tbuckley/cabot-search huggingface dataset:
TMET-05. INCREASING GLUTAMINE UPTAKE-LIPOGENESIS AXIS PROMOTES TUMOR RESISTANCE TO LYSOSOME INHIBITION
Authors: Yaogang Zhong, Feng Geng, Logan Mazik, Xinmin Yin, Aline Paixao Becker, Shabber Mohammed, Huali Su, Enming Xing, Yongjun Kou, Chengyao Chiang, Yunzhou Fan, Pui-Kai Li, Xiaokui Mo, Etienne Lefai, Liqing He, Xiaolin Cheng, Xiang Zhang, Arnab Chakravarti, Deliang Guo
Journal: Neuro-Oncology (2024)

Abstract An effective therapy for glioblastoma (GBM), the most lethal brain tumor, is lacking1-11. Several antipsychotic drugs, including pimozide, have recently been shown to have anti-GBM potential 12,13, but the development of tumor resistance diminishes their efficacy. Identifying the mechanisms for such resistance will help repurpose these brain-penetrant drugs for GBM therapy. Here, we found that pimozide inhibits cholesterol and fatty acids (FAs) release via lysosome-mediated lipid droplets (LDs) and lipoprotein hydrolysis, starving GBM cells of these essential building blocks. However, we identified that GBM cells become resistant to pimozide-based therapy due to an elevation of glutamine metabolism. Mechanistically, reductions in cholesterol and the promotion of signaling via sterol regulatory element-binding protein 1 (SREBP-1), a classical lipogenic transcription factor14, stimulate glutamine transporter ASCT2 expression, increasing glutamine uptake and consumption. Enhanced glutamine uptake leads to the release of ammonia that further stimulates SREBP-1 activation, thereby forming a feedforward loop to concurrently increase both glutamine metabolism and lipid synthesis, resulting in drug resistance. Pharmacological targeting of either ASCT2, or glutaminase (GLS) to limit glutaminolysis, abolishes this loop, and in combination with pimozide result in marked killing of GBM cells. Our study demonstrates that combinatorial targeting of glutamine metabolism and lysosomal function is a promising approach to treat GBM, which may be applicable to other aggressive cancers that are also addictive to glutamine and lipids.
IMMU-36. MULTI-OMIC CHARACTERIZATION OF A SYNGENEIC MOUSE CANCER STEM CELL MODEL OF GBM FOR PRECLINICAL APPLICATIONS
Authors: Kyle Heemskerk, Samir Assaf, Xiaguang Hao, Mathieu Meode, Smriti Kala, James Pemberton, Reza Mirzaei, J Gregory Cairncross, Peter Forsyth, V Wee Yong, Samuel Weiss, Franz Zemp, H Artee Luchman
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is resistant to many therapies including immunotherapies. There is an urgent need to explore the role of the microenvironment in resistance to therapy with tailored pre-clinical models. Using multi-omic approaches we describe a syngeneic cancer stem cell mouse model of GBM, with a spontaneous amplification of Igf2. We investigate whether Igf2 influences tumour and microenvironment cells to promote immunosuppression in GBM. Three cell lines were previously established from spontaneous brain tumours in C57Bl/6 Trp53+/-/Nf1+/- mice and maintained under neural stem cell culture conditions. Whole genome sequencing (WGS) was used to determine single nucleotide, copy number, and structural variation, revealing loss of both copies of Trp53 and Nf1 in all three cell lines. However only one cell line, mBT0309, developed tumors when orthotopically allografted. Analysis of genomic alterations and transcriptomics revealed that mBT309 exhibits amplification of the Igf2 loci and overexpression was confirmed at the RNA and protein level. Spatial and single cell transcriptomics showed that Igf2 is overexpressed in mBT0309 allografted tumours and correlated with specific transcriptomic programs. A high-parameter Imaging Mass Cytometry (IMCTM) panel was used for spatial proteomic analysis, to monitor the development of tumours in a time-course experiment. In vitro growth characteristics and stem marker expression in both transcriptomic and spatial IMC data suggest that high levels of Igf2 may regulate GBM stemness features. Analysis of human GBM datasets revealed that Igf2 amplified tumours have reduced CXCL11 expression. These findings suggest that high levels of Igf2 may influence immunosuppression by reducing T-cell recruitment. This syngeneic immunocompetent GBM stem cell model harbouring Igf2 amplification adds to the suite of models to study the GBM microenvironment and its role in immunosuppression and resistance to therapy.
CTIM-36. IN-SITU VACCINATION OF BIOPSY-ONLY GBM TUMORS BY TUMOR TREATING FIELDS PLUS ANTI-PD-1 IMMUNOTHERAPY RESULTS IN ROBUST ANTIGEN-SPECIFIC T CELL SELECTION AND EXPANSION, HIGH RESPONSE RATE, AND SIGNIFICANTLY EXTENDED SURVIVAL
Authors: Dongjiang Chen, Son Le, Ashley Ghiaseddin, Harshit Manektalia, Ming Li, Adam O’Dell, Maryam Rahman, David Tran
Journal: Neuro-Oncology (2024)

Abstract We have recently described a complete in-situ immunizing protocol against GBM using Tumor Treating Fields (TTFields) to activate the DNA sensor-dependent inflammasomes and immunogenic cell death. Here, we report successful in-situ vaccination of patients with newly diagnosed GBM, especially in those with bulky, biopsy-only tumors as compared to those with maximally resected disease, using TTFields together with pembrolizumab, an anti-PD-1 immunotherapy. Patients with biopsy-only tumors displayed a marked improvement in both progression-free survival (27.2m vs 9.6m; HR 0.37, 95%CI 0.16-0.85; P=0.014), overall survival (31.6m vs 18.8m; HR 0.4, 95%CI 0.17-0.92; P=0.023), and response rates (66.6% vs 25%) when compared to those with maximally resected tumors. Using a combination of bulk RNA-seq of enriched T cells and single-cell RNA-seq and TCR clonotyping of tumors and PBMC, we tracked clonal evolution of T cells and confirmed that TTFields’ adaptive immune activation followed a type 1 interferon trajectory (T1IFN) specifically through the DC compartment in patients with biopsy-only tumor. From DC, the T1IFN pathway engaged the adaptive immune system, highly correlated with T cell activation (Pearson r=0.81; P=0.000027), and strongly predicted for extended survival (HR 0.3; P=0.034). Importantly, we discovered the adaptive replacement of expanded T cell clones induced by TTFields and enhanced by pembrolizumab predicted for prolonged survival (P=0.031), leading to sustained T cell activation (Pearson r=0.72; P=0.0018) and robust generation of central memory CD4+ and CD8+ T cells, especially in responders with biopsy-only tumors. In recurrent tumors, the PD-1/PD-L1 axis was suppressed, while concurrent upregulation of alternative immune checkpoints was observed in the periphery and TME. This was coupled with ineffective compensatory T cell activation, suggesting potential mechanisms of resistance. These findings highlight the potent in-situ vaccination effects of TTFields and support its co-application with immune checkpoint inhibitors as a promising strategy for GBM, especially in patients with substantial residual tumor.
IMMU-53. ANTIGEN PRESENTATION BY TUMOR-ASSOCIATED MACROPHAGES MEDIATES PROGENITOR TO TERMINAL EXHAUSTION TRANSITION IN GBM AND OTHER SOLID TUMORS
Authors: Jessica Waibl-Polania, Alexandra Hoyt-Miggelbrink, William Tomaszewski, Lucas Wachsmuth, Selena Lorrey, Daniel Wilkinson, Emily Lerner, Karolina Woroniecka, John Finlay, Peter Fecci
Journal: Neuro-Oncology (2024)

Abstract While terminally exhausted T cells (Tex_term) retain important anti-tumor cytotoxic function, it is the relative preservation of renewable, stem-like progenitor exhaustion (Tex_prog) that better indicates immunotherapeutic responsivity. Although restraining the progression from Tex_prog to Tex_term thus takes on clinical significance, the cellular interactions in a tumor microenvironment (TME) governing such progression remain less established. Employing glioblastoma (GBM) and other solid tumors as models of severe exhaustion, we provide a detailed characterization of the progression from Tex_prog to Tex_term within the TME, where we observe a striking and disproportionate loss of Tex_prog over time, leading to a low progenitor exhaustion to terminal exhaustion ratio (PETER). We find exhaustion concentrated within tumor-specific T cell subsets, with cognate antigenic exposure requisite for acquisition of the Tex_term phenotype. However, we implicate tumor-associated macrophages (TAM), and not tumor cells, as the source of antigenic exposure governing the Tex_prog to Tex_term transition. Using cell – cell interaction analysis, we additionally highlight candidate receptor–ligand communications that may be specifically mediating the progression to Tex_term and resultant decline in PETER within the TME.
TMOD-22. MULTIREGION BIOPSIES AND CORRESPONDING NEUROSPHERE CULTURES REVEAL SPATIAL DIVERGENCE IN GLIOBLASTOMA EVOLUTION
Authors: Roberto Salatino, Jacob Geisberg, Ugoma Onubogu, Arantxa Romero-Toledo, Banjamin Oakes, Oszkar Szentirmai, Thomas McDonald, Franziska Michor, Michalina Janiszewska
Journal: Neuro-Oncology (2024)

Abstract Spatial organization of normal tissues is key for their function, yet the role of distribution of distinct clones of cancer cells in tumor is not usually studied as a potential vulnerability in cancer. This is of particular interest in glioblastoma (GBM), in which extensive intratumor heterogeneity hampers effectiveness of treatment. To better understand tumor evolution and the complexity of cancer ecosystem in GBM, we performed profiling of biopsies collected from MRI-defined regions of the tumors, spanning the surface, tumor core and deep tumor margins, which drive local recurrence after surgery. To test how spatially distinct biopsies differ in their cancer cell composition and to assess the tumor microenvironment heterogeneity, we took advantage of 5-ALA metabolite fluorescence, which accumulates in GBM cells and allows the surgeon to visualize cancer under blue light. We used it to separate cancer cells (predominantly 5-ALAhigh) from tumor microenvironment (5-ALAlow) and subjected the fractions to bulk and single cell transcriptomics, respectively. We found a gradient of cellular states associated with location in the tumor, with the deep margin samples having more 5-ALAlow cancer cells and generally less defined phenotype. We have also developed neurosphere cultures from our collection of spatially distant biopsies. Despite the selection pressure of the in vitro culture conditions, cells from different regions of the tumor adopted different morphologies, suggesting retention of some of their differential features. The differences between cultures were reflected in metabolism, proliferation, and differential sensitivity to a drug panel. Whole exome sequencing and transcriptomic analysis were also performed to identify the selection bottleneck of culture conditions, establish evolutionary trajectory of the distinct regions and neurosphere cultures, and test how strongly our cultures represent both the 5-ALAhigh and 5-ALAlow subpopulations of GBM cells. Our study identified properties associated with different spatial locations within GBM tumors, which will help uncover the cellular and microenvironmental dependencies that could lead to novel therapeutic targets for this highly heterogeneous tumor.
TMET-10. TARGETING PGM3 TO INHIBIT HEXOSAMINE PRODUCTION IS AN EFFECTIVE APPROACH TO TREAT GLIOBLASTOMA
Authors: Huali Su, Yaogang Zhong, Feng Geng, Yunzhou Fan, Yongjun Kou, Cheng-yao Chiang, Xiaokui Mo, Shino Magaki, Timothy F Cloughesy, Etienne Lefai, William H Yong, Arnab Chakravarti, Deliang Guo
Journal: Neuro-Oncology (2024)

Abstract Hexosamine biosynthesis pathway (HBP) mediated by a series of enzymes is highly upregulated in many cancers to promote the glycosylation of proteins and lipids, while which enzyme in this pathway is better to serve as anti-tumor target is unclear. Here, we found targeting GFAT1, the initial and rate-limiting enzyme in HBP, fails to inhibit the growth of glioblastoma (GBM), the most lethal brain tumor, due to this cancer dramatically elevating NAGK-mediated hexosamine salvage pathway. In contrast, targeting PGM3, the latter enzyme in HBP, blocks both de novo hexosamine synthesis and salvage pathways, effectively inhibiting GBM growth. We further identified HBP enzymes are upregulated by SREBP-1, a key lipogenic transcriptional factor. In turn, this upregulation promotes SREBP-1 activation to stimulate lipogenesis via stabilization of its key transporter SCAP by N-glycosylation modification. Together, our study uncovered a previously unrecognized HBP-SCAP-SREBP-1 feedforward loop and demonstrated targeting PGM3 is an effective approach to treat GBM.
CTIM-33. IMMUNE BIOMARKERS OF TREATMENT RELATED IMAGING CHANGES IN GLIOBLASTOMA PATIENTS TREATED WITH STANDARD OF CARE PLUS PEMBROLIZUMAB
Authors: Cheryl Claunch, Ramon Barajas, Prakash Ambady
Journal: Neuro-Oncology (2024)

Abstract Pseudoprogression is a post-treatment imaging phenomenon in glioblastoma (GBM) that mimics true progression. Immune checkpoint inhibition with pembrolizumab has shown clinical benefits in multiple cancers and is a burgeoning treatment in GBM. Discerning pseudoprogression, or treatment-related imaging changes, from true progression is essential for appropriate treatment recommendations. However, there are no reliable biomarkers that can differentiate between pseudoprogression and true progression. Our prospective single-arm study (NCT 03347617) evaluated immune cell sub-populations (B-cells, T-cells, NK cells, monocytes, and myeloid cells) in newly diagnosed GBM patients who received standard-of-care chemoradiation plus concurrent pembrolizumab after maximal safe resection. Flow cytometry was performed on blood collected at predetermined timepoints (pre-treatment, post-radiation, suspected progression, and confirmed progression) and immune cell sub-populations were evaluated as covariates in univariable and multivariable logistic regression analysis. Of the 56 patients enrolled in this trial, 51 completed blood collection. Median survival was 13.84 months. Fifteen (29%) patients had pseudoprogression by modified RANO criteria and 36 (70.5%) had suspected or confirmed progression. Univariable analysis identified the following serum derived immune populations as being significantly associated with pseudoprogression: cytotoxic T-cell percentage (CD3+CD8+; HR: 1.10; p=0.045); total NK Cells percentage (CD3+CD56+; HR:0.912; p=0.0.053); IGD+CD27-naïve B-cells of B-cell percentage (HR: 0.976; p=0.014); IGD+CD27+non-switched B of B-cell percentage (HR:1.07; p=0.036). Backward selection multivariable logistic regression analysis confirmed the significant association of cytotoxic T-cell percentage (CD3+CD8+; HR:1.02; p=0.049) with pseudoprogression while controlling for IGD+CD27+non-switched B of B-cell percentage (HR:1.01, p=0.116). Increasing levels of serum cytotoxic T-cells in GBM patients treated with standard-of-care plus pembrolizumab is associated with pseudoprogression and may be used to differentiate between true progression. Validation of results is needed in a control population treated with standard-of-care prior to clinical implementation. Future studies will utilize serum immune biomarkers coupled with radiomic features to better characterize the pseudoprogression signature in GBM.
QLTI-10. IMPACT OF A NEURO-ONCOLOGY HOSPITALIST MODEL ON INPATIENT CANCER CARE DELIVERY AT A SINGLE INSTITUTION
Authors: Mary Barden
Journal: Neuro-Oncology (2024)

Abstract Patients with brain tumors are often admitted to the hospital at critical stages of their disease course: initial diagnosis, relapse, end-of-life, and for management of serious complications. Patients who develop neurologic complications from systemic cancers and their treatments also frequently require management in the hospital setting. Most neuro-oncologists have busy outpatient practices and limited inpatient responsibilities. Their experience with hospital workflows, bandwidth to see inpatients, and comfort level managing certain diagnoses such as immunotherapy neurotoxicities may be variable, even within a single institution. Recent literature supports the beneficial role of the Oncology Hospitalist, a physician who specializes in the care of hospitalized patients with cancer. Oncology Hospitalist care improves length of stay, cost effectiveness, and the patient and oncologist experience. To our knowledge, the role of a hospitalist who specializes in the care of patients with neuro-oncologic issues has not yet been investigated. Here we describe the responsibilities and examine the impact of a Neuro-Oncology Hospitalist at a single institution over a 2-year period, with a focus on metrics of quality and efficiency of care. Patients and cancer care systems benefit from the dedicated inpatient presence of a neuro-oncologist, supporting the development of a Neuro-Oncology Hospitalist model.
DDDR-22. USE OF BIOPSY-DERIVED TUMOR ORGANOIDS FOR PERSONALIZED DRUG TESTING IN RECURRENT GLIOBLASTOMA
Authors: Christel Herold-Mende, Amelie Woellner, Rolf Warta, Junguo Cao, Adrian Paul, Maddalena Aquilla, Gerhard Jungwirth, Wolfgang Wick, Andreas von Deimling, Andreas Unterberg, Sandro Krieg, Martin Jakobs
Journal: Neuro-Oncology (2024)

Abstract To date, there are no effective systemic treatment options for recurrent glioblastoma (GBM). Furthermore, often surgical resection is not possible and tumors have acquired an increased chemo- or radioresistance. Patient-derived tumor organoids (PDTOs) provide a new exciting tool to test individual treatment responses. Aim of this study was to assess the feasibility of a personalized PDTO-based drug testing even from rare material such as stereotactic biopsies. PDTOs were prepared based on single cell suspensions from tumor material obtained either from open GBM resections (reference data set, n = 37) or from stereotactic biopsies (n = 8). Drug response curves (6-9 doses) were performed for 9 drugs including commonly used drugs such as temozolomide, lomustine, etoposide and temsirolimus. Viability was measured using CellTiterGlo (Promega) to assess half-maximal inhibitory concentrations (IC50). Medical records were reviewed for survival and molecular information such as the MGMT methylation status. Drug testing on PDTOs from open resections allowed to adjust the test range for each drug. Additionally, a significant association between increased temozolomide sensitivity of PDTOs and both, MGMT methylation and increased survival was observed. However, in 59% of the cases, no sensitivity to any of the drugs was seen, and only 17% were highly sensitive to more than one drug. Subsequent drug testing on PDTOs from biopsies of recurrent GBM revealed sensitivity in 3/8 cases against one (n=2) or two (n=1) of the drugs. However, sensitivity against drugs varied substantially in a patient-individual manner. We successfully developed a workflow to test drug sensitivity on PDTO even from low starting material obtained from stereotactic biopsies. Association of clinical outcome and MGMT methylation with temozolomide sensitivity corroborated the strength of this approach. Furthermore, patient-individual treatment responses strongly suggest for a future personalized drug testing.
DDDR-24. REAL WORLD EXPERIENCE USING THE IDH INHIBITOR IVOSIDENIB IN IDH MUTANT GLIOMA: TOLERABILITY AND OUTCOMES
Authors: Tyler Lanman, Gilbert Youssef, Raymond Huang, Rifaquat Rahman, Matthew DeSalvo, Thomas Flood, Elmira Hassanzadeh, Min Lang, Jason Lauer, Christopher Potter, Julie Miller, Daniel P Cahill, Juan Pablo Ospina Botero, Vihang Nakhate, Natalie Stec, Diana Shi, Wenya Linda Bi, Samuel McBrayer, Isabel Arrillaga-Romany, Eudocia Lee, Ugonma N Chukwueke, Lakshmi Nayak, Deborah Forst, Elizabeth Gerstner, Justin T Jordan, Jorg Dietrich, Tracy T Batchelor, David A Reardon, Patrick Wen, Luis Nicolas Gonzalez Castro
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Mutant isocitrate dehydrogenase (IDHm) inhibitors represent a novel therapeutic strategy for treating IDHm glioma, though their optimal use outside of clinical trials remains undefined. This study describes real world utilization of the IDH1 inhibitor, ivosidenib, in patients with IDHm glioma. METHODS We retrospectively reviewed clinical and radiographic data from IDHm glioma patients treated with ivosidenib monotherapy at Dana-Farber Cancer Institute and Massachusetts General Hospital from 2020-2024. Patients with a baseline MRI at ivosidenib initiation and at least 2 subsequent scans while on ivosidenib were included in radiographic response analysis (452 scans). RESULTS This cohort included 77 patients (39 males) age 17-75 years (median 41). Thirty-eight patients (49%) had astrocytomas and 39 (51%) had oligodendrogliomas; 48 (62%) had grade 2, 26 (34%) grade 3, and 3 (4%) grade 4 gliomas. Twenty-four patients (31%) received ivosidenib as first-line therapy and 53 (69%) received ivosidenib after failing prior treatments. Among those in the radiographic analysis, 4 (6%) demonstrated partial response, 4 (6%) minor response, 44 (62%) stable disease, and 19 (27%) progressive disease (PD). Significantly higher PD rates were seen in those with enhancing disease (p&amp;lt;0.001) or received ivosidenib as subsequent-line therapy (p=0.002); PD rate was similar between grades 2 and 3 in the first-line group (p=0.64). One-year progression free survival was 100% in the first-line group and 66% in the subsequent-line group. At the time of our analyses, 4 patients (5%) had died (all in the subsequent-line group). Infrequent side effects included CK elevation, QTc prolongation, transaminitis, and diarrhea. One patient (1%) was dose reduced and 3 (4%) discontinued drug due to side effects. CONCLUSIONS In this real world IDHm glioma cohort, ivosidenib was well-tolerated. Better response rates were seen in patients without enhancing disease at ivosidenib initiation and those who received the drug as first-line therapy.