tbuckley/cabot-search huggingface dataset:
DDDR-11. INHIBITING OXIDATIVE PHOSPHORYLATION AND HYPOXIA WITH ATOVAQUONE – A STRATEGY TO RADIOSENSITIZE DIFFUSE MIDLINE GLIOMA
Authors: Faiqa Mudassar, Prunella Ing, Sandy Nguyen, Cecilia Chang, Kristina M Cook, Zachary N Warnken, Geraldine O’Neill, Han Shen, Eric Hau
Journal: Neuro-Oncology (2024)

Abstract Diffuse midline glioma (DMG) is a uniformly fatal paediatric brainstem tumour with median survival of less than 1 year. Radiotherapy has been the only effective treatment for decades, but most DMGs recur within several months due to radioresistance. The hypoxic tumour microenvironment is a main feature of solid tumours including gliomas and a major contributor to radioresistance. Therefore, alleviating tumour hypoxia to enhance the effectiveness of radiotherapy is a potential therapeutic strategy to improve the survival outcomes of DMG patients. We found evidence suggesting increased mitochondrial oxidative phosphorylation (OXPHOS) in DMG. Hence, we aimed to target OXPHOS by decreasing the oxygen consumption rate (OCR) of DMG cells, which in turn will alleviate hypoxia by sparing more oxygen and subsequently improve the radiosensitivity of DMG cells. We performed a high-throughput screening to identify potent OCR inhibitors from a library of 1963 FDA-approved drugs. The most promising OCR inhibitor identified was atovaquone, a drug used for treatment of pneumocystis pneumonia and malaria. We found that atovaquone inhibited mitochondrial metabolism of DMG cells by specifically targeting the mitochondrial complex III. Increased mitochondrial reactive oxygen species after exposure to atovaquone suggested that it increases oxidative stress. The treatment alleviated hypoxia and decreased the expression of hypoxia-inducible factor-1a in 3-dimensional DMG neurospheres and improved the radiosensitivity in several DMG cultures. To overcome the poor bioavailability of commercially available atovaquone that results in low therapeutically effective brain concentrations, we tested its efficacy against the amorphous solid dispersion (ASD) atovaquone formulation which appears to enhance atovaquone levels in the brain. We found that both the formulations inhibited OCR and hypoxia at similar doses and enhanced DMG radiosensitivity. The combination of ASD atovaquone and radiation significantly improved survival in orthotopic DMG mouse model. Collectively, this data provides evidence of atovaquone as a potential radiosensitizer for DMG.
TMET-08. RADIATION-INDUCED SLC25A22 CONTRIBUTES TO GLIOBLASTOMA RADIORESISTANCE ACQUISITION THROUGH REMODELING GLUTAMATE METABOLISM
Authors: Byeongsoo Kim, Haksoo Lee, Dahye Kim, Junhyeong Park, Sujin Park, JiHoon Kang, HyeSook Youn, BuHyun Youn
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma Multiforme (GBM), a malignant primary brain tumor, is treated by surgical resection followed by chemo- and radiotherapy. Nevertheless, most GBM patients show dismal prognosis due to the radioresistance acquisition of GBM cells via metabolic rewiring. Therefore, it is urgently required to discover how metabolic rewiring attributes to GBM radioresistance, and its targeting strategies. To identify GBM radioresistance driver genes, we previously established radioresistance GBM cells (RGCs) via repetitive in vivo selection, followed by mRNA sequencing, and selected candidate genes that are altered in RGCs (fold change&amp;gt;2 or &amp;lt;0.5, p-value&amp;lt;0.05) and also related with GBM patients’ prognosis. Here, we focused on amino acid transmembrane transporter (Gene Ontology: 0003333) and found that SLC25A22 was the most increased in RGCs. SLC25A22 exhibits uni-directional properties, exporting glutamate to cytosol, resulting in cytosolic glutamate accumulation in RGCs. Using 13C glutamine isotope tracing analysis following mitochondrial fractionation, we quantified the mitochondrial metabolic flux of glutamine. Despite decreased 13C glutamate efflux from RGCs mitochondria after genetic inhibition of SLC25A22, glutamine metabolites (a-ketoglutarate, succinate, malate, fumarate) remained constant. Cytosolic glutamate, as a substrate, is incorporated into various biosynthetic pathways, especially glutathione (GSH) and proline synthesis pathways in radioresistant GBM cells. GSH protects GBM cells by scavenging radiation-induced reactive oxygen species. Whereas, proline, a rate-limiting substrate for collagen biosynthesis, leads GBM cells to show an invasiveness phenotype via extracellular matrix remodeling. Genetic inhibition of SLC25A22 using short hairpin RNA (shRNA) or microRNA-184 mimic suppresses RGCs radioresistance and aggressiveness. Additionally, intranasal administration of microRNA-184 mimic prolonged the survival (median survival: 26 days after irradiation) of GBM-bearing mice, compared with non-target control (median survival: 16 days after irradiation). Together, our study demonstrates that SLC25A22 upregulation confers GBM radioresistance by inducing cytosolic glutamate-driven biosynthesis and suggests SLC25A22 as a therapeutic target to overcome GBM radioresistance.
DISP-10. RACIAL AND SOCIOECONOMIC DIFFERENCES IN CLINICAL AND ACCESS TO CARE OUTCOMES IN NEUROSURGICAL-ONCOLOGY PATIENTS
Authors: Ashna Prabhu, Travis Perryman, Stuart Harper, Amani Carson, Lindsey Dudley, Alondra Delgadillo, Aidan Gor, Kunal Patel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Large database studies have identified racial and socioeconomic differences in neurosurgical-oncologic outcomes. For clearer insights and understanding, more detailed and prospective evaluation is needed. METHODS We retrospectively analyzed a database of 1475 patients undergoing surgery for CNS tumors over 5 years. Multivariate analysis, specific to various pathologies, was conducted to identify demographic and socioeconomic factors (including age, sex, racial identity, primary language, insurance status, and income estimate) associated with access to care and clinical outcomes. Additionally, prospective patient-centered interviews were conducted on neuro- oncology patients to qualitatively explore reasons for disparities in healthcare. RESULTS Significant associations were found between racial identities (White n=911; Hispanic n=285; Asian n=206; Black n=74) and sex (ANOVA p 0.0043), age (p&amp;lt;0.0001), income estimate (p&amp;lt;0.0001), primary language (p&amp;lt;0.0001), and insurance status (p&amp;lt;0.0001). Among different pathologies, presentation to the ED, rather than outpatient setting, was consistently associated with a non- English primary language (p=0.0312) and Medi-Cal insurance (p=0.0029). Time from imaging diagnosis to neurosurgical consultation was associated with non- English primary language (p=0.0262) and Medi-Cal (p=0.0030). Delay between recommendation for surgery and date of surgery was significant in Black patients (p=0.0112). A non- English primary language was negatively associated with having a gross total resection (p=0.0087). Notably, adjuvant treatments were less likely for those with non-English primary language (p=0.0203), Black race (p=0.0049), and Medi-Cal coverage (p=0.0014). Cox regression analysis identified only age (p&amp;lt;0.0001) as a predictor of poorer overall survival in oncologic cases. Prospective interviews identified cultural, economic (work- related), and healthcare navigation issues as reasons for differences in access to care. CONCLUSIONS Across the spectrum of neurosurgical oncology diagnoses, racial and socioeconomic factors independently associate with access to care but not clinical outcome variables. Further investigation is needed, particularly in patients with non- English primary languages and cultural attitudes towards chemotherapy and radiation therapy.
CTIM-03. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A NON-HEAVILY PRETREATED COHORT
Authors: Lorenzo Argao, Ying Yuan, Kathleen Wall, Tricia Kunst, Claudia Chambers, Elizabeth Vera, Caitlin Huguely, Masashi Watanabe, Ewa Grajkowska, Zied Abdullaev, Alvina Acquaye-Mallory, Kenneth Aldape, Brita Anderson, Lisa Boris, Daniela A Bota, Nicole Briceno, Eric Burton, Anna Choi, P J Cimino, Pierre Giglio, Carlos Kamiya-Matsuoka, Priya U Kumthekar, Jason Levine, Scott M Lindhorst, Byram Ozer, Marissa Panzer, Tina Pillai, Lily Polskin, Drew Pratt, Martha Quezado, Renee Tweneboah-Koduah, Jing Wu, Terri S Armstrong, Mark R Gilbert, Marta Penas-Prado
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND There is a paucity of salvage therapies for patients with rare CNS tumors. Nivolumab (PD-1 inhibitor) is approved for a variety of systemic cancers. We developed a multisite basket Phase II trial to evaluate Nivolumab for patients with recurrence of one of 12 selected rare CNS cancers. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated (≥ 3 prior therapies, vs. ≤ 2; including radiation and/or standard or experimental drugs). Cohort 1 has been completed. We report efficacy results and safety data of a preplanned interim analysis in Cohort 2 (non-heavily pretreated). METHODS In addition to progressive disease, eligibility includes available tumor tissue; age ≥ 18; KPS ≥ 70; no steroids at trial entry. Planned accrual: 75 in each cohort. Nivolumab dose: 240 mg IV every 2 weeks (4 doses), followed by 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when the sample size reached 32 in each cohort. RESULTS As of December 1, 2023, among 27 evaluable patients treated in the non-heavily pretreated cohort, 10 achieved SD ≥ 6 months (DCR 37%; 95% CI 19.4%,57.6%) – 6 high-grade meningiomas; 1 each: myxopapillary ependymoma with lung metastases; solitary fibrous tumor, gliomatosis (astrocytoma IDH mutant WHO grade 2), chordoma. A total of 56 Grade 3-5 AEs occurred; 13 (Grade 3-4) related to nivolumab, including Grade 3 gait disturbance (3); cerebral edema, cognitive disturbance, colitis, headache, hypotension, hypoxia, lymphopenia, pain, and pruritus (1 each), and one Grade 4 cerebral edema. The three Grade 5 AEs were disease-related. CONCLUSION Preliminary efficacy analysis exceeded the “go” boundary (i.e., &amp;gt; 5 responders) in the non-heavily pretreated cohort. Nivolumab showed an acceptable safety profile. Cohort 2 will continue to complete a planned accrual of 75 patients.
CTNI-47. A PHASE 1, RANDOMIZED, PERIOPERATIVE TRIAL OF VORASIDENIB AND IVOSIDENIB IN IDH1-MUTANT DIFFUSE GLIOMA: UPDATED RESULTS
Authors: Ingo Mellinghoff, Patrick Wen, Jennie Taylor, Elizabeth Taylor, Isabel Arrillaga-Romany, Benjamin Ellingson, Paria Mahboub-Johnson, Eric Baron, Islam Hassan, Lori Steelman, Jennifer Clarke, Timothy Cloughesy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Vorasidenib (VOR) and ivosidenib (IVO) showed clinical activity in subjects with isocitrate dehydrogenase mutant (mIDH) gliomas. We evaluated both agents in a phase 1, randomized, open-label perioperative trial (NCT03343197). Pharmacodynamics, pharmacokinetics, and preliminary objective response rate (ORR) data as of 29-April-2020 were previously reported (Mellinghoff et al. Nat Med. 2023). Progression-free survival (PFS) data were not mature at publication time. We report here longer-term follow-up results, including mature PFS. METHODS Participants with grade 2/3 non-enhancing mIDH1 R132H mutant gliomas were randomized to VOR (50 or 10 mg QD), IVO (500 or 250 mg BID), or no treatment (control) for 4 weeks prior to planned surgery, with the option to continue treatment with VOR or IVO post-surgery. Secondary objectives included PFS, ORR assessed by Investigator in the post-surgery period, and safety profile of VOR and IVO. RESULTS Enrollment completed in April-2019. 49 participants were randomized, of which 46 participants (24 oligodendroglioma, 20 astrocytoma, 1 anaplastic oligodendroglioma, 1 anaplastic oligoastrocytoma) received treatment with either VOR (N=24) or IVO (N=22) after surgery. As of 23-September-2023 data cutoff, 11 (46%) and 5 (20%) participants remain on treatment for VOR and IVO, respectively. Median (range) post-operative treatment duration was 44.7 months (0.9–62.7) for VOR, 23.9 months (0–62.7) for IVO. Median (95% CI) PFS was 41.4 months (9.3, NE) for VOR and 38.6 months (18.3, NE) for IVO. ORR per Response Assessment in Neuro-Oncology in low-grade gliomas (RANO-LGG) was 46% for VOR and 27% for IVO. Longer safety follow up will also be presented. CONCLUSION These results provide further evidence of prolonged response using IVO and VOR immediately following surgery in predominantly non-enhancing gliomas. This longer-term follow-up is consistent with Phase 3 INDIGO study results where VOR demonstrated PFS benefit with manageable safety compared with placebo in participants with non-enhancing mIDH gliomas.
CTNI-49. PRECISION MEDICINE CLINICAL TRIAL FOR ADULT PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Jiaying Chen, David A Solomon, Nancy Ann Oberheim Bush, Jennifer A Grabowsky, Cassie Kline, Deanna L Kroetz, Jennie W Taylor, Javier Villanueva-Meyer, Annette M Molinaro, John F de Groot, Nicholas A Butowski, Meghan Tedesco, Jane Rabbitt, Shawn L Hervey-Jumper, Manish Aghi, Mitchel Berger, Edward F Chang, Susan M Chang, Jennifer L Clarke
Journal: Neuro-Oncology (2024)

Abstract Salvage therapies for recurrent glioblastoma (rGBM) have limited efficacy, with median overall survival of 9 months (OS-9) and 6-month progression-free survival (PFS-6) of 10-25%. Given GBM’s molecular heterogeneity, targeting a single molecular abnormality in isolation has consistently failed as a strategy, and precision combination approaches are needed. An initial 15-patient cohort evaluated the feasibility and safety of treating patients with rGBM with an individualized treatment regimen; we added a second 15-patient expansion cohort to improve the power of preliminary efficacy assessment. Patients underwent clinically indicated surgery with genomic profiling using the UCSF500 targeted DNA sequencing panel. Each personalized treatment regimen combined up to 4 FDA-approved drugs, including one cytotoxic agent, as determined by consensus discussion at an individualized molecular tumor board for each patient. Bevacizumab was not utilized in these combinations. The primary objective of the combined 30-patient cohort was efficacy of individualized treatment regimens by OS-9; secondary objectives included safety and additional efficacy measures including PFS-6. Median age was 53 years (range 32-71). Of 30 patients, 18 were male, 23 were enrolled at first recurrence, 29 had IDH-wildtype glioblastoma, 1 had IDH-mutant astrocytoma, and 10 had MGMT promoter methylation. A total of 12 FDA-approved drugs were used in 18 combinations; the most common regimen prescribed was lomustine, afatinib, and abemaciclib (7; 23%,); second-most common was temozolomide, olaparib, and afatinib (4; 13%). OS-9 of the combined cohort was 70% (95% CI 0.55 – 0.89) and PFS-6 was 27% (95% CI 0.15 – 0.48), with median OS of 11.6 months (95% CI 9.7 – 16.7) and median PFS of 3.7 months (95% CI 2.0 – 5.5).While overall efficacy was modest, implementation of individualized treatment regimens in a timely fashion was safe and feasible for patients with surgically resectable rGBM. Analysis is ongoing to assess whether specific genomic profiles or treatment regimens were particularly efficacious.
DDDR-08. PIM1 INHIBITION: A NOVEL THERAPEUTIC APPROACH FOR IDH-MUTANT GLIOMAS
Authors: Qi Li, Olga Kim, Zach Sergi, Peng Lu, Taranjit S Gujral, Jing Wu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND PIM1, a constitutively active serine/threonine kinase has emerged as a relevant target in cancer treatment. Previously, we discovered that IDH-mutant glioma exhibited high kinase activity of PIM1, suggesting an increased sensitivity to PIM1 inhibition. Here we sought to investigate PIM1 inhibition as a therapeutic approach for IDH-mutant gliomas. METHODS Patient-derived IDH-mutant and wildtype glioma cell lines were used to evaluate the impact of PIM1inhibition on cell viability, proliferation, and colony formation. mRNA and protein expression of PIM1 were determined by qRT-PCR, Western-blot, and immunohistochemistry. m6A dot-blot assay was conducted to detect m6A RNA levels in glioma cells. m6A modification status and its location in PIM1 transcript were evaluated by m6A RNA immunoprecipitation array. RNA-binding protein immunoprecipitation was performed using anti-YTHDF1 antibody to identify PIM1 RNA-YTHDF1 protein interactions. RESULTS An upregulation of PIM1 protein is demonstrated in IDH-mutant patient tumor tissues and cells. A pan-PIM inhibitor, AZD1208 significantly suppressed cell viability, cell proliferation, and colony formation in IDH-mutant cells but had a lesser effect in IDH-wildtype cells. Interestingly, a lower mRNA expression of PIM1 is observed, while the protein level is significantly elevated in IDH-mutant cells compared to wildtype cells, suggesting post-transcriptional and translational regulation of PIM1 associated with IDH mutation. Mechanistically, 2-hydroxyglutarate, unique to IDH-mutant gliomas, competitively inhibits α-KG-dependent RNA demethylase FTO. We demonstrated suppressed FTO activity and an increased m6A RNA level in IDH-mutant glioma cells. An enrichment of m6A modification at motif “GG (m6A) CU” located in the 3’UTR is found in the PIM1 transcript. Furthermore, we demonstrated that the m6A modification site is recognized by the m6A reader YTHDF1 to promote protein translation, leading to an elevated PIM1 protein expression. CONCLUSION m6A RNA modification contributes to an enhanced PIM1 activity and thereby a selective sensitivity to PIM1 inhibition in IDH-mutant gliomas.
TMET-06. CLIP3 DOWNREGULATION LEADS TO RADIORESISTANCE IN GLIOBLASTOMA BY PROMOTING GLYCOLYTIC FLUX
Authors: Dahye Kim, Haksoo Lee, Byeongsoo Kim, Soomin Yum, Wooseok Kang, HaYeon Kim, Hyunkoo Kang, HyeSook Youn, BuHyun Youn
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma Multiforme (GBM), a highly aggressive primary brain tumor, often develops resistance to standard treatments such as ionizing radiation (IR), which leads to a median survival of about 15 months. GBM contains glioblastoma stem cells (GSCs), which are crucial in driving therapeutic resistance and recurrence. In our study, we conducted comprehensive analyses to evaluate the molecular changes associated with radioresistance and explored the role of the Spy1-CLIP3 axis as a key regulator of GSC maintenance. Our methods included quantitative PCR and immunoblotting to measure CLIP3 mRNA and protein levels, revealing a significant reduction in expression among radioresistant GBM cells. We found that exposure to IR leads to the upregulation of Spy1 and downregulation of CLIP3, contributing to the development of radioresistance in surviving GBM cells. We used metabolic flux analysis techniques to observe changes in glycolytic activity, which increased in correlation with CLIP3 downregulation. IR induces CLIP3 downregulation, increasing glycolytic activity by facilitating the trafficking of GLUT3, the primary glucose transporter in GSCs. Additionally, colony-forming ability was evaluated using colony-forming assay after treatment of glimepiride with or without IR. Glimepiride didn’t reduce colony-forming ability in non-irradiated cells, but when combined with IR, it significantly reduced colony-forming ability, possibly by disrupting maintenance of GSCs. Importantly, our data reveal that glimepiride, a CLIP3 activator targets GSCs metabolism and enhances radiosensitization while maintaining low toxicity. The radioresistant GBM cells that survive radiotherapy exhibit increased stemness and glycolytic activity mediated by the Spy1-CLIP3 axis. Overall, our findings suggest that clinical trials using glimepiride for GBM patients may potentially improve survival rates, particularly for those experiencing recurrence after radiotherapy. This research highlights the importance of targeting cellular metabolism and stem cell properties in the context of GBM radioresistance and suggests potential avenues for improving the effectiveness of existing treatments.
PATH-61. GENOMIC SIGNATURE IN NON-SMALL CELL LUNG CANCER PATIENTS METASTATIC TO BRAIN-A SINGLE INSTITUTION EXPERIENCE
Authors: Maha Zafar, Nkolika Nwankwo, Aswanth Reddy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Lung cancer is leading cause of cancer-related death in US, with 10-30 % of NSCLC patients developing brain metastasis, which challenges curative treatment and life expectancy. Somatic mutations in KRAS and EGFR genes have been commonly implicated with brain metastasis. Other studies have shown higher amplification frequencies in MYC, YAP1, and MMP13 and deletions in CDKN2A/B. METHODS We conducted a retrospective study on observational cohort of NSCLC patients from January 2022 to July 2023, using IRB-approved data in patients with confirmed brain metastasis (CBS). Beyond demographic information, data on genomic signatures was obtained from maximum parallel/next-generation sequencing on tumor biopsy samples. Comparative analysis was conducted to predict commonalities in brain metastasis gene signatures. RESULTS The study involved 143 newly diagnosed lung cancer patients, with 29 having CBS. Genomic data was available in 24 patients. Most common abnormality was noted in TP53 gene in about 47% of patients, followed by LRP1B (12%). Mutations in KRAS, EGFR, NF1, MET, SMARCA4, KEAP1, and STK11 genes were seen in two patients each. Interestingly, 3 of 4 patients with LRP1B had brain metastasis. Actionable mutations/rearrangements were significantly lower compared to general prevalence of these mutations (KRAS gene 8% and EGFR gene 5%). CONCLUSIONS Lung cancer with brain metastasis has an abysmal prognosis due to poor CNS penetration of chemotherapeutic agents. Surgical resection and RT remain cornerstones of treatment, but certain TKI has shown some potential. Our study uncovered a notably higher prevalence of TP53 mutation among patients with brain metastasis. While patient cohort was small, those harboring an LRP1B mutation exhibited significantly higher incidence of brain metastasis. Contrary to prevalent epidemiological data, our patient population demonstrated a lower frequency of targetable mutations (specifically in EGFR and KRAS genes). We hypothesize that this observation is due to a markedly higher smoking prevalence in our region.