tbuckley/cabot-search huggingface dataset:
IMMU-46. CROSS-TALK OF INNATE IMMUNE CELLS IN GLIOBLASTOMA PATHOPHYSIOLOGY: UNDERSTANDING NLRP3 AND NLRP12
Authors: Sushmita Rajkhowa, Durgesh Meena, Sushmita Jha
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) are malignant gliomas with an average survival of less than 14 months after diagnosis, despite surgery, chemotherapy, and radiotherapy. Tumor survival is aided by the heterogeneous cell populations in the tumor microenvironment. Two crucial innate immune cells of the brain, namely microglia and macrophages, favor a tumor-promoting microenvironment IN GBM. The nucleotide-binding domain leucine-rich repeat-containing receptor (NLR) family in astrocytes and microglia cells recognizes pathogen- and damage-associated molecular patterns that induce inflammation. NLRP3, upon activation, leads to cleavage and activation of Caspase-1, causing the proteolytic cleavage-mediated activation and conversion of pro-IL-1ß and pro-IL-18 to IL-1ß and IL-18, leading to pyroptosis. NLRP12 downregulates inflammatory responses in microglia and macrophages by regulating the NF-kB pathway. NLRP3 and NLRP12 have tumor-promoting and anti-tumour functions in various cancers. NLRP12 is a prognostic marker for glioblastoma, and its increased expression correlates with poor survival in GBM patients. However, the cellular and molecular mechanisms of NLRP3 and NLRP12 in GBM pathophysiology are largely unknown. This study aims to understand the effect of NLRP3 and NLRP12 expression in GBM, to interpret the pathophysiology, and to help develop future targeted therapeutic interventions. To understand the baseline expression of NLRP3 and NLRP12 in cell lines and patient-derived GBM cells, PCR, western blotting, and Immunocytochemistry were performed comparing WT and nlrp3-/- and nlrp12-/- cells. Differential expression of NLRP3 and NLRP12 in patient-derived cells can be compared to GBM, astrocyte, and microglia cell lines. This may be the underlying cause for intra and inter-tumor heterogeneity and resultant differential therapy outcomes. To understand cell-to-cell communication in GBM-like tumor microenvironments, heterocellular 3D organoids, and patient-derived tumor organoids were developed. Cell viability in 3D patient-derived tumor organoids decreased by up to 10% with Doxorubicin and 40% with Carboplatin treatment decreases compared to untreated controls. This suggests the scope of developing drugs targeting inflammation regulatory genes.
DISP-14. THE IMPACT OF DISTANCE IN TREATING GLIOBLASTOMA: A RETROSPECTIVE SINGLE CENTER STUDY
Authors: Samantha Kropp, Sam Tenhoeve, Yuxin Zhao, Ann Chen, Joe Mendez, Rachna Malani
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Glioblastoma (GBM) is an aggressive primary brain tumor associated with poor survival. Research shows that patients living in rural areas have poorer outcomes than those in metropolitan areas; however, little is known about how distance between patients and their subspecialist impacts outcomes. We explored the effect of distance from a National Cancer Institute-designated Comprehensive Cancer Center (CCC) has on overall survival (OS) and clinical trial enrollment for patients with GBM. METHODS Retrospective data was collected from patients with newly diagnosed GBM per the World Health Organization 2021 who received treatment at Huntsman Cancer Institute (HCI) from 2018 to 2022. Distance was evaluated as a categorical (near: 0-25 miles, intermediate: 25-40 miles, far: &amp;gt;40 miles) and continuous variable for analyses. In addition to univariable models, multivariable models adjusting for known prognostic factors were also performed. RESULTS A total of 167 patients were identified. Baseline characteristics including age, sex, race, and KPS scores were similar across groups. The univariable COX regression model found no significant difference in OS when comparing the near group to the intermediate (p=0.125) and far (p=0.599). However, the multivariable model found poorer OS in the intermediate group that was statistically significant when compared to the near group (HR (95% CI) = 1.55 (1.01, 2.39), p = 0.047). When comparing distances as a continuous variable, patients in the far group had statistically significant lower clinical trial enrollment rates (near group 43%, intermediate 35%, far 18%; p=0.0001). DISCUSSION Patients with GBM seeing a neuro-oncologist at our CCC did have a difference in OS as well as clinical trial enrollment when considering distance traveled. Clinical trials are standard of care for patients with GBM; our data provides evidence that distance from a CCC significantly affects trial enrollment, underscoring the importance of ensuring availability of resources for clinical trial participants.
DDDR-19. PHARMACOSCOPY FOR BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER (NSCLC)
Authors: Emilie Le Rhun, Julien Mena, Sohyon Lee, Yasmin Festl, Alicia Buck, Stefanos Voglis, Anna Maria Zeitlberger, Tobias Weiss, Carlo Serra, Marian Neidert, Luca Regli, Michael Weller, Berend Snijder
Journal: Neuro-Oncology (2024)

Abstract Brain metastases remain a common and important complication in the course of disease in patients with non-small cell lung cancer (NSCLC). While targeted therapies and immunotherapies have led to prolonged disease control in subsets of patients with brain metastases from NSCLC, there is still an urgent need for novel treatments after failure of these standards and after exhaustion of local therapies including surgery and radiotherapy. Here we performed an explorative feasibility study to profile ex vivo drug sensitivities across a large panel of classical anti-cancer as well as neuroactive drugs, using an automated imaging platform called “pharmacoscopy”. The anti-cancer drug panel included chemotherapies and targeted therapies such as receptor tyrosine kinase, cyclin dependent kinase, and BCL2 inhibitors. The neuroactive drug panel included antidepressants and antipsychotics. A total of 19 samples from 17 patients were dissociated after surgery and incubated with drugs for 48 hours ex vivo to measure drug sensitivities. Patient cancer cells were identified by immunofluorescence using EpCAM, TTF-1, or CK7 as markers whereas immune cells were identified by CD45. On-target drug activity (pharmacoscopy score) was measured by quantifying the specific reduction of cancer cells upon drug treatment. Among the top ranking drugs ex vivo, several patient samples displayed on-target responses to candidate targeted therapies such as the CDK4/6 inhibitor abemaciclib, the BCL2 inhibitor venetoclax, and the MEK inhibitor cobimetinib as well as unexpected sensitivies to certain neuroactive drugs. Integration of pharmacoscopy results with molecular data from next generation sequencing in the respective brain metastases tissues is ongoing. Overall, this study demonstrates the feasibility of pharmacoscopy-based functional drug testing in NSCLC brain metastases, and highlights novel opportunities of personalized treatment for future exploratory clinical studies in patients with brain metastases from NSCLC.
TMET-07. RADIORESISTANT GLIOBLASTOMA EVADES MITOCHONDRIAL LIPOTOXICITY THROUGH ALTERED DGKB AND DGAT1
Authors: Haksoo Lee, Dahye Kim, Byeongsoo Kim, Gaeun Yoo, JiYong Cha, Hyunkoo Kang, Jaewan Jeon, HyeSook Youn, BuHyun Youn
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor, with a median survival of only 15 months despite multimodal therapy. Radiotherapy is a conventional therapy of GBM treatment, but the development of radioresistance often leads to tumor recurrence and treatment failure. To elucidate the molecular mechanisms underlying radioresistance in GBM, we established radioresistant GBM cell lines through repeated exposure to ionizing radiation. Transcriptomic analysis revealed that diacylglycerol kinase beta (DGKB), an enzyme that converts diacylglycerol (DAG) to phosphatidic acid, was significantly downregulated in radioresistant GBM cells. Functional studies demonstrated that knockdown of DGKB or expression of a kinase-dead DGKB mutant resulted in DAG accumulation and reduced fatty acid oxidation. Conversely, overexpression of DGKB activated fatty acid oxidation, increased reactive oxygen species (ROS) production, and sensitized GBM cells to radiation. Interestingly, we found that radiation upregulated the expression of diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the conversion of DAG to triglycerides. Knockdown of DGAT1 using shRNA or miR-3918 mimic reduced lipid droplet formation and enhanced radiosensitivity both in vitro and in vivo. Furthermore, using Connectivity Map, we identified cladribine as a potential radiosensitizing agent that increases DGKB and decreases DGAT1. Cladribine effectively sensitized GBM cells to radiation and significantly prolonged the survival of mice bearing GBM xenografts. In conclusion, our study reveals a novel mechanism by which radioresistant GBM cells maintain lipid homeostasis through downregulation of DGKB and upregulation of DGAT1 to evade lethal mitochondrial lipotoxicity. Targeting the DGKB-DGAT1 axis represents a promising therapeutic strategy to overcome radioresistance and improve the outcomes of GBM patients.
IMMU-47. HUMAN MICROBIOTA INFLUENCE THE GLIOMA-IMMUNE LANDSCAPE AS DETERMINED BY SINGLE CELL RNA-SEQUENCING IN A MURINE MODEL OF GLIOMA
Authors: George Green, Alexis Cox-Holmes, Gillian Marlow, Anna Claire Potier, Yong Wang, Lianna Zhou, Dongquan Chen, Casey Morrow, Braden McFarland
Journal: Neuro-Oncology (2024)

Abstract We recently identified immunotherapy responder and nonresponder human microbiota compositions in the murine model of glioma. In this study, we sought to understand how human microbiota in mice influence the immune landscape in glioma. To test this, we utilized our novel humanized microbiome (HuM) mouse model (human microbiota transplanted into gnotobiotic mice) to determine the effect of immunotherapy in a mouse model of glioma utilizing single-cell RNA sequencing and 16S rRNA microbiome sequencing. We focused on two HuM mouse lines in this study: HuM1 (nonresponder) and HuM2 (responder). To confirm microbiota differences,16S rRNA sequencing revealed significant differences between alpha and beta diversity between HuM1 and HuM2 groups. HuM2 responder mice also displayed a significant increase in the relative abundances of Odoribacter, Muribaculaceae, and Ruminococcus genera compared to HuM1 mice. HuM1 and HuM2 mice were then injected with GL261 glioma cells into the brains, treated with one dose of anti-PD-1 or isotype control on day 13, and all mice were euthanized on day 14 for scRNA-sequencing of CD45+ cells in the tumors. We identified 21 clusters of immune cells in the tumors. Furthermore, we found significant differences between HuM1 and HuM2 mice in isotype control conditions including higher percentages of immature B cells, neutrophils, and microglia in HuM2 mice. In anti-PD-1 treated tumors, there was a robust increase in the percentage of innate immune cells in the tumor following, specifically the monocyte/macrophage (MM1; Cxcl10+) population in both HuM1 and HuM2 mice. However, the HuM2 MM1 cluster showed an increase in gene expression of Nos2 and decrease in Arg1, indicating that the MM1 population in HuM2 mice are more inflammatory (anti-tumor) compared to HuM1. Ultimately, our data demonstrate that the gut microbiome influences the tumor-immune landscape, and harnessing positive microbial compositions remains a viable translational avenue to pursue.
DDDR-30. ENHANCED CHEMO AND RADIO-SENSITIZATION OF GLIOMAS BY HSP90 INHIBITION WITH JIN-001, A NOVEL BLOOD-BRAIN BARRIER PENETRANT HSP90 INHIBITOR
Authors: Jihong Xu, Harsha S Sugur, Pratibha Sharma, Longfei Huo, Pushan Dasgupta, Xiaohua Chen, Ethan Seah, Deepa Sampath, Vinay K Puduvalli
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND HSP90, an abundant molecular chaperone, plays a pivotal role as a key regulator in the growth and survival of malignant cells and has been a therapeutic target in various cancers. We have previously reported a strong role for HSP90 inhibitors to disable DNA damage repair mechanisms and induce cell death. Here, we determined the effects of JIN-001 mediated HSP90 inhibition on alkylator and radiation induced DNA damage. Method: Using a panel of patient-derived glioma stem cells (GSCs) we determined the synergy scores for cell viability of JIN-001 (0.1µM to 0.5µM) in combination with radiation (RT) and Temozolomide (TMZ). We also examined cell cycle dynamics and cell death of the combination using flow cytometry (PI and PI/Annexin method) and cell viability assays. Additionally, organotypic human glioma slice cultures treated with JIN-001 and chemoradiation were analyzed for changes in gene and protein expression as well as cell viability in situ. Ongoing in-vivo studies are being conducted to further elucidate drug combination efficacy in mouse models. RESULTS JIN-001 sensitized the cells to chemoradiation leading to cell cycle arrest and cell death which was higher in the combination compared to single agent. Significant changes in expression of downstream molecules of homologous recombination pathway was noted (ATM, pATM, CHK1, pCHK1, ATR, pATR) in the cell lines and confirmed in human glioma slice culture. Based on the synergy score from four cell lines, an effective dose for combination of JIN-001+RT+TMZ was identified; Results of ongoing ex-vivo human glioma gene expression changes and in-vivo mouse studies will be presented. CONCLUSION Through a comprehensive analysis, we demonstrated that HSP90 inhibitor JIN-001 sensitizes glioma cells to radio-chemotherapy including in human glioma tissue. Our study underscores the potential of combining JIN-001 with standard therapies in glioma treatment in future clinical trials for patients with glioblastoma.
DISP-18. RACIAL DISPARITY IN THE UTILIZATION OF MOLECULAR DIAGNOSTIC AS A PROXY FOR SUB-OPTIMAL CLINICAL CARE IN GLIOBLASTOMA PATIENTS
Authors: Ping Zhu, Huy Do, Clark Chen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Molecular characterization of IDH mutation and MGMT-promoter methylation (MGMTm) are standard-of-care (SOC) diagnostics and essential to diagnosis, treatment, and prognosis of glioblastomas. Here, we determined the extent to which racial disparity occurs in this dimension of oncologic care. METHODS 31,439 glioblastoma patients were derived from the National Cancer Database (NCDB,2018-2021), with 20,736 IDH-wildtype patients with defined MGMT-status. Accessibility to SOC diagnostics was defined as whether patients got IDH/MGMT testing or not. Race/Ethnicity was grouped into Non-Hispanic White (NHW), Non-Hispanic Black, Asian/Pacific Islander, Hispanic, and Others. Receipt of SOC diagnostics and treatments, post-operative outcomes, and overall survival (OS) were explored using multivariable logistic regression, Kaplan-Meier method, and Cox proportional hazards models. RESULTS Relative to NHWs, all racial minority groups were less likely to have undergone IDH or MGMT-testing. These effects remain robust after adjusting for economic status, insurance, and facility type. Patients who received neither IDH nor MGMT-testing were 38% less likely to undergo SOC concurrent chemo-/radiation therapy (cCRT) relative to those having both testing. Further, patients having neither IDH nor MGMT-testing showed significantly higher risk of 30-day mortality (aOR:2.20), 90-day mortality (aOR:1.60), and hazard of death (median OS:8.9-mon,aHR:1.09,p=0.002) than those having both testing (median OS:12.9-mon). Of those tested for both IDH/MGMT, the odds of bearing a methylated MGMT-promoter remained relatively constant across five racial groups. Non-NHW glioblastomas patients were significantly less likely to receive SOC-modality. Of the patients who underwent IDH/MGMT-testing and cCRT, median OSs were 23.7 and 14.4-mon for MGMT-methylated and unmethylated glioblastoma, respectively. No significant difference in hazards of death for racial/ethnic minorities compared to NHWs was detected, regardless of MGMT-methylation status. CONCLUSIONS Our findings suggest that non-NHW glioblastoma patients are less likely to undergo SOC diagnostic (IDH/MGMT) testing, which serves as a proxy for receipt of sub-optimal clinical care. For glioblastoma patients who underwent SOC molecular testing and treatment, survival is similar across racial groups.
NIMG-26. GLIOBLASTOMA TISSUE INVASION MAPPING WITH NOVEL HYPOXIA-TARGETED BLOOD OXYGENATION-LEVEL DEPENDENT MRI
Authors: Vittorio Stumpo, Jacopo Bellomo, Christiaan Hendrick Bas van Niftrik, Martina Sebök, Zsolt Kulcsar, Michael Weller, Andrea Bink, Luca Regli, Jorn Fierstra
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma is a devastating incurable malignant primary brain tumor exhibiting an erratic growth pattern and brain tissue invasion exceeding the typically depicted contrast-enhancing lesion on MRI. This behaviour is strongly associated with the presence of aberrant vasculature. Advanced clinical neuroimaging techniques, however, have not provided convincing imaging markers to determine glioblastoma tissue infiltration and monitor treatment effects. We investigated a new imaging technique based on blood oxygenation-level dependent (BOLD) MRI contrast with precise hypoxic respiratory targeting in order to better determine tumor tissue invasion not restricted to the typically depicted focal glioblastoma lesion on contrast-enhanced MRI. METHODS A computer-controlled gas blender was used to induce transient and standardized hypoxic stimulus in isocapnic conditions during echo-planar-imaging acquisition in patients with brain tumors.8,9 Data were preprocessed using SPM and in-house written MATLAB scripts. The induced BOLD signal changes were used to calculate %BOLD signal change during hypoxic stimulus with respect to the baseline, contrast to noise (CNR) ratio and goodness-of-fit (Rsquared) for each voxel in the whole-brain and automatically segmented region of interest (contrast-enhancement, necrosis, edema) and overlayed using color-maps onto anatomical high resolution T1. RESULTS Hypoxic targeting during gas modulation could be performed with high reproducibility, caused no discomfort in patients with brain tumors and was able to induce strong signal change during hypoxic stimulus with high contrast-noise ratio and Rsquared. In particular, when compared with other tumors, BOLD hypoxia glioblastoma tissue invasion maps show very distinct hypoxic signal responses in some cases extending beyond the focal -contrast-enhancing- glioblastoma lesion. CONCLUSION The ability to map at voxel level BOLD hypoxia signal patterns may determine a novel therapeutic imaging marker based on structural vascular alterations in the tumour tissue infiltration zone before these become appreciable with standard neuroimaging. This may support a refinement and tailoring of tumor resection and improve follow-up after resection and during treatment i.e. chemoradiotherapy.
CTNI-46. WINDOW-OF-OPPORTUNITY TRIAL OF ULIXERTINIB FOR MAPK-ACTIVATED LOWER GRADE GLIOMAS IN ADULTS
Authors: Nazanin Majd, Carlos Kamiya-Matsuoka, Ying Yuan, Evguenia Gachimova, Chetna Wathoo, Samir Dagher, Melissa Chen, Ian McCutcheon, John Slopis, John de Groot
Journal: Neuro-Oncology (2024)

Abstract Overexpression of MAPK (Ras-Raf-MEK-ERK) signaling is well known in NF1-associated tumors. MEK inhibition has shown promising results in pediatrics NF1-associated tumors. In addition, we have observed augmented MAPK signaling and anti-tumor activity with MAPK inhibition in preclinical models of CIC-mutated vs. wild-type oligodendroglioma. Ulixertinib is a small molecule inhibitor of ERK that is being developed as a novel anti-cancer drug. A phase I study of ulixertinib in advanced solid malignancies had shown two central nervous system responses. We hypothesized that ulixertinib crosses the blood-brain barrier (BBB) and it will result in improved responses in MAPK-activated lower-grade gliomas in adults (recurrent NF1-mutated gliomas grade 1,2,3 and oligodendrogliomas grade 2,3 which are enriched in CIC-mutation). This is a window-of-opportunity study of ulixertinib in patients ≥18 yo. Twenty patients who are candidates for non-emergent surgical resection will be enrolled (10 in each cohort). Patients will receive neoadjuvant ulixertinib at 600mg BID. Selected patients will undergo CSF collection 1-week after and all will undergo surgical intervention 2-weeks after initiation of ulixertinib. Patients will then continue treatment until disease progression or unacceptable toxicity. Primary endpoints are ulixertinib tumor concentration and tumor/plasma ratio in enhancing and non-enhancing disease. Secondary endpoints include median PFS, overall response rate (ORR) and disease control rate at 12mo, duration of response, time-to-next intervention and time-to-response, safety profile, and ulixertinib CSF and tumor/CSF ratio. Exploratory endpoint includes ORR of plexiform neurofibromas in NF1 patients. To date, 4 patients have been dosed; 3 CIC-mutated oligodendroglioma and 1 NF1-mutated glioma. A fifth patient with NF1-mutated glioma has been consented. Upon collection of tumor tissue on all 5 patients, initial assessment of tumor and CSF drug concentration will be conducted and presented at the conference. Ulixertinib’s ability to cross the BBB could influence what tumor types may be explored for further patient benefit.
DNAR-09. GB13 IS A POTENT NEOADJUVANT TREATMENT OPTION FOR IL13RA2-EXPRESSING GBM AND IMPROVES STANDARD-OF-CARE THERAPY
Authors: Harrison Laukhuff, Maija Woodruff, Randy Schrecengost
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common primary adult brain cancer and is uniformly fatal. Despite maximum safe surgical resection followed by radiation and temozolomide chemotherapy, current median survival is 14-18 months. GB13 is a novel therapy for treatment of GBM and received Orphan Drug Designation by the Food and Drug Administration (FDA) for treatment of malignant gliomas. GB13 specifically targets the tumor-restricted IL13Ra2 receptor that is highly expressed in GBM, among other cancers, but not on non-cancerous cells. IL13Ra2 represents a clinically viable target for directed therapies and is being explored by numerous approaches. Previous data demonstrate that GB13 potently kills GBM and diffuse midline glioma (DMG) cells and tumors, IL13Ra2 correlates to GB13 sensitivity and, GB13 can significantly improve the cytotoxic effects of ionizing radiation (IR) when tested in models of pediatric diffuse midline glioma. In the current studies, the ability of GB13 to enhance the effects of IR were explored using IL13Ra2-positive and negative GBM models. Major findings demonstrate that neoadjuvant GB13 treatment increases cytotoxic effects of IR, enhances cell apoptosis and decreases cell viability. These results were not observed in IL13Ra2-negative settings, demonstrating the necessity for this clinical target. Mechanistically, increased cell death was caused by sustained apoptotic signaling through caspase-mediated pathways. Preclinical models support the use of GB13 prior to radiation for decreased tumor proliferation. Using multiple models, our results identify a temporal benefit for treating GBM tumors prior to IR and this should be tested in future clinical studies.