pathogenesis remain unknown. In this study, we sought to close this knowledge gap and functionally determine why children harboring pathogenic ELP1 germline variants are at an increased risk of developing SHH-MB. Mice were genetically engineered to mimic heterozygous Elp1 LOF (Elp1HET). We studied the effect of loss of ELP1 in GNPs using a combination of molecular profiling, immunophenotyping, and cellular assays. GNPs from Elp1HET exhibited a spectrum of molecular and biochemical hallmarks of malignant transformation including increased DNA replication stress, DNA damage, accelerated cell cycle progression, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs engineered to harbor somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing an explanation for the specificity of ELP1-associated tumors in SHH-3, and their exclusivity with TP53-mutant tumors. Treatment of ELP1-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. Collectively, our findings functionally substantiate the role of ELP1 deficiency in predisposition to SHH-3 MB and nominate therapeutic strategies to overcome p53 inhibition as a rational treatment option.
NIMG-39. THE “RESECTABILITY INDEX” AS A NOVEL OBJECTIVE PREDICTOR OF SURVIVAL FOR PATIENTS WITH ADULT-TYPE DIFFUSE GLIOMAS
Authors: Noah Nichols, Nitish Seenarie, Raymund Yong
Journal: Neuro-Oncology (2024)

Abstract Extent of resection (EOR) is a strong prognostic factor for patients with adult-type diffuse gliomas. Whole brain tractography (WBT) allows visualization of tumors in relation to functional subcortical white matter tracts connecting eloquent cortex. We developed a preoperative metric, the resectability index (RI), to estimate tumor resectability based on pre-resection volume (PRV) and unresectable tumor volume (UTV). We explore if RI predicts progression-free survival (PFS) and overall survival (OS). We retrospectively reviewed the charts of consecutive patients with adult-type diffuse gliomas resected from 2013-2020. Only patients with pre-operative DTI MRIs were included. UTV was the total overlapping volume of tumor with functionally significant tracts (corticospinal, arcuate, optic, fornix) and deep structures (basal ganglia, thalamus, brainstem). RI was (PRV-UTV)/PRV. Seventy-nine patients were included with an average age of 56 years at time of surgery. Glioblastoma was the most common histology (68%). Tumors were located in the left hemisphere (LH) (48%), right hemisphere (RH) (39%), and bilateral hemispheres or midline (BHM) (13%). EOR for LH, RH, and BHM tumors was 0.8, 0.91, and 0.29, respectively (P = 0.1^7). RI for LH, RH, and BHM tumors was 0.86, 0.912, and 0.44, respectively (P = 0.00021). Cox regression was used to model PFS and OS based on age, preoperative KPS, WHO grade, EOR, and RI. Age, recurrent status, bilaterality, residual tumor volume (RTV) and UTV predicted PFS (CI = 1.01 – 1.06, P = 0.002). For OS, UTV and RI were more strongly predictive than RTV or EOR. In a Cox regression model consisting only of preoperative variables, RI was independently predictive of OS. RI is a novel metric with potential efficacy for preoperative survival prognostication in patients with diffuse gliomas. RI may enable neurosurgeons to provide HGG patients with more accurate information about expected benefits of surgical intervention than is currently possible. RI will also enable more valid comparisons of HGG patient cohorts treated at different institutions.
IMMU-37. PRE-TREATMENT INNATE INFLAMMATION ASSOCIATES WITH SURVIVAL AFTER POLIO VIROTHERAPY AND CAN BE MODULATED TO SENSITIZE GLIOMAS TO IN SITU VACCINATION
Authors: Lalita Mazgaeen, William Kornahrens, Jr Minh-Huy Giang, Georgia Howell, Aaron Briley, Michelle Bowie, Smita Nair, David Ashley, Annick Desjardins, Matthias Gromeier, Michael Brown
Journal: Neuro-Oncology (2024)

Abstract Early-stage clinical trials in glioblastoma (GBM) have tested various virotherapy strategies, yet only a subset of patients appear to benefit. We previously demonstrated that a recombinant poliovirus (PVSRIPO) functions by inducing MDA5-dependent, type I interferon (IFN) dominant innate inflammation in myeloid cells to provoke durable and functional antitumor T cell responses in mice. Long-term survival after intratumoral PVSRIPO infusion was observed in a subset of patients with recurrent GBM (rGBM) in two clinical trials. Survival after PVSRIPO was associated with higher pre-treatment intratumoral neutrophil density and MHC-class II gene expression, but also higher pre-treatment inflammatory cytokines in blood. Post-treatment induction of type I/III IFNs detected in blood one day after PVSRIPO infusion also associated with survival of patients with rGBM, suggesting that the proficiency of IFN responses to PVSRIPO may dictate therapy outcome. In human ex vivo glioma tissue assays, only a subset of gliomas mounted type I IFN responses to PVSRIPO and STING agonist treatment, in a manner linked with higher pre-treatment IL-1b levels, and lower CXCL10 induction after treatment. Thus, baseline innate inflammation either influences or reflects the capacity of glioma tumors to respond to virotherapy. Strikingly, in glioma bearing mice, peripheral vaccination against tumor irrelevant vaccines in alum adjuvant (i.e., against antigens not expressed by the tumor) induced bone marrow, spleen and intratumoral innate inflammation; rescued the antitumor efficacy of PVSRIPO in an otherwise refractory glioma model; and improved survival after intratumor STING agonist therapy. Notably, peripheral vaccination induced intratumoral neutrophil and CD4+ T cell inflammation, and increased MHC-class II expression on myeloid cells. These data imply a role for pre-treatment systemic innate immune training in the antitumor efficacy of virotherapy and indicate that modulating either systemic innate inflammation and/or the inflammatory status of bone marrow myeloid progenitors may sensitize gliomas to virotherapy.
CTNI-44. NCT03643549 PHASE IB/II TRIAL: EFFICACY, SAFETY, AND BIOLOGICAL MECHANISMS OF OBJECTIVE RESPONSES IN RECURRENT GBM PATIENTS WITH UNMETHYLATED MGMT PROMOTER TREATED WITH SEQUENTIAL BORTEZOMIB AND TEMOZOLOMIDE
Authors: Dorota Goplen, Mohummad Aminur Rahman, Jorunn Brekke, Surendra Kumar, Victoria Arnesen, Even Birkeland, Anne Simonsen, Andreas Waha, Kirstin Marienhagen, Leif Oltedal, Judit Haasz, Hrvoje Miletic, Frode Selheim, Tora Skeidsvoll Solheim, Petter Brandal, Stein Atle Lie, Martha Chekenya
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is amongst the deadliest malignancies in adults, but especially for patients with unmethylated MGMT promoter (uMGMT) who gain limited benefit from the standard treatment. We previously demonstrated that proteosome inhibitor bortezomib (BTZ), inhibited NFkB activation,depleted MGMT protein and sensitized uMGMT GBM cells to Temozolomide (TMZ). Thus, a phase I/II trial testing sequential combination BTZ+TMZ was launched to investigate safety and clinical benefit. METHODS Recurrent GBM patients with uMGMT promoter, progressing ≥12 weeks after radiotherapy, KPS≥70 and radiologically measurable lesions were enrolled. The trial was powered for n=63 patients compared with n=102 historical controls. Patients received BTZ 1.3mg/m² IV on days 1, 4, and 7 of each 4-week cycle, starting on day 3 with oral 200mg/m² TMZ for 5 days/week. Whole exome sequencing (WES) of tumor DNA was conducted to identify genetic changes and LC-MS/MS used to asses proteomic changes in plasma collected during treatment. RESULTS As of January 2024, 54 patients (median 55y (25-70); 38 males, 16 females) were treated. The median KPS 90 (range 70-100) and NANO score was 1 (range 0-7). QoL was preserved, with mild /moderate adverse events. Adjusted analyses showed overall survival (OS) of 16.2 months compared to 8.4 months for uMGMT control patients, HR0.48, 95%CI[1.057-2.74],P=0.028. Objective radiological responses stable disease or better were observed in 22% (12/54) patients. Survival from recruitment was 10.5 months for responders vs. 4.8 months for rest of cohort, P=0.054 HR2.55, 95%CI[0.984-5.94]. Preliminary data indicate 78% (7/9) of responders harboured amplified EGFR vs. 38% in rest-of-the patients. The responders differentially expressed proteins critical for cellular processes, including ADAMTSL4, NCAM1, AZGP1, MMP2, CD163, and IL6ST. CONCLUSION Sequential BTZ+TMZ therapy is safe, effective and showed clinical benefit. EGFR amplification may be a predictive biomarker for response through NFκB activation, that is targeted by BTZ thereby depleting MGMT protein and enhancing treatment efficacy. Sequential BTZ+TMZ treamtment may represent additional treatment option at recurrence.
DDDR-07. FUNCTIONAL GENOMICS<i>IN VIVO</i> USING CRISPR/CAS9 IDENTIFIES POTENTIAL METABOLIC VULNERABILITIES WITHIN MELANOMA BRAIN METASTASIS
Authors: Yanxia Ma, Nhat Nguyen, Wei He, Sanjay Singh, Rongjie Fu, Liang Zhang, Sheri Holmen, Phil Jones, Michael Davies, Han Xu, Chibawanye Ene
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Inhibition of the oxidative phosphorylation (OxPhos) pathway in mice suppressed the growth of melanoma brain metastasis but not extracranial or primary skin melanoma. This indicates that melanoma brain metastasis may have targetable metabolic vulnerabilities. Human clinical trials, however showed toxicities following OxPhos pathway inhibition. This suggests that more selective metabolic targets are needed to minimize off target effects. METHODS We designed a focused CRISPR guide RNA (gRNA) lentiviral knockout library targeting 106 metabolism genes significantly enriched in human melanoma brain metastasis (n=88) relative to extracranial (n=50) or primary skin melanoma (n=52). We infected mouse B16F10 melanoma cell lines with the CRISPR library and implanted 1X106 cells subcutaneously or intracerebrally into male (n=3) and female (n=3) C57/Bl6 mice. DNA from cell lines and tumor samples were sent for next generation sequencing. Candidate metabolism genes that may drive growth of melanoma lesion within the brain were identified based on loss of gRNA copies in brain relative to skin. RESULTS The CRISPR/Cas9 in vivo screen identified metabolic genes whose knockout resulted in loss of gRNA clones within established B16F10 melanoma brain lesions relative to skin lesions. These putative metabolism targets included specific components in the oxidative phosphorylation pathway, choline metabolism, and ubiquitin cascade activation. CONCLUSION Using a focused CRISPR/Cas9 in vivo screen, we uncovered potential metabolic targets within established mouse melanoma brain lesions. vWe are currently performing the in vivo screen in melanoma mouse models with spontaneous brain metastasis. Top 3 hits across all models will be validated individually prior to a compound screen for inhibitors.
QLTI-07. COLLABORATIVE RESEARCH SUITE FOR GENOMIC ANALYSIS, DATA REPORTING AND WORKFLOW CUSTOMISATION
Authors: Vijay Sreegiriraju, Vijaylaxmi Roy, Devraj Lath, Pankaj Mishra, Yashoda Ghanekar, Subhashini Sadashivam, Pallavi Goel, Vikas Pawar, Surya Madiraju, Amit Ray
Journal: Neuro-Oncology (2024)

Abstract The genomic analysis pipeline involves multiple stages, including data extraction, transformation, and loading (ETL), exploratory data analysis (EDA), machine learning (ML) modeling, and reporting. The ETL stage involves data profiling and quality control measures to ensure data integrity and consistency. The EDA stage employs statistical and visualization methods to understand data distribution, identify patterns, and detect anomalies. Machine learning modelling involves supervised classification techniques, such as logistic regression and support vector machines (SVMs), to predict tumour classification and develop gene signatures. Unsupervised classification techniques, such as K-means clustering and Hierarchical clustering, identify patterns and relationships in genomic data. Quality metrics evaluate data completeness, accuracy, and consistency, ensuring data reliability and validity. The integration of data science techniques into a comprehensive framework can be achieved with the development of Application Dashboards that provide real-time insights into genomic data across every stage of the analysis pipeline. This enables clinical researchers and bioinformaticians to make informed decisions quickly, improving turn-around time and accelerating the discovery of new insights. In contrast to conventional methods of using stand-alone scripts, these dashboards offer a reusable and scalable solution, allowing for easy modification and adaptation to new datasets and analysis pipelines, thereby reducing development effort and increasing productivity. The dashboards constitute a centralized platform for data visualization, exploration, and analysis, facilitating collaboration and communication among research team members. With customizable and interactive visualizations, users can explore genomic data from multiple dimensions and the integration of multiple sources, including genomic and transcriptomic data. The technologies used to power this Research suite include Streamlit for Web App development, Python for data analysis, Opensearch for data storage and other utility libraries for reporting.
PATH-59. HISTOLOGIC CORRELATES FOR MOLECULAR FEATURES IN MENINGIOMAS
Authors: Harrshavasan Congivaram, Vineeth Thirunavu, Lucas Santana-Santos, Pouya Jamshidi, William Chen, Khizar Nandoliya, Madina Sukhanova, Heather Smith, Matthew McCord, Alicia Steffens, Jordain Walshon, Kathleen McCortney, Mariah Flowers, Wenxia Wang, Xinyan Lu, Maciej Lesniak, Adam Sonabend, Matthew Tate, Osaama Khan, Amy Heimberger, Daniel Brat, James Chandler, David Raleigh, Stephen Magill, Mark Youngblood, Craig Horbinski
Journal: Neuro-Oncology (2024)

Abstract Histologic findings are the primary determinant of meningioma prognosis and post-operative management. However, the association of specific pathologic features with molecular alterations has not yet been comprehensively investigated. Here we utilized a large dataset of well-characterized meningiomas to identify correlates between clinically relevant histological and molecular features. Detailed histologic information was collected for 809 resected meningiomas, including cases with DNA methylation (n=380), copy number array (n=252), next-generation sequencing (n=52), RNA risk score (n=394), and/or TERT promoter profiling (n=238). Analyses were conducted on prognostic pathologic features, including WHO Grade, Ki-67, mitotic index (MI), brain invasion, and atypical histologic findings (necrosis, hypercellularity, prominent nucleoli, sheeting, and small cells). Correlation with molecular variables was performed using Fisher’s Exact Tests, including DNA methylation subgroup, RNA risk score, CNV profiles, and TERT promoter mutations. All statistics were corrected for multiple hypothesis testing. Nearly 65% of meningiomas exhibited at least one atypical histologic feature. Among said features, Ki-67/MI, WHO Grade, sheeting, and necrosis were associated with recurrent lesions and known clinical features of aggressive meningiomas. Several histologic features, including hypercellularity, elevated Ki-67/mitotic index, and WHO grade, also correlated with DNA methylation and RNA risk groups. Several chromosomal arm events were related to specific pathologic features (prominent nucleoli, Ki-67, MI, and grade), including chromosomes 1, 4, 10, 14, and 18. Our analysis highlights the continued value in screening for histologic markers of aggressive behavior in meningiomas, as they correlate with the presence of high-risk molecular features and may serve as proxy markers when advanced molecular testing is not available.
EXTH-78. A NOVEL BISPECIFIC S100A4/TFR ANTIBODY TO REPROGRAM THE GLIOMA TUMOR MICROENVIRONMENT AND TARGET GLIOMA STEM CELLS
Authors: Thomas Wong, Jia-Shiun Leu, Xuejun Fan, Reece Kang, Nourhan Abdelfattah, Fransisca Leonard, Ningyan Zhang, Kyuson Yun
Journal: Neuro-Oncology (2024)

Abstract GBM (glioblastoma) is the most common and aggressive primary brain tumor in adults. While immunotherapy is a promising treatment modality for GBM, most clinical trials have thus far only provided a modest benefit to GBM patients. We propose that enhancing the efficacy of immunotherapy for GBM requires approaches that increase T cell infiltration and reprogram the myeloid cells to a more pro-inflammatory state. S100A4 is a major regulator of stemness, epithelial-mesenchymal transition, and a critical regulator of immune suppressive myeloid and T cell phenotypes in GBM. Targeting S100A4 in either glioma or stromal cells is sufficient to reprogram the tumor immune landscape and extend survival of glioma bearing mice, indicating that S100A4 is a promising immunotherapy target. We recently developed a S100A4 blocking monoclonal antibody; however, this antibody does not cross the blood brain barrier (BBB) efficiently to confer significant therapeutic benefit, limiting its efficacy in treating GBM. To overcome this challenge, we generated a bispecific S100A4-TfR antibody (BsA) that allows robust BBB penetration, and tested this in a pre-clinical syngeneic, orthotopic mouse model of GBM. Using ELISA, confocal immunofluorescent microscopy, flow cytometry, and bulk RNA sequencing, we report that systemic administration of the S100A4-TfR BsA results in increased immune cell infiltration with a preferential increase in CD4 T cell infiltration, and potent immune remodeling of the tumor microenvironment to a more pro-inflammatory state. Furthermore, the BsA is taken up by glioma cells intracellularly, which is correlated with depletion of intracellular S100A4 and decreased nuclear SOX2 localization, which would reduce stemness of glioma cells. Functionally, in vitro BsA treatment of primary glioma cell cultures shows decreased S100A4 expression, proliferation, and self-renewal. Our results suggest that S100A4-TfR BsA is a novel dual activity inhibitor to simultaneously reprogram the GBM immune landscape and reduce glioma stemness.
DDDR-21. MPT0G521 AS A DUAL INHIBITOR OF LSD1 AND HDAC: A POTENTIAL THERAPEUTIC AGENT AGAINST PARENTAL AND TEMOZOLOMIDE-RESISTANT GLIOBLASTOMA MULTIFORME
Authors: Wei-Lun Lo, Jian-Yin Chuang, Ming-Shao Wu
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and poor prognosis. Resistance to temozolomide (TMZ), the standard chemotherapy for GBM, further complicates treatment. This study investigates the effects of MPT0G521, a dual inhibitor of LSD1 and HDAC, on both parental and TMZ-resistant GBM cells to determine its potential as a therapeutic agent. MATERIALS AND METHODS TMZ and MPT0G521 were introduced in our study. Human GBM cell lines A172 and patient-derived primary GBM cells Pt#3, along with their TMZ-resistant counterparts, were cultured under specified conditions. Assays conducted include cell proliferation (MTT), colony formation, cell cycle analysis via flow cytometry, and western blot analysis for protein expression. Statistical significance was evaluated using ANOVA. RESULTS MPT0G521 exhibited significant anti-proliferative activity and toxicity against both parental and TMZ-resistant GBM cells in a dose- and time-dependent manner. Treatment with MPT0G521 led to reduced cell viability and colony formation. Cell cycle analysis revealed G2M phase arrest and increased subG1 phase, indicating cell cycle disruption and apoptosis. Western blot analysis showed upregulation of histone H3 methylation and acetylation, confirming the dual inhibitory action of MPT0G521 on LSD1 and HDAC. Additionally, MPT0G521 modulated markers of cell cycle and apoptosis, including increased levels of cleaved caspase-3 and PARP. CONCLUSION MPT0G521 demonstrates potential as an effective therapeutic agent against GBM by inhibiting cell proliferation, inducing cell cycle arrest, and promoting apoptosis in both parental and TMZ-resistant cells. These findings support further investigation of MPT0G521 as a promising treatment for GBM, particularly in cases resistant to standard chemotherapy.