tbuckley/cabot-search huggingface dataset:
EXTH-64. MECHANISMS OF MITOCHONDRIAL COMPLEX-I SENSITIVITY IN GBM
Authors: Biplab Dasgupta, Matthew Horchar, Mruniya Gawali, Pankaj Desai, Kwangmin Choi, Angelo D’Alessandro
Journal: Neuro-Oncology (2024)

Abstract The biguanide metformin that is widely used for the management of Type 2 diabetes is being evaluated as an anti-neoplastic agent in cancer trials including GBM (NCT02780024, NCT03243851). The mechanisms of action of metformin as an anti-neoplastic agent is still being investigated, but recent studies have unequivocally demonstrated that its therapeutic effects in tumor cell growth and signaling are dependent on inhibition of mitochondrial complex I. Based on the success of metformin in combination therapy in some cancers, new generation of mitochondrial complex I inhibitors (MCI-i) such as IM156, IACS-010759, are currently under investigation. Diffusion of metformin across the plasma membrane occurs slowly. Its entry is facilitated by two transporters OCT1 and OCT2 that are not well expressed outside the liver and kidney. This presents a problem due to its lack of accumulation in other tissues at therapeutic concentrations. Therefore, identification of tumor subtypes that respond better to lower concentrations of metformin may be leveraged for targeted metformin therapy. Metformin GBM trials may be unsatisfactory since there are no molecular markers to distinguish metformin responders from non-responders. Identification of molecular markers may greatly improve metformin and other MCI-i-based therapy in GBM. By examining TCGA data and experimental analysis, we have identified that PDHA, that catalyzes pyruvate to acetyl Co-A, is a predictive molecular marker for MCI-i sensitivity in GBM and potentially beyond GBM. PDHA expression varies widely in patient tumors, potentially due to differential methylation. We are performing joint pathway analysis by examining differentially expressed genes and stable isotope tracing studies to determine distinct metabolic signatures in the two subsets of GBM. We are also performing Classification And Regression Tree (CART) analysis on a cohort of sixty primary GBM lines and tissues to predict if PDHA expression provides a binary outcome for MCI-i sensitivity.
TMIC-55. CHARACTERIZATION OF THERAPEUTICS EFFECTS IN GLIOBLASTOMA THROUGH INTEGRATED SPATIAL SINGLE-CELL MULTIOME PROFILING OF LONGITUDINAL SAMPLES: UNVEILING CLINICALLY RELEVANT SUBTYPES OF PATHOLOGICAL CHANGES
Authors: Maxime Vanmechelen, Nazari Pouya, Jan Beckervordersandforth, Daphne Leunissen, Basiel Cole, Brecht Decraene, Yanti De Visser, Gautam Shankar, Maikel Verduin, Carmen Bravo, Tom Moors, Jayesh Telang, Julie Messiaen, Danielle Eekers, Annelies Claeys, Marleen Derweduwe, Axel Zurhausen, Francesca Bosisio, Frank Weyns, Thomas Daenekindt, Peter Van Eyken, Mieke Govers, Ferdinand Mennens, Koos Hovinga, Steven De Vleeschouwer, Clement Paul, Martijn Broen, Marc Vooijs, Raf Sciot, Asier Antoranz, Jon Pey, Ernst Jan Speel, Ann Hoeben, Frederik De Smet
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) remains a highly malignant, intrinsically resistant and inevitably recurring brain tumor with dismal prognosis. The aggressiveness and lack of effective GBM treatments can be attributed to the highly heterogeneous and plastic nature of GBM tumor cells, which easily confer resistance to standard-of-care (SOC) therapy. While tumor progression has also been attributed to interactions with the tumor microenvironment, quantitative data describing these interactions are still largely missing. Here, we used an multiome approach combining high-dimensional, multiplexed immunohistochemistry and spatial transcriptomics to map evolutions in the spatial, single-cell tissue architecture of 357 paired adult GBM tumor samples derived from 52 patients at diagnosis (ND) and upon recurrence (REC) following SOC treatment. We mapped the spatial distribution of a multitude of GBM tumoral subtypes across this multicentric cohort, through which we identified a high level of heterogeneity defined by specific tumoral niches within and across patients and which evolved when subjected to SOC therapy. In addition, we describe the relationship of the various tumoral niches with their local immune-infiltrates, highlighting an even more immunosuppressive environment following SOC resistance. Finally, by aligning these findings to the observed genomic aberrations and the clinical data of the patients, we are now able to more precisely describe the heterogeneous landscape of glioblastoma and how it evolves under SOC treatment at spatial, single-cell resolution.
CNSC-37. ROLE OF PGE2-REGULATED NEUROINFLAMMATION IN CONSTRUCTING NEURON-NK-GLIOMA CIRCUIT FOR GLIOBLASTOMA
Authors: Hsien-Chung Chen, Wen-Chang Chang, Tsung-Yi Hsu
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM), known for its aggressive nature and poor prognosis, frequently recurs and resists standard treatments such as temozolomide (TMZ). This resistance is partly due to complex interactions within the tumor microenvironment, particularly involving neuronal excitation. Recent insights suggest that neuronal activity, through mechanisms like neurogliomal synapses, not only promotes glioma cell proliferation but also contributes to the chemoresistance observed in recurrent tumors. Our focus is on Prostaglandin E2 (PGE2), a mediator that regulates neuronal excitation, and its role in the recurrence and resistance of GBM. We discovered that PGE2 upregulates synaptic proteins and alters neurotransmitter profiles, enhancing tumor cell survival and resistance to TMZ. Specifically, increased levels of neurotransmitters such as glutamine and asparagine were observed in PGE2-rich environments, correlating with heightened chemoresistance and tumor recurrence. Co-culture experiments further demonstrated that PGE2-treated neuronal cells could induce resistance in adjacent GBM cells. These findings highlight the potential of targeting PGE2 pathways as a therapeutic strategy. A significant advancement in our study was the development and application of compound #038, a novel celecoxib derivative designed to cross the blood-brain barrier (BBB). This compound demonstrated enhanced efficacy in inhibiting GBM growth and improving survival rates in mouse models, indicating its potential as an effective therapeutic agent against GBM.
QOL-18. MANAGING CANCER AND LIVING MEANINGFULLY (CALM) IN PRIMARY AND SECONDARY MALIGNANT BRAIN TUMOR PATIENTS: INTERIM ANALYSIS OF A PHASE IIC RANDOMIZED CONTROL PILOT TRIAL
Authors: Ashlee Loughan, Autumn Lanoye, Alexandria Davies, Chris Kleva, Giuliana Zarrella, Amber Fox, Gary Rodin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with both primary and secondary brain tumors demonstrate substantial psychological distress but have been historically excluded from psychological research. Managing Cancer and Living Meaningfully (CALM), a supportive- expressive- psychotherapy, has proven to reduce depression and death-anxiety in advanced cancer patients but trials in neuro-oncology have been limited. Interim analyses (50% accrual) of the first randomized control pilot trial (RCT) of CALM in neuro-oncology are presented here. METHODS In this ongoing NIH ORBIT model Phase IIc pilot RCT, 60 adults with primary or secondary malignant brain tumors and heightened distress (PHQ/DADDS) are randomized (2:1) to a six-session CALM intervention or usual care. Data collection includes established feasibility and acceptability metrics, intervention satisfaction surveys and interviews, and clinically meaningful changes in distress severity scores across three timepoints (pre-, post-CALM, follow-up). RESULTS Of 64 patients screened, 36 were eligible and 32 enrolled (n=20 CALM, n=12 Control; 65% female; 90% White; Mage=46yrs). A multimodal recruitment model was used. Currently, assessment completion rates are: post-CALM (80%) and follow-up (67%). Reasons for withdrawal include disinterest in intervention topics (n=1) and lost to follow-up (n=1). Intervention retention is currently at 90%, with 8 participants still in active treatment. No adverse events have been documented. Perceived benefit appears high (4.1/5) and all participants report they would recommend CALM to others. Pre- to post-CALM, depression severity reductions appear equal across arms (CALM PHQ-9=30%; Control=33%) but death anxiety severity reductions appear more prevalent in the treatment group (CALM DADDS=70%; Control=50%). CONCLUSIONS Interim data suggests promising feasibility and acceptability results in this pilot RCT. Enrollment, retention, and assessment completion rates appear adequate. Participants are reporting high benefit and recommendation of CALM. Improvement in death anxiety appears greater in those treated with CALM compared to controls. These interim RCT findings are promising and suggest completion of the current phase.
CSIG-23. CYTOMEGALOVIRUS-INFECTED HUMAN GLIOBLASTOMA CELL LINES SHOW AN AGGRESSIVE PHENOTYPE ASSOCIATED WITH UPREGULATION OF IL-6/STAT3 AND AKT SIGNALING
Authors: Vida Tajiknia, Noe Mercado, Eain Murphy, Sean lawler
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cytomegalovirus (CMV) has been implicated in glioblastoma (GBM) pathogenesis by affecting stemness, angiogenesis and immune pathways. Clinical trials targeting CMV in GBM patients have shown some early promise, and CMV seropositivity has been associated with poorer outcomes. However, the underlying mechanisms remain unclear. Here we investigated the effects of CMV infection on critical signaling pathways in GBM (IL6/STAT3, and Akt signaling) based on the hypothesis that CMV may contribute to poorer outcomes in GBM by increasing oncogenic signaling. MATERIALS AND METHODS Human U251 and LN229 GBM cell lines were infected with mCherry expressing human CMV TB40 strain at a multiplicity of infection (MOI) of 0.5. We performed basic phenotypic studies in vitro and investigated the status of IL6/STAT3, and Akt signaling by Western blotting. RESULTS Both LN229 and U251 cell lines were readily infectable by CMV. Infection of U251 cells was over 90% and in LN229 cells was approximately 60%. Interestingly expression of CMV was sustained over many passages in these cell lines. Infection was also verified by the presence of the CMV pp65 protein assessed by Western blotting. Measurement of cell proliferation indicated faster growth after CMV infection. Interrogation of key pro-oncogenic signaling pathways in GBM revealed a robust upregulation of IL6, as well as phospho(Tyr705)-STAT3 and phospho(Thr308)-Akt. This elevation of pro-oncogenic signaling pathways was observed in both cell lines compared with controls. CONCLUSIONS Here we show for the first time that infection of human GBM cell lines with CMV results in a more aggressive phenotype associated with upregulation of IL6/STAT3 signaling as well as a significant increase in phospho-Akt levels. We are currently studying sensitivity to standard therapies and additional molecular changes in these cells. These data support the hypothesis that CMV causes more aggressive disease and that CMV is a relevant therapeutic target in GBM.
NIMG-48. MEASURABLE DISEASE AS BASELINE CRITERION FOR RESPONSE ASSESSMENT IN GLIOBLASTOMA TRIALS – A COMPARATIVE STUDY OF MRI-BASED (RANO 2.0) VERSUS PET-BASED (PET RANO 1.0) ASSESSMENT
Authors: Katharina Johanna Müller, Robert Forbrig, Jonas Reis, Lilian Wiegand, Enio Barci, Sophie Kunte, Lena Kaiser, Stephan Schönecker, Christian Schichor, Patrick Harter, Niklas Thon, Louisa von Baumgarten, Matthias Preusser, Nathalie Lisa Albert
Journal: Neuro-Oncology (2024)

Abstract Response assessment in glioblastoma relies on measuring contrast enhancement on MRI according to RANO 2.0 criteria, and ‘measurable disease’ often serves as inclusion criterion for clinical trials. Recently, criteria based on amino acid PET have been proposed for response assessment in clinical trials (PET RANO 1.0). Here, we compare ‘measurable disease’ as defined by PET RANO 1.0 with the standard MRI-based RANO 2.0 criteria in glioblastoma patients. In this retrospective single-center study, we identified patients with newly diagnosed IDH-wildtype glioblastoma who underwent [18F]FET PET and MRI after resection or biopsy and before chemoradiotherapy. Two independent investigators analyzed ‘measurable disease’ according to PET RANO 1.0 versus MRI-based RANO 2.0 criteria. Additionally, lesion size and uptake intensity, including maximal and mean target-to-background ratio, were assessed. We evaluated 136 patients with 76 cases after biopsy and 60 after microsurgical resection. Using RANO 2.0, 35/76 patients (46.1%) had measurable disease in the biopsy group, and 25/60 (41.6%) in the resected group (median sum of maximum cross-sectional diameters: 39.7mm and 28.0mm, respectively). Utilizing PET RANO 1.0, a significantly higher proportion (overall 123/136, 90.4%; 66/76 (86.8%) after biopsy; 57/60 (95.0%) after resection) had measurable disease (p&amp;lt;0.001). None of the 10 patients in the biopsy group nor of the 3 patients in the resected group without measurable disease on PET had measurable disease on MRI. Contrariwise, 32/41 patients (73.2%) in the biopsy group and 30/35 (85.7%) in the resected group without measurable disease on MRI exhibited measurable disease on PET. PET RANO 1.0 identifies a significantly higher number of patients with ‘measurable disease’ compared to conventional MRI-based criteria in the perioperative period of glioblastoma. PET-based assessment may thus serve as a novel baseline parameter for evaluating treatment response in glioblastoma trials, that may allow the enrollment of larger patient populations. Further validation in prospective trials is warranted.
NIMG-53. MRI-BASED RADIOMICS FOR DIFFERENTIATION BETWEEN PERIFOCAL EDEMA AND NON-CONTRAST-ENHANCING GLIOBLASTOMA FOCI
Authors: Frederic Thiele, Felipe Saviolli, Annamaria Biczok, Veit Stöcklein, Sophia Stöcklein, Christian Schichor, Niklas Thon, Jonathan Weller
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Various intracranial tumors can lead to the development of perifocal edema. Differentiating edema from tumor on MRI might be easy in metastases and meningiomas but can be challenging in patients with glioblastoma. We set out to compare and characterize perifocal edema and non-contrast-enhancing glioblastoma foci by means of radiomic feature analysis. METHODS In this single-center, retrospective study, patients with intracranial tumors and perifocal edema on preoperative T2/FLAIR-sequences were included. Patients diagnosed with brain metastasis, meningioma or glioblastoma were eligible. Tumor and edema volumes were semi-automatically segmented and extracted. After image registration, contrast-enhancing tumor and necrosis on T1-weighted sequences were subtracted from T2/FLAIR-hyperintense tumor and perifocal edema. Radiomic features were computed. Distribution of radiomic features were tested using the Shapiro-Wilk test. ANOVA or Kruskal-Wallis tests were applied to compare the features. Significant features were identified based on p-values (&amp;lt;0.05) and post-hoc Tukey’s Honest Significant Difference (HSD) tests were conducted. RESULTS The cohort comprised n=60 patients and was split in three groups according to histopathology (metastases, meningioma, glioblastoma). Each subgroup comprised n=20 patients (33.3%). 107 radiomic features of the T2-hyperintensity, after subtraction of contrast-enhancing tumor and necrosis, were tested for each patient. 18 radiomic features (17%) that mainly comprised measures of shape, texture and intensity distribution, e.g., sphericity (p&amp;lt;0.01), surface/volume (p&amp;lt;0.01), entropy (p&amp;lt;0.01), skewness (p&amp;lt;0.01) and kurtosis (p&amp;lt;0.01), showed no significant difference between metastases and meningiomas but differed significantly from the T2-hyperintensity of glioblastoma. The textual complexity of glioblastoma was significantly higher (p&amp;lt;0.01). CONCLUSION Radiomic feature analysis unraveled many features that might be helpful in differentiating perifocal edema from tumor infiltration. Future studies should aim at validating our results and further exploring the T2-hyperintensity of glioblastoma patients, e.g., suspected edema versus suspected tumor infiltration zone.
EXTH-82. TUMOR ORGANOID PREDICTED THERAPEUTIC RESPONSES TO NOVEL EPIGENETIC DRUGS VIA HIGH-THROUGHPUT SCREENING
Authors: Goeun Bae, Milagros Suarez Palacios, Reid T Powell, Clifford C Stephan, Xiaonan Li, Yuchen Du
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION The treatment choices for pediatric brain tumors are still very limited. Epigenetic therapy emerges as a promising option recently. The lack of in vitro models that represent tumors in vivo and can be scalable for large scale drug screening is major barrier. We have developed tumor organoids from patient-derived orthotopic xenograft and performed a multi-stage high throughput screening for single or combined epigenetic agents and radiation therapy in tumor organoids. METHOD Primary xenograft tumor cells were cultured in matrix and cancer stem cell culture medium in 384-well plates. Radiation sensitivity was examined at 5 different doses. Epigen40 (40 drugs/compounds) targeting various epigenetic modifications was used alone to identify agents with the most cell killing (4 doses for up to 19 days). The drugs that showed partial activity were combined with radiation (at 5 doses) to evaluate additive or synergistic effects. The anti-tumor efficacy of selected drug was then evaluated in vivo. RESULTS The conditions of organoid growth and screen variability were optimized. 7 tumor organoids including 4 glioblastomas and 3 medulloblastomas were successfully established and characterized. The different radio-sensitivities were observed among these models. 7 compounds (JIB-04, SP2509, AS-8351, GSK J4 HCI, 3-Deazaneplanocin A HCL, Chaetocin, TC-E-5003) were shown to effectively suppress organoid growth. Chaetocin, methyltransferase SUV39H inhibitor, demonstrated broadly active and highly potent inhibition across all 7 tested organoids. In addition, bioinformatic analysis identified a subset of epigenetic inhibitors combined with radiation that produced additive anti-tumor activities in vitro. Unfortunately, in vivo treatment of Chaetocin (0.25mg/kg) didn’t convey consistent anti-tumor effects as shown in vitro whereas a high risk of drug toxicity to the mice. CONCLUSION Tumor organoids were successfully developed from primary tumors. With our optimized assay using primary tumor organoids and a multi-stage high throughput drug screening, a novel panel of epigenetic drugs that effective alone or additively with radiation was identified.
SURG-33. INTRAOPERATIVE ULTRASSOUND X SODIUM FLUORESCEIN FOR GLIOMA SURGERY: WHICH IS BETTER?
Authors: Aline Lariessy Campos Paiva, João Luiz Vitorino Araujo, Renan Maximillian Lovato, Gabriel José dos Santos, André Luca Barongeno de de Mendonça, Hallison Rodrigues de Andrade, Jean Gonçalves de Oliveira, José Carlos Esteves Veiga
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Improve quality of life with a maximum surgical resection is the main goal of neurosurgeons. A better delimitation of intrinsic brain tumors are required for achieving a maximum tumor removal. There are several technologies that may help. Considering two of them that have an easier access and are cheaper, we compared a high definition ultrasound (BK 3000) and sodium fluorescein (SF) during glioma surgeries. METHODS Adult patients with main radiological hypothesis of low or high grade glioma were included in a PhD study previously approved by ethics committee. 3-5mg/kg of SF was administered by intravenous infusion during anesthetic induction. An specific craniotomy transducer was used in all cases. All procedures were guided by the same neurosurgeon. RESULTS High definition ultrasound allows an excellent tumor delimitation in high and low grade tumors. However the gray scale and distinction of brain structures and residual lesion was difficult for surgeons who are not habituated to ultrasound use. SF did not help low grade glioma removal, and in these cases ultrasound were superior. Increased fluorescence is easily detected when compared to ultrasound information’s. For small residual tumor, SF helps more than US. For both technologies, when the surgical site had blood, the evaluation about grade of resection is not accurate because in ultrasound appears a posterior shadow and considering SF it seems that there are not further tumor because blood does not have increased fluorescence. CONCLUSIONS US showed superiority for low grade gliomas resection. Considering high grade, both technologies helps in different moments during the surgery and are complimentary. We used an specific probe for neurosurgery that has high quality and allowed detailed evaluations. These technologies helps surgeons take quick decision and optimized brain tumor removal. The neurosurgeon should be more familiar to US images because provide a real time evaluation with low cost. KEY WORDS: ultrasound; fluorescein; gliomas; brain tumors
IMMU-29. B7-H3-TARGETED CAR-T AND CAR-NK CELLS AGAINST HUMAN GLIOBLASTOMA
Authors: Tetsuro Tachi, Noriyuki Kijima, Hideki Kuroda, Koki Murakami, Naoki Hosen, Haruhiko Kishima
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma multiforme (GBM) is the most lethal primary brain tumor, necessitating novel therapies. Chimeric antigen receptor (CAR) T-cell therapy has recently shown efficacy against GBM. However, this approach is costly and time-consuming due to its personalized nature. Alternatively, CAR-transduced natural killer (NK) cells offer a potential “off-the-shelf” immunotherapy option, as they do not cause graft-versus-host disease. This study aimed to assess the anti-GBM efficacy of CAR T and NK cells targeting B7-H3, a protein highly expressed in GBM. To achieve this, CAR T cells targeting B7-H3 were developed using known anti-B7-H3 scFv sequences. Additionally, cord blood-derived NK cells were transduced with the B7-H3 CAR. Both types of CAR-modified cells were tested for their anti-GBM activity in vitro. Moreover, their anti-tumor effects were evaluated in an in vivo xenograft model using patient-derived GBM cells. The results demonstrated that both B7-H3 CAR T cells and CAR NK cells exhibited significant cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of these CAR-modified cells into the xenograft model significantly reduced tumor growth. In conclusion, B7-H3 targeted CAR T cells and cord blood-derived CAR NK cells both show potential in eliminating GBM cells, suggesting promising avenues for future GBM treatment strategies.