bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDDR-11. INHIBITING OXIDATIVE PHOSPHORYLATION AND HYPOXIA WITH ATOVAQUONE – A STRATEGY TO RADIOSENSITIZE DIFFUSE MIDLINE GLIOMA
Authors: Mudassar Faiqa , Ing Prunella , Nguyen Sandy , Chang Cecilia , Cook Kristina M , Warnken Zachary N , O’Neill Geraldine , Shen Han , Hau Eric 
Published: November 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.
DDDR-21. MPT0G521 AS A DUAL INHIBITOR OF LSD1 AND HDAC: A POTENTIAL THERAPEUTIC AGENT AGAINST PARENTAL AND TEMOZOLOMIDE-RESISTANT GLIOBLASTOMA MULTIFORME
Authors: Lo Wei-Lun , Chuang Jian-Yin , Wu Ming-Shao 
Published: November 2024

Abstract

INTRODUCTION
Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and poor prognosis. Resistance to temozolomide (TMZ), the standard chemotherapy for GBM, further complicates treatment. This study investigates the effects of MPT0G521, a dual inhibitor of LSD1 and HDAC, on both parental and TMZ-resistant GBM cells to determine its potential as a therapeutic agent.

MATERIALS AND METHODS
TMZ and MPT0G521 were introduced in our study. Human GBM cell lines A172 and patient-derived primary GBM cells Pt#3, along with their TMZ-resistant counterparts, were cultured under specified conditions. Assays conducted include cell proliferation (MTT), colony formation, cell cycle analysis via flow cytometry, and western blot analysis for protein expression. Statistical significance was evaluated using ANOVA.

RESULTS
MPT0G521 exhibited significant anti-proliferative activity and toxicity against both parental and TMZ-resistant GBM cells in a dose- and time-dependent manner. Treatment with MPT0G521 led to reduced cell viability and colony formation. Cell cycle analysis revealed G2M phase arrest and increased subG1 phase, indicating cell cycle disruption and apoptosis. Western blot analysis showed upregulation of histone H3 methylation and acetylation, confirming the dual inhibitory action of MPT0G521 on LSD1 and HDAC. Additionally, MPT0G521 modulated markers of cell cycle and apoptosis, including increased levels of cleaved caspase-3 and PARP.

CONCLUSION
MPT0G521 demonstrates potential as an effective therapeutic agent against GBM by inhibiting cell proliferation, inducing cell cycle arrest, and promoting apoptosis in both parental and TMZ-resistant cells. These findings support further investigation of MPT0G521 as a promising treatment for GBM, particularly in cases resistant to standard chemotherapy.
DDDR-25. IBUDILAST AND ANTI-PD-L1 COMBINATION TREATMENT SIGNIFICANTLY IMPROVES SURVIVAL IN A SEX-DEPENDENT MANNER IN A MURINE MODEL OF GLIOBLASTOMA
Authors: Jarmula Jakub , Lee Juyeun , Kurlich Andrew , Matsuda Kazuko , Bayik Defne , Lathia Justin 
Published: November 2024

Abstract

INTRODUCTION
Glioblastoma (GBM) is the most common primary malignant brain tumor, and there remains a significant need for new treatments. Previous trials studying immune checkpoint inhibitors (ICI) as single agents have been negative. Ibudilast is a brain penetrant inhibitor of the macrophage migration inhibitory factor (MIF)-CD74 interaction that sensitizes GBM to temozolomide in vitro and alters myeloid-derived suppressor cells in vitro and in vivo. The purpose of this study was to investigate whether ibudilast increases ICI efficacy in a murine model of GBM.

METHODS
6-week-old male and female C57BL/6 mice were implanted with SB28 cells intracranially. One week after implantation, each group was randomized to receive intraperitoneal treatment with either: ibudilast (50 mg/kg), anti-PD-L1 (1mg/kg), combination, or vehicle control. Mice were euthanized at neurological endpoint. Survival was modeled with Cox proportional hazards regression.

RESULTS
Among females, there was a significant difference in survival among treatment groups (p=0.0002). Specifically, combination treatment led to significantly longer survival compared to ibudilast (p=0.004) and control (p=0.03), but not anti-PD-L1 (p=0.12). Among males, there was no significant difference in survival among groups (p=0.40). Males had significantly shorter median survival compared to females (overall: 18 versus 22 days, combination treatment: 20 days versus 32 days, anti-PD-L1: 14 versus 22 days, ibudilast: 17 versus 17 days, control: 18 versus 22 days, p=0.02).

CONCLUSIONS
Ibudilast with anti-PD-L1 is a promising combination treatment against GBM. Future research is needed to identify the mechanisms underlying this treatment regimen and its sex-dependent effect. These results may inform the development of a combination new clinical trial, as ibudilast is currently being evaluated in the newly-diagnosed and recurrent GBM setting with temozolomide.
DDDR-27. BMP SIGNALING MODULATES APOPTOTIC AND NON-APOPTOTIC CELL DEATH IN GLIOBLASTOMA
Authors: Lee Weaverly Colleen , Salinas Jennifer , Nathanson David , Dixon Scott 
Published: November 2024

Abstract
Recurrence occurs in approximately 90% of glioblastoma (GBM) patients, in part due to the tumors becoming resistant to cell death in response to existing therapies. These therapies often trigger apoptosis; however, apoptosis is only one of several different forms of cell death. We hypothesize that activating non-canonical death mechanisms could provide a back door to killing treatment-resistant GBM cells. To test this hypothesis, we first developed a new imaging-based high-throughput method to directly quantify cell death in 3D models. Using this method, we find patient-derived GBM spheroids to be resistant to the induction of cell death in response to various standard-of-care and experimental therapeutic compounds. To further investigate mechanisms underlying this resistance, we screened a panel of extracellular protein ligands for the modulation of cell death response. We find that bone morphogenic protein (BMP) signaling increases resistance to several apoptosis-inducing compounds, including temozolomide and tyrosine kinase inhibitors. Intriguingly, BMP signaling simultaneously enhanced sensitivity to a novel non-apoptotic cell death pathway triggered by the small molecule CIL56. Efforts are ongoing to further understand how BMP signaling governs apoptotic and non-apoptotic cell death mechanisms. Nevertheless, our results suggest a novel approach to treating GBM, centered upon the modulation of BMP signaling combined with the use of agents that induce non-apoptotic cell death.
DDDR-30. ENHANCED CHEMO AND RADIO-SENSITIZATION OF GLIOMAS BY HSP90 INHIBITION WITH JIN-001, A NOVEL BLOOD-BRAIN BARRIER PENETRANT HSP90 INHIBITOR
Authors: Xu Jihong , Sugur Harsha S , Sharma Pratibha , Huo Longfei , Dasgupta Pushan , Chen Xiaohua , Seah Ethan , Sampath Deepa , Puduvalli Vinay K 
Published: November 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.
DDDR-41. A GENOME-WIDE CRISPR/CAS9 SCREEN IN GLIOBLASTOMA STEM CELLS UNVEILS SYNTHETIC LETHAL INTERACTIONS AND RESISTANCE MECHANISMS OF JIN001, A BLOOD-BRAIN BARRIER-PENETRANT HSP90 INHIBITOR
Authors: Chen Xiaohua , Anvar Nazanin Esmaeili , Colic Medina , Xu Jihong , Liang Jiyong , Sharma Pratibha , Huo Longfei , Sugur Harsha S , Hart Traver , Puduvalli Vinay K 
Published: November 2024

Abstract
Glioblastomas (GBMs) are aggressive brain tumors characterized by extensive genetic heterogeneity and therapeutic resistance. Heat shock protein 90 (Hsp90) is a molecular chaperone that stabilizes and facilitates the proper folding of numerous proteins, including oncogenic drivers and is overexpressed in cancers. Hsp90 inhibitors can disrupt multiple oncogenic signaling pathways by degrading various client proteins essential for tumor growth and survival, making them attractive therapeutic candidates for GBMs. We have previously reported on the efficacy of Hsp90 inhibitors against gliomas. However, cancer cells develop resistance to Hsp90 inhibitors by upregulating compensatory chaperones (e.g., Hsp70), mutating client proteins, or activating alternative survival pathways, reducing the long-term efficacy of these agents. Combination approaches overcoming such resistance mechanisms are needed. JIN001, a novel Hsp90 inhibitor, demonstrates superior blood-brain barrier (BBB) penetration, and high potential for clinical translation. we performed a genome-wide CRISPR/Cas9 knockout screen using the Toronto Knockout Library v3 (TKOv3) with screen selection pressure from JIN001 in GBM stem cells (GSC272) to identify synthetic lethal interactions and resistance mechanisms associated with JIN001 treatment. Experiments were performed in triplicate with two time points, T22 and T37. Quality control analysis of the NGS data indicated excellent quality and consistency between different replicates. DrugZ analysis revealed a set of sensitive and resistant genes, informing potential combination therapies and further elucidating JIN001’s mechanism of action. Validation studies for the top synthetic lethal targets are underway to confirm the identified interactions and will be presented. This CRISPR-Cas9 screen offers valuable insights into JIN001’s therapeutic potential, reveals new combination strategies to overcome resistance to Hsp90 inhibitors and for use of these agents in other cancers, and paves the way for the development of more effective GBM combination treatment strategies.
EPID-05. THE INCREASED RISK OF MENINGIOMA AMONG INDIVIDUALS WHO ARE NON-HISPANIC BLACK IS MAGNIFIED AMONG MALES AND AMONG THOSE DIAGNOSED WITH GRADE 2-3 TUMORS
Authors: Walsh Kyle , Price Mackenzie , Raleigh David R , Kruchko Carol , Barnholtz-Sloan Jill S , Ostrom Quinn T 
Published: November 2024

Abstract

BACKGROUND
Demographic factors associated with elevated meningioma incidence include older age, female sex, and Black race. There are limited data exploring how meningioma risk in Black persons varies across the lifespan, interacts with sex, and differs by tumor grade.

METHODS
The Central Brain Tumor Registry of the United States (CBTRUS) is a population-based registry combining data from the CDC’s National Program of Cancer Registries and NCI’s Surveillance, Epidemiology and End Results Program, covering the entire U.S. population. Meningioma diagnoses from CBTRUS (2004-2019) were used to calculate incidence rate ratios (IRRs) for non-Hispanic Black individuals (NHB) as compared to non-Hispanic White individuals (NHW) across 10-year age intervals, and stratified by sex and WHO tumor grade (grade 1 versus grades 2/3, combined).

RESULTS
From 2004-2019, a total of 53,890 NHB individuals and 322,373 NHW individuals were diagnosed with a primary meningioma. The NHB to NHW IRR was elevated, beginning in the third decade of life (IRR=1.19; 95%CI: 1.11-1.28), peaking in the seventh decade (IRR=1.29; 95%CI: 1.26-1.31), and persisting throughout the lifespan. The IRR peaked in the seventh decade of life across strata of tumor grade, but, within this age group, NHB race/ethnicity was associated with substantially higher risk of grade 2/3 tumors (IRR=1.59; 95%CI: 1.48-1.70) than grade 1 tumors (IRR=1.27; 95%CI: 1.24-1.29). Meningioma risk was elevated in NHB females compared to NHW females (IRR=1.16; 95%CI: 1.15-1.18) and among NHB males compared to NHW males (IRR=1.22; 95%CI: 1.19-1.25), revealing synergistic interaction between NHB race/ethnicity and male sex (PInteraction=0.001).

CONCLUSIONS
This study identifies an elevated risk of meningioma in NHB relative to NHW, beginning shortly after puberty and continuing across the lifespan. NHB race/ethnicity conferred higher risk of meningioma among men than among women, and higher risk of developing WHO grade 2/3 than grade 1 tumors. These results highlight meningioma as a major potential source of racial disparities in neuro-oncology.
EPID-06. ACROMEGALY AND THE RISK OF CANCER: A NATIONWIDE POPULATION-BASED LONGITUDINAL COHORT STUDY IN KOREARUNNING TITLE: ACROMEGALY AND THE RISK OF CANCER
Authors: Kim Yeo Song , Yun Jae-Seung , Kim Hyunho , Jeun Sin Soo , Lee Jung Eun , Kim Bongseong , Ko Seung-Hyun , Ahn Yu-Bae , Han Kyungdo , Yang Seung-Ho 
Published: November 2024

Abstract

INTRODUCTION
Previous reports on cancer risk in patients with acromegaly have inconsistent findings. Using a nationwide population-based cohort, we primarily investigated whether overall and site-specific cancer risk are increased in patients with acromegaly.

MATERIALS AND METHODS
The study included 2,382 acromegaly patients and 11,910 controls aged above 20, from 2006 to 2016. Cox hazards regression analysis was used, adjusting for baseline covariates.

RESULTS
Among the 2,382 patients with acromegaly, overall cancer occurred in 244 (10.2%), while the 11,910 controls had 707 (5.9%) occurrences (HR: 1.90 (95% CI: 1.63-2.22). Acromegaly patients had the highest relative risk for brain cancers with an HR of 6.80 (95% CI: 2.83-16.38) and significantly higher risk of lymphoma, thyroid cancer, multiple myeloma, pancreatic cancer, and colorectal cancer. Even after five years from the diagnosis of acromegaly, patients with acromegaly had a significantly higher incidence of cancer. Risk of cancer in general and stomach cancer in specific was significantly higher in patients under the age of 50 compared to older patients. There was no sex difference.

CONCLUSIONS
This nationwide longitudinal cohort study shows an increased risk of cancer in acromegaly patients. Active and long-term cancer screening is necessary to improve the prognosis in patients with acromegaly.
EPID-11. RATES OF CRANIOTOMIES FOR BRAIN METASTASES AFTER INTRODUCTION OF IMMUNOTHERAPY
Authors: Pelcher Isabelle , Begley Sabrina , Sreenivasan Sanjeev , Ziemba Yonah , Travaglia Isabella , Ratra Avi , Schulder Michael 
Published: November 2024

Abstract
Immunotherapy has revolutionized the treatment paradigm for patients with brain metastases and has been found to prolong overall survival. We sought to determine whether rates of craniotomies for the treatment of brain metastases has decreased since the introduction of immunotherapy into routine treatment regimens. Pathology records were queried at our institution from 2011-2022 to include all patients surgically treated for brain metastases. A total of 885 samples from 789 unique patients were analyzed. National data was queried from the NSQIP database from 2011-2022 to include patients surgically treated for brain metastases with a total of 14,494 cases. A Craniotomy for Metastases Index (CMI) was generated to reflect the total number of craniotomies performed over time. The most common institutional primary cancers were lung (46.1%), breast (17.4%), and gastrointestinal (10.1%), with the most common lung cancers being adenocarcinoma (57.11%) and non-small cell carcinoma (11.52%). The institutional CMI demonstrated a non-significant decrease in the number of craniotomies (R2=0.0545, p=0.46) across all time ranges, as well as no significant change in CMI when comparing rates from 2011-2016 and 2017-2022 (p=0.37). The national CMI demonstrated a significantly positive slope of 0.03 (R2=0.544, p=0.006), as well as a significant increase (p=0.005) in craniotomies when comparing rates from 2011-2016 and 2017-2022. Despite the growing use and efficacy of immunotherapy in the treatment of brain metastases and increasing overall survival, the rates of craniotomies had no change institutionally and increased nationally. Several reasons for these findings may include: longer overall survival of patients with systemic cancer can lead to the development of metastatic brain tumors later in their disease course, improvement of surgical techniques making resection safer, and variable response of patients to stereotactic radiosurgery (SRS). Further studies should be conducted to determine the effect of SRS on these findings. Surgical resection remains the mainstay in the treatment of brain metastases.
EPID-19. INTERACTION BETWEEN GERMLINE AND SOMATIC GENETICS TO ELUCIDATE RISK OF ADULT DIFFUSE GLIOMA
Authors: Eckel-Passow Jeanette , Kosel Matthew , Decker Paul , Kollmeyer Thomas , Drucker Kristen , Molinaro Annette , Francis Stephen , Wiencke John , Wrensch Margaret , Lachance Daniel , Tobin W Oliver , Jenkins Robert 
Published: November 2024

Abstract
Acquired tumor alterations are part of the WHO diagnosis of glioma. However, germline predisposition to these alterations is unknown. GWAS in European and Asian populations identified germline variants in 30 regions, many in or near genes that also acquire alterations, suggesting that interactions between inherited and acquired genetics are involved in glioma development. To evaluate such interactions, we used 3686 glioma cases and 1889 controls. A case-control design and multinomial logistic regression were used to identify germline variants associated with development of TERT-promoter mutant gliomas, generating two interesting observations. First, TERT germline variants were associated with predisposition to IDHwt glioma that have a TERT promoter mutation, but not with IDH-mutant codeleted gliomas that have a TERT promoter mutation. Second, two novel regions were observed in this more homogeneous subgroup of TERT mutated tumors: variants in TXNDC11 (OR=2.66, p=5.7x10-8) and RUVBL2 (OR=3.1, p=5.8x10-8). High tumor expression of TXNDC11 is associated with poor prognosis in glioma and RUVBL2 interacts with TERT to affect telomerase activity. Similar analyses are being performed on additional clinically relevant acquired alterations. In parallel, case-case GWAS analyses were performed to evaluate germline variants associated with other tumor alterations. Comparing IDH-mutant versus IDHwt stratified by rs55705857 genotype, the most significant variants were PHLDB1 (p=1.2x10-13) and D2HGDH (p=2.1x10-10), highlighting the importance of these two variants independent of CCDC26 for the development of IDH-mutant glioma. As a parallel approach, we utilized recursive partitioning and regression trees (rpart) to classify IDH mutation status using the 30 known variants. The top four branches of the regression tree included CCDC26, D2HGDH, PHLDB1, and MAML2, as well as two Asian variants (RAB27A, CYP4F12). This highlights the importance of utilizing variants discovered in non-European populations in analyses. Overall, understanding these interactions are necessary to develop therapeutics, stratify clinical trials, and to develop relevant tumor models.