tbuckley/cabot-search huggingface dataset:
DDEL-12. LOCAL DELIVERY OF CHEMOTHERAPIES VIA BIORESORBABLE IMPLANT IN MENINGIOMAS
Authors: Mark Youngblood, Ziying Hu, Khizar Nandoliya, Vineeth Thirunavu, Wenxia Wang, Shejuan An, Matthew McCord, Thomas Sears, Mateo Gomez, Anh Tran, Alicia Steffens, Jordain Walshon, Kathleen McCortney, Mariah Flowers, Stephen Magill, John Rogers, Craig Horbinski
Journal: Neuro-Oncology (2024)

Abstract Many meningiomas recur despite repeated surgical resections and radiation, and patients must undergo progressively morbid surgical procedures due to recurrent or progressive disease. However, unlike most gliomas, meningiomas do not diffusely infiltrate throughout the brain on a single-cell basis, but instead recur and invade locally. Thus, they may be particularly vulnerable to localized chemotherapy. To investigate this, we screened 13 patient-derived primary meningioma cell cultures and two commercially available meningioma cell lines using a library of 147 FDA-approved compounds. We identified drugs with elevated potency across all meningiomas, including bortezomib (mean IC50 = 7nM) and romidepsin (mean IC50 = 18nM), as well as drugs with selective potency against specific samples, such as docetaxel (IC50 range 6nM to &amp;gt;10uM). We reasoned that delivery of a multi-drug cocktail with independent anti-neoplastic mechanisms would provide the strongest therapeutic effect in meningiomas. As systemic treatment with combination agents resulted in severe toxicity in mice, we performed local injection of bortezomib / romidepsin / docetaxel (BRD) triple therapy over 24 days in flank xenografts of IOMM-LEE and CH157 meningiomas. Tumor growth was reduced by 71-88% relative to vehicle (p&amp;lt;0.01), and mice showed no systemic toxicity with local therapy. Notably, the addition of radiotherapy did not further enhance the effect of BRD. To optimize local delivery, we developed a polyanhydride bioresorbable wafer designed to fit in a meningioma resection cavity, analogous to carmustine wafers used in gliomas. Intracranial implantation of wafers caused no local toxicity or inflammation in mice. Docetaxel-loaded wafers prevented the growth of flank-injected IOMM-LEE cells relative to wafers without drug (0 mm3 vs. 230 mm3 at 3 weeks post-injection, N=5/group, p&amp;lt;0.01). Our results demonstrate that bioresorbable wafers containing a cocktail of potent chemotherapies may be an effective new strategy against locally aggressive meningiomas.
EXTH-59. ESTABLISHING GAUSSIA LUCIFERASE REPORTER AS A BIOMARKER FOR ESTIMATING THERAPEUTIC RESPONSE AND PROGRESSION-FREE SURVIVAL IN PATIENT-DERIVED XENOGRAFT MODELS OF GLIOBLASTOMA
Authors: K’Ashé McKinney, Christopher Tse, Chencai Wang, Francesco Sanvito, David Nathanson, Benjamin M Ellingson
Journal: Neuro-Oncology (2024)

Abstract Serial monitoring of tumor burden in patient-derived xenograft (PDX) models used for testing new cancer drugs via MRI and other imaging techniques can be costly. We theorized that transducing the Gaussia luciferase (GLuc) reporter gene into glioma PDX models (GliomaPDOX) allows for GLuc to be used as a biomarker for tumor burden. This current study investigates whether changes in the rate of GLuc secretion over time (i.e., “growth rate” changes) can predict survival in GliomaPDOX. Optimal cutoff values to define disease progression via GLuc measurements were established resulting in a strong association between progression-free survival (PFS) and overall survival (OS). The pLenti-CMV-sGluc-T2A-EGFP plasmid was packaged into a second-generation lentiviral system via HEK293FT cells, and the resulting virus transduced into directly-isolated glioma patient cells to establish the MGMT-Unmethylated and MGMT-Methylated GliomaPDOX. MGMT-Unmethylated GliomaPDOX were treated with placebo or Temozolomide (TMZ) until endpoint. MGMT-Methylated GliomaPDOX were treated with placebo or TMZ for three weeks or TMZ for six weeks until endpoint. Treatment response was monitored through GLuc measurements obtained via tail blood collection. The optimal cutoff for time to progression was a 30% increase in GLuc, which yielded a significant positive association between PFS and OS across all models and treatments (R2 = 0.8177, p&amp;lt;0.0001). Compared to the MGMT-Methylated placebo and MGMT-Unmethylated groups, the MGMT-Methylated treatment groups exhibited substantial changes in GLuc growth rates and significantly longer PFS and OS (p&amp;lt;0.0001). More specifically, the six-week MGMT-Methylated TMZ-treated group demonstrated a significant difference in GLuc growth rates and a considerable PFS (p&amp;lt;0.0038) and OS increase (p&amp;lt;0.0049) when compared to the three-week MGMT-Methylated TMZ-treated group. Therefore, GLuc measurement is a valuable biomarker for PDX tumor burden and can be used to estimate treatment response and PFS.
PATH-53. DNA MUTATION SEQUENCING AND METHYLATION ANALYSIS OF SOMATIC<i>NF1</i> MUTANT IDH-WILDTYPE GLIOBLASTOMA IDENTIFIES THREE EPIGENETIC GROUPS AND<i>CDKN2A/B</i> LOSS AS A NEGATIVE PROGNOSTIC BIOMARKER
Authors: Kanish Mirchia, Sixuan Pan, Emily Payne, John Liu, Zain Peeran, Poojan Shukla, Jacob Young, Rohit Gupta, Jasper Wu, Joanna Pak, Kyounghee Seo, Tomoko Ozawa, Brian Na, Alyssa Reddy, Steve Braunstein, Joanna Phillips, Susan Chang, David Solomon, Arie Perry, David Raleigh, Mitchel Berger, Adam Abate, Harish Vasudevan
Journal: Neuro-Oncology (2024)

Abstract The tumor suppressor NF1 is frequently mutated in IDH-wildtype glioblastoma. However, the molecular subgroups and clinically relevant biomarkers within somatic NF1 mutant, IDH-wildtype glioblastomas remain incompletely understood. Here, we combine methylation arrays and targeted DNA sequencing to identify epigenetic subgroups and clinical biomarkers within non-syndromic NF1 mutant IDH-wildtype glioblastoma. We identified 186 patients treated at the University of California San Francisco between 2016-2024 with newly diagnosed IDH-wildtype glioblastoma containing a somatic pathogenic NF1 mutation on a CLIA certified targeted DNA sequencing assay. Illumina EPIC DNA methylation arrays (n=129 patients) were processed using the minfi package and Heidelberg random forest classifier (v12.8). Downstream analyses including hierarchical clustering and survival analyses were performed in R. DNA sequencing identified 12 recurrently altered genes in greater than 10% of cases across cell cycle regulators (CDKN2A/B, TP53, RB1), PI3K signaling (PTEN, PIK3R1, PIK3CA), epigenetic modifiers (ATRX, SETD2), and growth factor signaling (EGFR, PDGFRA, PTPN11). DNA methylation analysis revealed three epigenetic subgroups. Group 1 showed lower median patient age and significantly increased TP53 co-mutation rate. Group 2 contained a significantly higher proportion of male patients and was significantly enriched for RB1 and TERT promoter alterations, with a majority of tumors classified as GBM-MES using the Heidelberg classifier. Group 3 showed a significantly higher proportion of female patients and was significantly enriched for homozygous CDKN2A/B deletion. Homozygous CDKN2A/B loss was associated with significantly worse overall survival across the entire non-syndromic NF1 mutant glioblastoma cohort but not in a propensity score matched NF1 wildtype glioblastoma cohort. DNA methylation profiling revealed three epigenetic subgroups characterized by distinct clinical features, co-mutation patterns, and reference DKFZ methylation classifier identities. CDKN2A/B loss may be a negative prognostic biomarker specifically in NF1 mutant glioblastomas; future multi-institutional studies are required to validate these findings and their therapeutic implications in a larger, representative cohort.
TMIC-49. TUMOR-DERIVED SPERMIDINE DRIVES IMMUNE SUPPRESSION IN THE GLIOBLASTOMA MICROENVIRONMENT VIA CD8 T CELL DEPLETION AND FUNCTIONAL ATTENUATION
Authors: Justin Lathia, Kristen Kay, Juyeun Lee, Zeneng Wang, Matthew Grabowski, Mark Brown, Stanley Hazen, Defne Bayik
Journal: Neuro-Oncology (2024)

Abstract A hallmark of glioblastoma (GBM) is an immunosuppressive microenvironment that is partially driven by tumor cell-derived secreted factors, highlighting the need for a more complete understanding of local immune suppressive mechanism. Altered secreted metabolite levels are observed in the GBM microenvironment; specifically, spermidine (a polyamine), which functions to drive cell proliferation, apoptosis, T cell lineage commitment, and myeloid cell-mediated suppression. However, the direct link between GBM cell-derived spermidine and the tumor microenvironment has yet to be determined. In syngeneic mouse GBM models, spermidine levels were increased in the tumor microenvironment and exogenous administration of spermidine accelerated tumor aggressiveness in an immune dependent-manner. Mechanistically, spermidine administration increased apoptosis of CD8+ T-cells and generated an exhausted phenotype. When ornithine decarboxylase (ODC1, the rate limiting enzyme in spermidine synthesis), was knocked down in tumor cells, no direct effect was observed on tumor cell growth. However, there was an increase in time to tumor succumbence and a concomitant increase in CD8+ T-cells and decrease in CD8+ T cell exhaustion. In GBM patients, there was a negative correlation between ODC1 expression and CD8+ T-cells present near the tumor. Additionally, patients with a favorable prognosis had significantly lower intratumoral levels of spermidine compared to patients with a poor prognosis. Taken together, these results demonstrate that spermidine functions as a tumor cell-derived metabolite that drives tumor progression through reducing CD8+T cell number and altering their phenotype. These findings have clinical implications as clinical trials using a polyamine biosynthesis inhibitor alone have not been very effective in GBM patients, suggesting the need for additional combination immunotherapies. Finally, spermidine is also produced at prominent levels by commensal gut microbes as well as absorbed from consumption of foods such as mushrooms; investigation into how these distal spermidine sources impact GBM growth via the gut-brain axis is actively ongoing.
EXTH-13. COMBINED ANTI-ANGIOGENIC TREATMENT TO INCREASE INTRATUMORAL PERSISTENCE OF CAR T-CELLS IN LUNG CANCER BRAIN METASTASES
Authors: Jens Blobner, Constantin Eberle, Laura Dengler, Alexander Beck, Katharina J Müller, Nico Teske, Tao Xu, Philipp Karschnia, Hellen Ishikawa-Ankerhold, Niklas Thon, Joerg-Christian Tonn, Marion Subklewe, Sebastian Kobold, Patrick N Harter, Veit R Buchholz, Louisa von Baumgarten
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Metastatic lung cancer, especially when it spreads to the brain, shows a devastating prognosis. Immunotherapeutic approaches including CAR T-cells show promise in hematologic malignancies. However, the presence of immunosuppressive factors within the tumor microenvironment and physical barriers like elevated interstitial pressure due to dysfunctional tumor vessels are one of the main obstacles especially in solid tumors. Evaluation of the potential synergy between anti-angiogenetic drugs and CAR T-cells in this context are an ongoing investigation. METHODS Here, we set up an immunocompetent syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning microscopy (TPLSM). This model allows in vivo characterization of fluorescent tumor cells and CAR T-cells on a single cell level over time. Intraparenchymal injection of red fluorescent EpCAM-transduced Lewis Lung carcinoma cells (EpCAM/tdtLL/2 cells) followed by injection of EpCAM-directed or undirected CAR T-cells into the adjacent brain tissue was performed. Additionally, aVEGF-A combined with aVEGF-R2 and the respective isotype control were injected intraperitoneally. RESULTS Compared to undirected CAR T-cells, mice receiving EpCAM-directed CAR T-cells showed higher intratumoral CAR T-cell densities after intraparenchymal injection. This finding was accompanied with reduced tumor growth and eventually translates into a survival benefit. However, intratumoral CAR T-cell numbers diminish over time indicating insufficient persistence inside of the tumor microenvironment. Additional anti-VEGF-A/VEGF-R2 treatment results in reduced tumor growth after EpCAM/GFPCAR T-cell and GFPT-cell treatment, respectively. Interestingly, in vivo imaging reveals higher intratumoral CAR T-cell numbers after anti-angiogenic treatment compared to isotype controls pointing towards enhanced CAR T-cell persistence resulting in a survival benefit. CONCLUSION Collectively, our findings indicate that locally injected CAR T-cells may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Additional anti-angiogenic treatment provides a mechanism to enhance intratumoral CAR T-cell persistence and reduce tumor growth.
INNV-08. PRE-CLINICAL AND CLINICAL EVIDENCE FOR THE TREATMENT OF DMG/DIPG USING EMULATE THERAPEUTICS’ ULTRA-LOW RADIO FREQUENCY MAGNETIC FIELD SIGNAL TECHNOLOGY
Authors: Xavier Figueroa
Journal: Neuro-Oncology (2024)

Abstract EMulate Therapeutics, Inc. (EMTx) has developed a technology that emulates the effects of chemical compounds via a magnetic field. Our research has led to the development of a radio frequency energy (RFE) signal (A1A) that emulates the effects of paclitaxel. Pre-clinical studies demonstrate an effect in slowing down and inhibiting tumor growth. The results of feasibility (Phase I/II) clinical trials testing the EMTx technology for treating recurrent GBM (rGBM) were published in CNS Oncology (CNS Oncol 2023 Pages CNS102, Accession Number: 37462385 DOI: 10.2217/cns-2022-0016). Reported results suggest that the A1A signal is non-inferior to best supportive care (BSC) and when the A1A signal is combined with BSC, a 3-month increase in overall survival (OS) was observed. Diffuse intrinsic pontine gliomas (DIPG) are a rare pediatric central nervous system (CNS) tumor. Survival is measured at under 12 months, with no clinical trials demonstrating a significant increase in OS in 20 years (9 months median survival post radiation therapy). EMTx’s compassionate use program (Hælo® medical device) demonstrated safety and suggested a clinical benefit, with 12 of 14 patients surviving more than 12 months, with median survival of 17 months. EMTx recently completed an orthotopic mouse model of DIPG at University of California San Francisco. The results from exposing the mice to the A1A signal demonstrated a significant survival advantage (P = 0.0163) via the slowing down of cell division. Data to be submitted for peer review publication. The animal model is encouraging and supports the observed results of our compassionate use program. EMTX will submit these results to the FDA for regulatory approval via the Humanitarian Device Exemption pathway. The company will conduct a study with DIPG patients from both the US and India. Subject to FDA protocol approval, 30-35 patients will be recruited to participate in this pediatric neuro-oncology trial, which will be a best supportive care + single therapy (Hælo®) clinical trial.
NIMG-08. IMAGING FINDINGS AND PROGNOSTIC FACTORS IN DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Yasuhito Kegoya, Yoshihiro Otani, Ryosuke Ikemachi, Ryo Omae, Shohei Nishigaki, Yohei Inoue, Tsuyoshi Umeda, Madoka Hokama, Ryo Mizuta, Ryoji Imoto, Naoya Kemmotsu, Yasuki Suruga, Shuichiro Hirano, Fumiyo Higaki, Kana Washio, Norio Yamamoto, Shinichiro Koizumi, Kazuhiko Kurozumi, Joji Ishida, Yoshihiro Tanaka, Shota Tanaka
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Diffuse hemispheric glioma, H3 G34-mutant (DHGs), are a newly categorized tumor in pediatric-type diffuse high-grade gliomas in the 2021 World Health Organization classification, with a poor prognosis. DHGs has been reported to occur in less than 1% of all gliomas, but prognostic factors have not been fully investigated in previous studies due to small sample sizes. In this study, we investigated the relationship between clinical factors, including imaging findings, and prognosis in patients with DHGs. METHODS We searched Medline through the PubMed database using two search terms: “G34” and “glioma”, between 1 April 2012 and 1 July 2023. We retrieved articles that described imaging findings and overall survival (OS), and added one DHG case from our institution. We defined midline invasion (MI) as invasion to the contralateral cerebrum, brainstem, corpus callosum, thalamus, and basal ganglia on magnetic resonance imaging. The primary outcome was 12-month survival, estimated using Kaplan–Meier curves and logistic regression. RESULTS A total of 96 patients were included in this study. The median age was 22 years, and the proportion of male patients was 48.4%. Lesions were most frequently located in the frontal lobe (52.6%). MI was positive in 39.6% of all patients. The median OS of all cases was 14.4 months. Univariate logistic regression analysis with 12-month OS as the outcome showed that the MI-positive group had a significantly higher mortality than that in the MI-negative group, and the gross total resection achieved group had a significantly lower mortality than that in the group that underwent biopsy alone. Multivariate logistic regression analysis revealed that MI was an independent prognostic factor in DHGs. CONCLUSIONS Similar to glioblastomas, DHGs have a poor prognosis if they invade deep structures or the contralateral cerebrum; however, safe and maximal tumor resection may prolong survival.
TMOD-12. DEFINING THE ROLE OF THE DAAM2 R414W GERMLINE VARIANT IN FAMILIAL GLIOMA
Authors: Tiffany Choy, Qi Ye, Benjamin Deneen, Melissa Bondy, Hyun Kyoung Lee
Journal: Neuro-Oncology (2024)

Abstract Malignant glioma is the most common primary brain tumor in adults, leading to high morbidity and mortality due to its aggressive nature and limited efficacious treatment options. To improve this prognosis, research has focused on genetic factors that may contribute to glioma. While most glioma cases arise from sporadic somatic mutations, approximately 5-10% are classified as familial glioma, stemming from inherited genetic variations. Although several studies have explored mechanisms behind somatic mutations in glioma, less is known about hereditary variants that promote glioma susceptibility. We recently discovered five germline mutations in Daam2 (Dishevelled associated activator of morphogenesis 2) from familial glioma patients. To examine the role of these mutations in familial glioma, we overexpressed these mutations in patient-derived glioma stem-like cells, which were subsequently orthotopically xenografted into immunodeficient mice. We identified that one of these mutations, Daam2-R414W, promotes tumor cell proliferation both in vitro and in vivo. To further understand the role of the Daam2-R414W mutation in familial glioma, we generated a knock-in immunocompetent mouse model with the Daam2-R414W mutation. In these mutant mice, we found an increased number of proliferating glial progenitor cells in the subventricular zone compared to Daam2 wildtype mice, suggesting the potential of the Daam2-R414W mutation to influence glial progenitor expansion to stimulate glioma initiation. Furthermore, to establish a potential mechanism, we performed proteomic profiling of Daam2 wildtype and Daam2-R414W overexpression tumors and found enrichment of Git1, a GTPase-activating protein involved in cytoskeletal remodeling, suggesting that the Daam2-R414W variant may interact with Git1 to promote tumor invasion. Our findings thus far identify a hereditary genetic variant with the potential to increase the risk of glioma, shedding light on the repercussions of a human developmental gene variant and its potential to disrupt normal cellular machinery to promote malignancy and glioma development.
PATH-19. DIAGNOSTIC UTILITY OF MOLECULAR PROFILING IN ADULT DIFFUSE GLIOMA
Authors: Makoto Ohno, Takuma Nakashima, Hirokazu Sugino, Shunsuke Yanagisawa, Daisuke Kawauchi, Takaki Omura, Takuma Aoki, Akihiko Yoshida, Hiromichi Suzuki, Yoshitaka Narita
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION With the publication of World Health Organization Classification of the Central Nervous System Tumors (WHO CNS5), molecular profiling has become essential for the diagnosis of CNS tumors. To test for the diagnostic molecular alterations, we developed a targeted DNA sequencing panel (Nakashima et al. 2024) to analyze 113 genes, chromosomal abnormalities, and MGMT promoter methylation. This study aimed to evaluate our diagnostic approach using the targeted sequencing panel. PATIENTS AND METHODS We included 72 cases of diffuse adult gliomas diagnosed at our institute between June 2023 and May 2024. We analyzed the tumor diagnoses based on the pathological and immunohistochemical findings as well as the targeted sequencing panel findings. RESULTS The tumor diagnoses were as follows: glioblastoma, IDH-wildtype: 32 cases, astrocytoma, IDH-mutant: 17 cases, oligodendroglioma, IDH-mutant and 1p/19q-codeleted: 15 cases, others: 8 cases. Among 32 cases of IDH1/2 mutations, 28 cases (87.5%) with IDH1 R132H mutation were diagnosed by immunohistochemistry using anti-IDH1 R132H antibody, whereas 4 (12.5%) (3 with IDH2 mutation, and 1 with IDH1 R132S) were diagnosed by the targeted sequencing panel. Of the 32 glioblastoma cases, 6 (18.8%) did not show necrosis or microvascular proliferation and were diagnosed based on either TERT promoter mutation, EGFR amplification, or chromosome 7/chromosome 10 abnormalities. Moreover, 24 out of 26 resected cases (92.3%) were diagnosed morphologically, whereas 4 of 6 biopsy cases (66.7%) were diagnosed molecularly (p=0.0056). Among the 17 cases of astrocytoma, IDH-mutant, 2 (11.8%) showed homozygous deletion of CDKN2A/B. There were 4 cases (5.6%) out of 72 that did not satisfy the diagnostic criteria for glioblastoma, astrocytoma, oligodendroglioma. CONCLUSION Approximately 95% of cases were diagnosed based on WHO CNS5 criteria with molecular profiling. We also demonstrate molecular profiling is useful in glioblastoma diagnostics, especially in biopsy cases where morphological diagnostic evidence is not recognized.