tbuckley/cabot-search huggingface dataset:
TMOD-13. IDENTIFYING MOLECULAR SIGNATURES OF PPM1D-MUTANT DIPGS
Authors: Ipsita Kundu, Adam Kebede, Eric Morin, Jaldeep Langhnoja, Phonepasong Arounleut, Pratiti Bandopadhayay, Timothy Phoenix
Journal: Neuro-Oncology (2024)

Abstract Diffuse Intrinsic Pontine Glioma (DIPGs) are universally fatal pediatric tumors with a median survival of only 9-12 months. PPM1D-truncating mutations (PPM1Dtr), which promote its phosphatase activity and suppress TP53 function, are found in approximately 15% of DIPG tumors. PPM1Dtr are mutually exclusive to TP53 mutations, and present unique therapeutic opportunities to reactivate wild-type TP53. Another distinct feature of PPM1Dtr DIPGs is the co-occurrence of PI3K/AKT/mTOR pathway alterations, such as PIK3CA. There is an unmet need to elucidate the underlying molecular mechanisms of DIPG and identify novel therapeutic vulnerabilities that will improve outcomes of this devastating tumor. We hypothesize that PPM1D-mutant DIPGs can be therapeutically targeted by reactivating the p53 signaling pathway and other complementary pathways which cooperate with PPM1Dtr. To investigate this, we have generated Trp53- and Ppm1d-mutant isogenic DIPG murine models to determine how specific oncogenic alterations function in DIPG formation, growth and treatment sensitivity. Current studies aim to examine differences in sensitivity to standard of care treatment modalities and leverage next generation sequencing techniques to uncover additional vulnerabilities. We found notable differences upon addition of PIK3CA mutations in the context of PPM1Dtr DIPG tumor formation, growth, survival, and lineage identity. Ongoing studies using whole genome transcriptomics to compare tumor models will provide insight into the molecular signals and cell state changes driven by individual genetic alterations. Furthermore, by comparing isogenic TP53 and PPM1Dtr mutant DIPG models, we aim to further delineate the molecular mechanisms that drive differential sensitivity of TP53 wild-type tumors. The immune-competent nature of our murine models also provides us with a unique opportunity to delineate tumor immune microenvironment changes. Leveraging this information and our novel murine models, our long-term goal is to develop combinatorial therapeutic strategies to improve outcomes for this deadly disease.
CTNI-65. DETERMINANTS OF LONG-TERM SURVIVAL IN PATIENTS WITH IDH-MUTANT GLIOMAS
Authors: Sophie Katzendobler, Jonathan Weller, Sebastian Niedermeyer, Jens Blobner, Christoph Trumm, Rupert Egensperger, Patrick Harter, Louisa von Baumgarten, Veit Stoecklein, Joerg-Christian Tonn, Michael Weller, Niklas Thon
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Survival times of patients with IDH-mutant gliomas is variable and can extend to decades. Many studies only provide progression-free rather than overall survival times and prognostic factors remain ill-defined. Here we explored clinical disease characteristics of long-term survivors within a large cohort of patients with extended follow-up. METHODS This single-center, retrospective analysis included 114 patients with IDH-mutant glioma that either died due to tumor-related causes or survived at least 15 years after first diagnosis. Patient characteristics, outcomes, and prognostic factors were stratified by short- (&amp;lt; 15 years) versus long-term (≥ 15 years) survival. Initial diagnosis was (re-)classified according to the WHO 2016 classification. Uni- and multivariate analyses were performed. RESULTS Overall, 66 patients (58%) were diagnosed with astrocytoma and 48 patients (42%) with oligodendroglioma. Median follow-up of the survivors was 16.6 years (range 15-28.9). 62 tumor-related deaths (54%) had been reported at database closure. Patients that died before reaching 15 years survival time had been diagnosed with astrocytoma in 41 (72%) and oligodendroglioma in 16 cases (28%). The long-term survivor cohort comprised 25 patients (44%) with astrocytoma and 32 patients (56%) with oligodendroglioma. Long-term survival was associated with grade 2 histology (p &amp;lt; 0.01), smaller tumor volumes (p &amp;lt; 0.01), and lack of contrast enhancement (p = 0.02). 41 long-term survivors (72%) were initially monitored by a wait-and-scan strategy as opposed to 16 patients (28%) in the cohort of short-term survival (p&amp;lt;0.01). In patients with oligodendroglioma, a higher KPS was associated with longer survival (HR 0.25; 95% CI 0.02-0.67; p = 0.05). Tumor resection (HR 0.43; 95% CI 0.22-0.86; p = 0.02) and wait-and-scan strategies (HR 0.34; 95% CI 0.14-0.79; p = 0.01) were associated with longer survival in patients with astrocytoma. CONCLUSION Tumor resection followed by a wait-and-scan strategy may yield excellent survival times, especially in patients with IDH-mutant grade 2 astrocytoma. Age appears not be an important predictor for survival in patients with IDH-mutant gliomas.
CTNI-08. DOSE ADJUSTED TEDDI-R FOR PRIMARY CNS DIFFUSE LARGE B-CELL LYMPHOMA
Authors: Richard Green, Candy Miranda
Journal: Neuro-Oncology (2024)

Abstract We report our initial experience treating 4 patients with the dose adjusted TEDDI-R protocol as reported by Dunleavy et al in 2015. The median age was 63 years, 2 patients were male, median KPS 60. Two patients were newly diagnosed: one of these had inadequate renal function for methotrexate; and the other had experienced acute methotrexate leukoencephalopathy. Two patients were treated for their first recurrence, having progressed during therapy with the MT-R protocol; one of these received salvage WBRT prior to starting. The protocol consisted of temozolomide 90 mg/sq m IV, cycles 1-6, days 2-5; etoposide 45 mg/sq m/day IV cycles 1-6, Days 2-5; liposomal doxorubicin 40 mg/sq m IV, cycles 1-6, day 2; dexamethasone 10 mg PO bid, cycles 1-6, days 1-5; ibrutinib 560 mg qd starting 3 days before cycle 1, day 1, then 560 mg qd, cycles 1-6, days 1-10; rituximab 375 mg/sq m IV cycles 1-6, days 1-2; and cytarabine 70 mg via Ommaya reservoir, cycles 2-6, days,1 and 5. Aspergillosis prophylaxis with isavuconazonium 372 mg mg PO bid was used. Overall, only 1 patient completed all 6 planned cycles; the median number of cycles completed was 4.5. Both newly diagnosed patients died during therapy; one died after 1 cycle from CMV colitis, and the other after 5 cycles from tumor recurrence, pneumonia, and septic shock. One patient with recurrent disease achieved a complete response and went on to high dose chemotherapy and autologous bone marrow transplantation; the other had a partial response after 4 cycles but died from pulmonary embolism. Median PFS for the newly diagnosed patients was 177 days, and for the recurrent patients, 221 days. Median OS for the cohort was 242 days. These preliminary data suggest that the TEDDI-R protocol was relatively toxic, especially for patients with poor neurological function, but can be an effective salvage therapy after progression on methotrexate-based therapy.
RBIO-09. EFFECTS OF RADIATION ON THE HIPPOCAMPUS AND HIPPOCAMPAL NEUROGENESIS: A SYSTEMATIC REVIEW OF INJURY MECHANISMS AND INTERVENTION STRATEGIES
Authors: Sandra Leskinen, Samir Alsalek, A Gabriella Wernicke
Journal: Neuro-Oncology (2024)

Abstract PURPOSE To understand how radiation affects the hippocampus and hippocampal neurogenesis. Radiotherapy is a common modality in the treatment of brain tumors that targets malignant cells with radiation. However, unintended iatrogenic injury may extend to adjacent healthy cells. The hippocampus is a particular area of concern, given its vital role in memory and learning and capacity for neurogenesis. METHODS We searched the PubMed, Embase, and Web of Science databases for studies assessing the effects of radiation on the hippocampus and hippocampal neurogenesis, adhering to PRISMA guidelines. Animal studies were evaluated according to the ARRIVE guidelines for pre-clinical studies. The SYRCLE risk of bias tool was utilized to examine potential bias among studies. Study characteristics, including study design, sample size, experimental methods, radiation dose, and results were collected and synthesized. RESULTS Ninety-two studies met inclusion criteria, and the majority of studies investigated rat and/or mouse models (n = 91, 98.9%). Across studies, cranial irradiation was consistently found to be associated with detrimental effects on hippocampal function and structure through molecular alterations to gene and protein expression, neuronal cell apoptosis, disruption of dendritic spines, and initiation of pro-inflammatory processes. The consequences for neurogenesis were mostly focused on the dentate gyrus of the hippocampus. These effects manifested as cognitive deficits in hippocampus-dependent tasks such as memory and learning. Behavioral (e.g., running) and pharmacological (e.g., PPARα agonists) interventions against the deleterious effects of radiation suggest the potential to address radiation-induced hippocampal disruption and cognitive deficits. The majority of studies were found to have an unclear risk of bias. CONCLUSIONS This systematic review highlights the effects of cranial radiation on hippocampal neurogenesis and their association with disruptions in memory and learning. Future research should continue to focus on delivering radiotherapy that spares susceptible regions in the brain, preserving patients’ cognitive function and quality of life.
IMMU-22. TWIST1-MEDIATED ENDOTHELIAL PLASTICITY DRIVES GLIOBLASTOMA RESISTANCE TO CAR T IMMUNOTHERAPY
Authors: Fan Yang, Md Naushad Akhtar, Yanqing Gong, Yi Fan
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common and most aggressive malignant primary brain tumor in adults. Among the most lethal human malignancies, GBM is highly resistant to cytotoxic treatments and molecularly targeted therapies, and also generally refractory to T cell–based immunotherapies, largely due to their immunologically cold nature, i.e., characterized by a paucity of tumor T cell infiltrates that result from the immunosuppressive microenvironment. Here, we identify a distinct mechanism driven by spatiotemporal interaction of leukocytes with tumor stromal cells, namely, mesenchymal-like population of endothelial cells (ECs) form an immunosuppressive vascular niche that regulates macrophage polarization and induces GBM resistance to CAR T immunotherapy. Our single-cell transcriptome analyses of human and mouse GBM tumors identify a subpopulation of ECs acquire robust immunosuppressive phonotypes to drive alternative macrophage polarization. These ECs are spatially localized proximately to immunosuppressive macrophages and selectively express Twist1. Furthermore, we reveal a Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which Twist1+ tumor ECs produce osteopontin to locally promote immunosuppressive macrophage phenotypes. Genetic or pharmacological ablation of Twist1 reverses macrophage-mediated immunosuppression and enhances T cell infiltration and activation, leading to reduced GBM growth and extended mouse survival. Importantly, pharmacological inhibition and lipid nanoparticle-mediated targeted inactivation of Twist1 overcome GBM resistance to Egfrviii CAR T cell immunotherapy. Thus, these findings uncover a spatially restricted mechanism controlling vasculature-mediated tumor immunity and suggest that targeting endothelial Twist1 may offer exciting opportunities for GBM immunotherapy.
TMOD-33. DOES PRE-CLINICAL DRUG ACTIVITY PREDICT PHASE II CLINICAL EFFICACY IN GLIOBLASTOMA? A DETAILED ANALYSIS
Authors: Arman T Zadeh, Elliot J Crooks, Josephine Volovetz, Anthony R Sloan, Justin D Lathia, Andrew Dhawan
Journal: Neuro-Oncology (2024)

Abstract Despite decades of research, there are fewer than six FDA-approved therapies for glioblastoma (GBM). The drug approval process relies on studies establishing pre-clinical activity, most commonly using murine models, followed by in human studies establishing safety and then efficacy. Although murine models for GBM have allowed for insights into tumor biology, their utility in assessing the efficacy of novel anti-cancer therapies remains highly debated. Here, we sought to establish whether there was any relationship between drug activity in preclinical models and phase 2 clinical trial outcomes. Using ClinicalTrials.gov (NIH), all phase 2 trials in glioblastoma up to December 2023 were queried and downloaded. Trials that were never started, had not yet started, were withdrawn, not completed, or contained indications beyond glioblastoma were excluded. Studies examining anti-tumor effects of an investigational agent with or without bevacizumab, temozolomide, or radiation therapy in glioblastoma were included, and studies examining alternative dosing strategies, various medical devices, or drug combinations, were excluded. The corresponding preclinical studies were identified via literature review for each clinical trial. Data including the progression free and overall survival benefit, mouse models used, and sample sizes were extracted from each study. 659 trials between 1994 and 2023 were included for analysis. Of these, 272 (41%) were for monotherapies, examining 90 unique small molecules. Preclinical endpoints included murine survival and tumor weight. In comparing mouse survival and tumor size to progression free and overall survival in humans, our preliminary analysis did not reveal any clear correlation. The correlation between preclinical and clinical drug response in GBM remains uncertain. Future work will examine whether mouse genotype, immune status, or GBM cell line used affected the degree of concordance with human clinical trial data. Our analysis suggests that further investigation into preclinical models of GBM, and standardized reporting of preclinical models, are needed.
EXTH-57. EXPLORING NOVEL ROUTES FOR NON-INVASIVE DRUG ADMINISTRATION: INTRADERMAL DELIVERY FOR THE TREATMENT OF BRAIN TUMORS
Authors: Seunghyun Kim, Akanksha Mahajan, Rachel Jarvis, Alexander Stegh
Journal: Neuro-Oncology (2024)

Abstract Effective non-invasive drug delivery to brain tumors remains challenging, despite extensive exploration of these methods, due to the blood-brain barrier (BBB). Intranasal drug delivery has emerged as a promising alternative approach, as it circumvents limitations on tumor access imposed by the BBB when administering therapeutics systemically and limits the occurrence of systemic toxic responses to treatment. The intranasal route of administration allows therapeutic access to brain tumors through pathways involving the olfactory and trigeminal nerves (TNs) that connect the nasal passage to the brain. However, effective nose-to-brain delivery is impeded by rapid mucosal drug clearance in the nasal cavity, drug aspiration, and ingestion. Since the TN arises from the brainstem and its branches innervate the facial skin, in addition to muscles, meninges, and respiratory mucosa, we tested the hypothesis that facial intradermal administration targeting the V2 branch of the TN could be an alternative strategy to harness TN-mediated brain delivery to bypass the BBB. Here, we developed Spherical Nucleic Acids (SNAs) consisting of a 15nm spherical gold nanoparticle core functionalized with radially oriented fluorophore-tagged ssDNA as a model therapeutic. We observed the delivery of the SNAs to the brain starting 4 hours post intradermal injection, with the SNA accumulation in the tumor persisting over time. Using ex vivo fluorescent imaging, comprehensive immunofluorescence microscopy, and flow cytometry we confirmed the SNA accumulation in the brain, dura, TN, and cervical lymph nodes. In particular, we demonstrated that SNAs were enriched in the neuronal cell bodies of the trigeminal ganglia and within the epineurium and perineurium of the TN. The SNAs were also enriched in CD45-positive immune cells. In conclusion, this study credentialed facial intradermal administration of SNAs as a promising non-invasive method for brain drug delivery to target intracranial tumors.
NCOG-42. SPEECH-SPECIFIC ERRORS IN LEXICAL RETRIEVAL PREDICT GLIOMA MOLECULAR FEATURES
Authors: Jasleen Kaur, Amit Persad, Sena Oten, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2024)

Abstract Recent work confirms that low and high-grade gliomas, remodel neural circuits which influence speech production. The extent to which speech kinetics and category of speech error during lexical retrieval may predict glioma molecular features remains unknown. Here, we extracted audiovisual speech production from 550 patients totaling over 26,400 individual stimuli to identify correlations with glioma molecular features including IDH, TERT, 1p19q co-deletion, and CDK2AB. Nonparametric statistics were used for analysis. IDH wild-type tumors were more likely to be temporoparietal, while IDH mutant tumors were more likely to be insular (p=0.02). Patients with IDH wild-type glioblastoma exhibited more errors (8.23 vs 3.79, p=0.02), with a higher occurrence of anomia (p=0.004), circumlocution (p=0.034) and general delay (p=0.04) when compared with IDH mutant WHO grade 4 astrocytoma. Binomial logistic regression identified lexical retrieval anomia, circumlocution, and initiation delays as an independent predictor of having an IDH wild-type tumor. Within the IDH mutant group, anomia (p=0.03) and articulation (p=0.014) errors were associated with malignant molecular features (after controlling for prognostic variables such as tumor volume). Binomial logistic regression identified articulation or anomia for picture naming as an independent risk predictor for WHO grade 2 gliomas with greater risk molecular features (based on Ki67 and CDK2AB). Distinct patterns of language errors were observed in patients with IDH wild-type and IDH mutant tumors. Further work is required to elucidate the functional and biological correlates of these findings.
ANGI-13. LONG NON-CODING RNA<i>LINC03045</i> REGULATES GLIOBLASTOMA INVASION VIA<i>WASF3</i>
Authors: Krutika Deshpande, Tammy Doan, Kathleen Tsung, Kristie Liu, Jane Han, Eddie Loh, Li Ding, Wentao Yang, Josh Neman, Yali Dou, Frank Attenello
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is an aggressive, heterogeneous tumor characterized by extensive infiltration of tumor cells within the surrounding brain parenchyma. Invasive tumor cells that evade surgical resection, chemoradiation and immune responses underlie GBM recurrence, necessitating the evaluation of factors that govern them. A recently completed unbiased lncRNA CRISPRi screen done by our lab identified LINC03045 as the top potential regulator of GBM invasion in Matrigel assays. Since enhanced LINC03045 expression was also found to be significantly associated with glioma tumor grade and patient survival (p&amp;lt;0.0001), here we characterized potential mechanisms by which it regulates GBM invasion. Mediators of lncRNA effect were identified via differential expression analysis in LINC03045 knockdown glioma cells and TCGA glioma datasets, and assessed for tumor invasion in 2D and 3D assays using knockdown and rescue experiments. Differential expression analysis of protein-coding genes associated with reduced LINC03045 expression in vitro and in GBM TCGA RNAseq data revealed high positive correlation with WASF3 (p=0.016), a regulator of JAK-STAT signaling and cytoskeletal scaffolding. siRNA-mediated WASF3 knockdown was associated with significant decrease in invasion in 2D-Matrigel assays in U87 (16.4%, p&amp;lt;0.001), U251(27.3%, p&amp;lt;0.001) and patient-derived USC02 (25.7%, p&amp;lt;0.001) glioma cells. Additionally, 3D invasion assays showed reduced invasion of WASF3KD U87 gliomaspheres (41.1%, p=0.011) into the surrounding matrix. Finally, WASF3 overexpression in USC02s demonstrated rescue of invasive capacity lost with LINC03045 knockdown (p&amp;lt;0.01). Taken together, RNA-seq analysis of downstream effectors of LINC03045, coupled with tumor invasion studies establish downstream mediator WASF3 as a novel regulator of GBM invasive potential.
TMIC-53. USE OF CEREBRAL OPEN-FLOW MICROPERFUSION TO IDENTIFY POTENTIAL ONCOMETABOLITE, L-2-HYDROXYGLUTARATE, IN GLIOBLASTOMA CHEMOTHERAPY ADAPTATION
Authors: Ian Olson, Amelia Stepniak, Rebecca Chen, Rafal Chojak, Jason Miska, Atique Ahmed
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is among the most prevalent and lethal brain tumors, comprising nearly half of all central nervous system malignancies and imparting a median overall survival of only 18-20 months. One major challenge in curing this disease is the limited understanding of how GBM cells biologically respond to treatments like radiotherapy and chemotherapy, including temozolomide (TMZ), in real-time. A significant challenge is observing changes within the tumor interstitial fluid (ISF), which mediates adaptive intercellular signaling between tumor cells and their surrounding tumoral and stromal neighbors. Microfluidic sampling methods, such as cerebral microdialysis and microperfusion, have started to provide valuable insights into the ISF signaling dynamics. These methods enable real-time biomolecular monitoring of this often-neglected component of the tumor microenvironment (TME). We have performed in vivo cerebral open-flow microperfusion (cOFM) pilot studies to identify metabolomic and proteomic changes within the tumor ISF resulting from differential treatment with either TMZ or vehicle control. Among these metabolite and protein changes, we identified an increase in 2-hydroxyglutarate (2-HG). While D-2-HG is a hallmark metabolite of isocitrate dehydrogenase mutant (IDH-mut) tumors, our model utilized the IDH wild-type (IDH-WT) CT2A mouse-syngeneic glioma model. Subsequent analysis of enantiomeric confirmation characterized this to be predominantly L-2-HG. Follow-up in vitro studies have shown that elevated L-2-HG plays a functional role in IDH-WT patient-derived glioma cells via non-canonical HIF1α stabilization and subsequent expression of HRE genes. This suggested that L-2-HG may play a similar role in IDH-WT GBM as D-2-HG plays in IDH-mutant tumors. This study demonstrates the potential of L-2-HG to function as a chemo-responsive oncometabolite in the TME of highly aggressive IDH-WT glioblastoma. By targeting the metabolic and signaling properties of L-2-HG, it may be possible to prevent chemo-resistant adaptations mounted by GBM cells when treated with TMZ.