bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDDR-13. ST-401, A BRAIN PENETRATING MICROTUBULE TARGETING AGENT THAT KILLS GLIOBLASTOMA IN INTERPHASE AND BY DISRUPTING MITOCHONDRIA FUNCTION
Authors: Khan Kainat , Sarroza Dennis , Vicente Juan , Wordeman Linda , Sancak Yasemin , Stella Nephi 
Published: November 2023

Abstract
The development of small molecular entities that can effectively penetrate the blood-brain barrier and kill glioblastoma (GBM) is crucial in Neuro-Oncology. ST-401, a unique microtubule depolymerizer, has shown remarkable potential as a therapeutic agent for GBM in PD-GBM isolates (nanomolar potencies) and in vivo preclinical GBM models (potencies DNA-damaging agents). This study aims to investigate the novel mechanism of action of ST-401 and its impact on GBM cell death. We recently showed that increasing concentrations of ST-401 disrupts mitochondrial function, leading to cell death initially in interphase and then in mitosis. Through single-cell RNA sequencing analysis, significant changes in mRNA related to mitochondrial functions were observed, including ribosomal proteins and OXPHOS genes. The study focuses on the role of mitochondria in GBM tumorigenesis and explores how ST-401 affects mitochondrial OXPHOS function. We identified three GBM cell lines (U251, SNB-19, and SF-539) with increasing vulnerability to ST-401, respectively, as measured by using WST-1, an index of mitochondria OXPHOS. Further investigation using the Seahorse platform demonstrated that SF-539 cells treated with ST-401 exhibited a loss of spare capacitance and significantly reduced mitochondrial function, including basal and maximal OXPHOS response, as well as ATP production. In conclusion, our results emphasize the existence of specific subtypes of GBM that show vulnerability or resistance to the antitumor effects of ST-401. Identifying these subtypes is crucial for advancing precision Neuro-Oncology and facilitating human trials. Our results also suggest that ST-401's inhibition of microtubule function and induction of cell death in interphase are associated with the loss of mitochondrial respiratory function. Given the limited treatment options for brain tumors and the challenges in delivering drugs across the blood-brain barrier, the development of brain-penetrant drugs like ST-401 holds great promise. Funded by NIH (CA244213 to NS and NS106924 to NS).
DDDR-14. DEVELOPMENT OF A NOVEL CYP17A1-TARGETED INHIBITOR FOR GLIOBLASTOMA
Authors: Chen Hsien-Chung , Hsu Tsung-I 
Published: November 2023

Abstract
Glioblastoma (GBM) is a highly aggressive and invasive brain tumor, resistant to current standard treatments, including temozolomide (TMZ) and radiotherapy. Despite these interventions, GBM's intrinsic drug resistance often renders it incurable, thus highlighting the dire need for novel therapeutic strategies. In this study, we used ultra-high pressure liquid chromatography-mass spectrometry to examine the levels of neurosteroids in tumor specimens from primary and recurrent GBM patients. This led to the discovery of differential expression patterns, most notably in androgen, including dehydroepiandrosterone and testosterone. Our results indicated androgen over-production weakens the GBM's sensitivity to TMZ by inducing post-translational modification of Sp1 protein, which aids in DNA repair. Interestingly, Sp1 activity is further enhanced by histone deacetylase (HDAC) 6, which in turn diminishes the DNA damage caused by TMZ. In addition, proteomic analysis revealed an overexpression of cytochrome (CYP) 17A1, particularly in recurrent GBM, which led us to hypothesize that a drug inhibiting both CYP17A1 and HDAC6 could potentially serve as a viable treatment for TMZ-resistant GBM. To validate this, the drug was tested in vitro on U87MG-R cells and patient-derived Pt#3 TMZ-resistant cells, demonstrating the therapeutic efficacy based on cell viability assays. In vivo testing in the TMZ-resistant GBM orthotopic mouse model also showed promising anti-tumor activity, with treated mice demonstrating increased survival times compared to controls. In conclusion, our findings suggest that this drug targeting both CYP17A1 and HDAC6 presents a potential breakthrough in GBM-targeted therapy, addressing the pervasive issue of TMZ resistance.
DDDR-15. RESISTANCE TO TARGETED ANTI-MITOTICS IN GLIOBLASTOMA IS DRIVEN BY STAT3 ACTIVATION AND THERAPY INDUCED SENESCENCE
Authors: Kenchappa Rajappa , Zarco Natanael , Dovas Athanassios , Argenziano Michael , Haddock Ashley , Canoll Peter , Rosenfeld Steven 
Published: November 2023

Abstract
Tumor cells require the mitotic spindle to drive chromosome separation in metaphase, which has made the spindle a compelling target for development of anti-mitotics. However, most of these spindle inhibitors target microtubules and can thereby be highly neurotoxic. This has motivated development of targeted anti-mitotics that inhibit non-microtubule components of the spindle, including kinesins and mitotic kinases. These drugs are not neurotoxic and prolong survival in tumor patients, but resistance limits their efficacy. We reported (Kenchappa et al., Cell Reports, 2022) that resistance to one of these—ispinesib, a highly specific inhibitor of the mitotic kinesin Kif11—requires two functions of STAT3: activation of transcription in the nucleus and of oxidative phosphorylation in the mitochondria. Inhibiting both functions reverses ispinesib resistance. Furthermore, combining ispinesib with a CNS-permeant STAT3 inhibitor significantly prolongs survival over ispinesib alone in both immunocompetent and PDX GBM models. We now report that resistance to two other targeted anti-mitotics—alisertib (Aurora Kinase inhibitor) and volasertib (Polo Like Kinase inhibitor)—works similarly and can likewise be reversed with STAT3 inhibitors. For all three of these anti-mitotics, resistance goes hand-in-hand with development of therapy-induced senescence (TIS) in approximately half of GBM cells. TIS cells secrete a variety of soluble factors, referred to as the senescence associated secretory phenotype (SASP), which stimulate stemness, angiogenesis, and immunosuppression. We propose that: 1) TIS cells require STAT3 for survival, and that they in turn maintain a drug resistant state by suppressing mitosis in the remaining, non senescent cells through components of the SASP; and 2) by killing TIS cells, STAT3 inhibitors restore anti-mitotic sensitivity in the remaining, non-senescent tumor cells. We propose that this STAT3/TIS model of resistance may also apply to how resistance develops to other GBM therapies, and may guide similar translational approaches to enhancing therapeutic efficacy.
DDDR-20. FOSL1 INDUCES TMZ-CHEMORESISTANCE IN GLIOBLASTOMA VIA REGULATION OF IL-6-STAT3TYR705PATHWAY-MEDIATED STEMNESS
Authors: Sim Jeongmin , Park JeongMan , Kim Yu Jin , Kim Dongkil , Cho Kyunggi , Moon Ju Hyung , Sung Kyoung Su , Lim Jaejoon 
Published: November 2023

Abstract
Glioblastoma (GBM) is the most lethal brain tumors with intensive resistance to drug. Although glioblastoma has been tried to treat with diverse strategies, drug resistance is still concerning. Finding new therapeutic targets to improve conventional drug sensitivity has remained a major challenge. Here, a novel therapeutic target, FOSL1, to conventional drug resistant patients was established, in which FOSL1 knockdown restores the temozolomide (TMZ) sensitivity via regulation of IL-6-induced stemness characteristic in glioblastoma cells. We show that FOSL1, contributing to poor prognosis of GBM patients, is closely linked chemo-resistant molecular signatures. In glioblastoma cells, FOSL1 knockdown is affect to apoptosis, G0/G1 arrest, tumor migration and expression of stemness hallmark. These alterations were induced by FOSL1-mediated IL-6-pSTAT3Tyr705 activation via MGMT independent manner. Finally, we show that vemurafenib, targeting FOSL1 expression, can be potential therapeutics for TMZ resistant glioblastoma. Taken together, our results demonstrate that FOSL1 facilitates TMZ chemoresistance via regulating IL-6-pSTAT3Tyr705-mediated stemness in GBM cells. FOSL1 can represent a novel therapeutic target to overcome GBM chemoresistance.
DDDR-27. CLASS I HDAC INHIBITOR AGAINST TM-MEDIATED NETWORK CONNECTIVITY IN GLIOBLASTOMA
Authors: Weil Sophie , Azorín Daniel Domínguez , Hoffmann Dirk , Horschitz Sandra , Jabali Ammar , Jung Erik , Koch Philipp , Wick Wolfgang , Winkler Frank 
Published: November 2023

Abstract
Tumor microtubes (TMs) are long thin cellular protrusions extended by one glioblastoma cell to connect to another and integrate into a communicating network that contributes to glioblastoma’s high therapy resistance. Understanding the biological functions of tumor cell connectivity and overcoming network resistance has emerged as a new therapeutic opportunity. The combinatorial treatment of an anti-TM compound with a cytotoxic treatment has come to focus after it was shown that non-connected glioblastoma cells are more vulnerable to cytotoxic therapy. Besides the development of therapies against specific proteins in TM function, other drugs have also been repurposed and tested for their anti-TM activity and potential additional benefits with radiotherapy. Among these, we tested histone deacetylase (HDAC) inhibitors regarding their potential to overcome TM mediated connectivity and thereby open vulnerabilities in glioblastoma. To investigate the drugs, we applied our drug testing pipeline in vitro and in vivo. Here, we observed fewer TMs in an in vitro monolayer of glioblastoma monoculture after treatment with a class I HDAC inhibitor as opposed to two other compounds from the HDAC inhibitor group. In a 3D co-culture model with human neuronal organoids, treatment with the most promising class I HDAC inhibitor showed a dose-dependent inhibitory effect on cell proliferation and TMs. We then continued to examine the HDAC inhibitor’s effect in our in vivo two photon microscopy model with radiotherapy as cytotoxic co-treatment. After the implantation and establishment of xenograft glioblastoma under a chronic cranial window in mice, treatment with the HDAC inhibitor was started and a course of radiotherapy was added. After six weeks after treatment start, tumors of the co-treated animals were smaller than in animals that were only irradiated. Further studies will involve the examination of the underlying biological mechanism of the anti-TM effects and continued long-term treatment to further improve overall anti-tumor effectivity.
DDDR-32. EVALUATING THE THERAPEUTIC EFFECTS OF SMALL MOLECULE INHIBITORS OF CDK4/6 AND FAK IN PRECLINICAL MENINGIOMA MODELS
Authors: Ijad Nazanin , Waller Katie , Nayyar Naema , Yamazawa Erika , Summers Elizabeth , Migliarese Christian , Galanis Evanthia , Sarkaria Jann , Vaubel Rachael , Wakimoto Hiroaki , Brastianos Priscilla 
Published: November 2023

Abstract

BACKGROUND
New therapies are needed for meningioma since treatment options are limited once patients have exhausted surgery and radiation. FAK, CDK4/6 and RAF/MEK represent potential targets because of synthetic lethality with NF2, loss of CDKN2A, and activation of MAPK signaling pathway in meningioma, respectively. The objective of this study was to evaluate the efficacy of targeting FAK, CDK4/6 and RAF/MEK as monotherapies and combination therapies in traditional and patient-derived cell lines and xenografts.

METHODS
In vitro, cell viability and proliferation assays were used to test abemaciclib (CDK4/6 inhibitor), defactinib (FAK inhibitor) and VS-6766 (RAF/MEK inhibitor) as monotherapy and in combination. To better recapitulate the meningioma microenvironment, targeted agents were evaluated with Matrigel, an artificial extracellular matrix. The efficacy of VS-4718 (in vivo formulation of defactinib) and abemaciclib were evaluated in a subcutaneous IOMM-lee meningioma model (having CDKN2A loss) in nude mice. Furthermore, we are establishing cell cultures and patient-derived cell and xenograft (PDX) models using freshly-resected tissue from patients with recurrent or high-grade (WHO grade 2-3) meningiomas.

RESULTS
In vitro evaluation identified the combination of defactinib with abemaciclib resulted in a synergistic decrease in cell viability relative to each monotherapy alone, while the combination of defactinib+VS-6766 was not beneficial. The presence of Matrigel enhanced the sensitivity of all three agents. In vivo, we observed improved survival in mice treated with abemaciclib vs control (45 days vs 26 days; p=0.03), as well as combination of VS-4718 + abemaciclib vs control (44 days vs 26 days; p=0.04, Gehan-Breslow-Wilcoxon test). We did not observe survival extension with VS-4718 monotherapy. Lastly, we successfully established an orthotopic meningioma PDX using a WHO Grade 3 tumor for evaluation of novel therapies in meningioma.

CONCLUSION
Abemaciclib showed promising efficacy in preclinical meningioma xenografts with CDKN2A loss. Studies to evaluate these therapies in other orthotopic models are underway.
EOLP-02. EFFECT OF HEALTH DISPARITIES ON END OF LIFE CARE IN GLIOBLASTOMA, IDH WILDTYPE (GBM) PATIENTS
Authors: Helfer Cassandra , Ludmir Ethan , Farinholt Paige , Rao Ganesh , Patel Akash , Jalali Ali , Mandel Jacob 
Published: November 2023

Abstract
GBM is the most common malignant brain tumor in adults. Given the highly aggressive course and rapid neurologic decline, end of life care is critical. Proactive referral to hospice care is associated with improved quality of life and is recommended under current oncology guidelines. Utilization of these services is limited, with hospice referral rates ranging from 60-75%. The role of healthcare disparities upon quality of end of life care remains unclear. The goal of this study was to investigate the influence of healthcare disparities upon hospice service utilization by comparing patients at Ben Taub (BT), a Houston public safety net hospital, to Baylor St. Luke’s (BSL), a private academic institution. 50 patients (16 BT, 34 BSL) diagnosed with GBM, IDH wildtype, since 2016 were analyzed via retrospective chart review. Patient demographics and insurance status varied, with BT patients more likely to be Hispanic or African American (BT 94%, BSL 29%) and to be uninsured or insured via the county financial aid program (BT 88%, BSL 6%). Hospice referral rates were overall consistent with prior studies (BT 75%, BSL 68%). BT patients were referred to hospice later (BT 3.8, BSL 5.5 weeks mean survival after referral, p=0.118) and were more likely to be referred while in an inpatient setting (BT 75%, BSL 36%, p=0.07). Additionally, BT patients were more likely to be admitted to the hospital in the month prior to death (BT 44%, BSL 33%, p=0.537) and to die in an inpatient setting (BT 19%, BSL 3%, p=0.096). These findings call attention to the impact of healthcare disparities upon utilization of end of life services. Further research is needed to investigate factors contributing to these discrepancies and implement tools to improve quality of life in all patients with late-stage GBM regardless of race, socioeconomic, or insurance status.
EOLP-04. EXTRA-NEURAL DISSEMINATION OF MYC-ACTIVATED INFANT MEDULLOBLASTOMA DESPITE MULTIMODAL THERAPY
Authors: Horbaczewski Alysia , Jacobsen Chad , Kelly Amy , Pearsal Katherine , Ladra Matthew , Kilburn Lindsay , Gass David 
Published: November 2023

Abstract
Extra neural metastases of infant medulloblastoma portend poor prognosis. Previous reports were in patients receiving treatment with radiation alone or patients with ventriculoperitoneal shunt (VPS). Recently with multimodal therapy, reports of extra-neural medulloblastoma are rarely reported. We report two patients with stage M3 MYC-Activated Infant Medulloblastoma who received aggressive therapy yet developed extra-neural relapses. The first case was a 2-year-old male who underwent gross total resection, which was complicated by hydrocephalus requiring VPS placement. He completed treatment as per ACNS0334 and achieved a near-complete response. Next, he received four cycles of five drug anti-angiogenic therapy followed by 2 cycles of expanded access therapy with I-3F8 antibody. He progressed both in brain and spinal cord, then received palliative craniospinal irradiation with boost. Two months following radiation, he died of disease with significant pancytopenia and hypoechoic nodules throughout the liver, suggestive of disseminated disease. Our second patient is a five-year-old girl, who was diagnosed at age two. She achieved a CR after treatment as per ACNS0334. She then enrolled on a clinical trial with Difluoromethylornithine (DFMO) for three months. On initial disease evaluation, she had progression in brain and spine. She underwent palliative radiation with craniospinal irradiation and boost with concurrent Indoximod on phase 2 clinical trial. Following radiation, she received compassionate use indoximod and temadar for 24 months and remained in CR. Three months after stopping therapy, she progressed to left orbit, pelvis and ribs. She is currently receiving palliative care. MYC-activated medulloblastoma has a very poor outcome and requires multimodal including radiation to achieve remission. Despite aggressive therapy, disease is highly evasive and can spread extracranially to multiple areas including bones, bone marrow, liver, and abdomen. Novel therapies and more exhaustive surveillance regiments need to be developed to limit extracranial dissemination and achieve more durable remissions.
EPID-02. HISTORY OF ALLERGY OR ATOPY DECREASES RISK OF BRAIN METASTASIS IN LUNG CANCER AND MELANOMA
Authors: Neff Corey , Price Mackenzie , Liu Zhen , Cioffi Gino , Barnholtz-Sloan Jill , Walsh Kyle , Fecci Peter , Ostrom Quinn 
Published: November 2023

Abstract
Both allergy/atopy and autoimmune disease (AD) are associated with decreased prevalence of glioma. We leveraged cancer registry data combined with Medicare claims to investigate the effect of prior atopy/AD on incidence, and overall survival, of brain metastasis (BrM) in lung cancer (LC) and melanoma. Surveillance, Epidemiology and End. RESULTS: data linked to Medicare claims were obtained, containing cases of melanoma and LC diagnosed from 2008-2017. Patients &lt; 65 years of age, enrolled in Medicare Advantage, with prior/subsequent cancer diagnosis, or missing variables were excluded. History of allergy/atopy/ or AD (≥6 months prior to primary cancer diagnosis) and BrM status were identified by ICD-9/ICD-10 codes and SEER variables. Treatment pattern was determined using ICD-9/ICD-10 and HCPCS/CPT codes. Time to BrM and overall survival among individuals diagnosed with BrM were estimated via Cox proportional hazards regression adjusted for age, sex, race/ethnicity, stage at diagnosis, treatment, and Charlson comorbidity score. Of the 154,203 and 66,593 cases of LC and melanoma, 18.6% and 2.5% developed BrM at any point, respectively. Among LC with BrM, 27% and 16% had atopy and/or AD (compared to 33% and 20% in LC without BrM), while there were 26% and 16% of cases with atopy and/or AD among melanoma with BrM (compared to 33% and 18% in melanoma without BrM). History of atopy was associated with decreased hazard of BrM in melanoma and LC (HR=0.73, p-value&lt; 0.001 and HR=0.90, p=0.024, respectively). Among those with a BrM, both history of atopy and AD were associated with improved survival in LC (HR=0.90, p&lt; 0.001 and HR=0.95, p&lt; 0.001) but not melanoma. History of AD is associated with a moderate survival benefit in LC with BrM, while history of allergy/atopy decreased incidence of BrM in LC and melanoma. Further research is necessary to identify potential causes of this association.
EPID-19. THE INFLUENCE OF FACILITY TYPE ON INTRACRANIAL MENINGIOMA TREATMENT AND OUTCOMES: PREDICTING OVERALL SURVIVAL USING THE NATIONAL CANCER DATABASE
Authors: Brown Nolan , Chakravarti Sachiv , Gendreau Julian 
Published: November 2023

Abstract
There is a growing body of evidence demonstrating improved outcomes for patients with CNS neoplasms treated at academic centers (ACs) versus non-academic centers (non-ACs). This represents a potential healthcare disparity within neurosurgery. Herein, we investigate the relationship between facility type and surgical outcomes in meningioma patients. METHODS: The National Cancer Database was queried for adult patients diagnosed with intracranial meningioma requiring intervention between 2004 and 2019. Patients were stratified by facility type and the Mann-Whitney U and Fisher exact tests were used for bivariate analysis of continuous and categorical variables. Multivariable logistic and linear regression were used to assess whether demographic variables predicted treatment at non-ACs. Furthermore, multivariate cox proportion hazard and log-rank tests were used to determine whether facility type was related to overall survival (OS). RESULTS: In total, 314,651 patients diagnosed with meningioma were included; 122,112 (38.8%) patients were treated at an AC and 192,539 patients (61.2%) were treated at a non-AC. On bivariate analysis, patients treated at an AC were more likely to be white (30.7% vs 24.7%, p&lt; 0.001), have an income higher than $63,000 (31.8% vs 29% p&lt; 0.001) and have a larger tumor (43.3±113.6 vs 39.3±106.8, p&lt; 0.001). On multivariate Cox models, the risk of death for patients treated at ACs was 16.7% lower than that of non-AC patients (HR = 0.883, 95% CI 0.858–0.908, p &lt; 0.001). When controlling for demographic and clinical variables, patients treated at ACs were more likely to undergo surgical intervention (OR = 1.059, 95% CI 1.033-1.087, p &lt; 0.001) but less likely to receive radiotherapy (OR = 0.921, 95% CI 0.897-0.947, p &lt; 0.001). CONCLUSIONS: Our results indicate that AC facility type is associated with disparate survival outcomes in treatment of intracranial meningiomas. Namely, patients treated at non-ACs appear to suffer a survival disadvantage.
EPID-22. AN INTEGRATED, MULTI-DATABASE ANALYSIS OF THE SAFETY OF BENIGN MENINGIOMA RESECTION IN OCTOGENARIANS
Authors: Zhu Ping , Ma Jun , Chen Clark 
Published: November 2023

Abstract

OBJECT
Given that multiple co-morbidities are present in up to 80% of octogenarians, resection of benign tumors, such as meningiomas, is a challenging proposition, especially in the context of frailty naturally associated with aging. Here, we characterized the patterns of clinical practice, morbidity, and mortality associated with benign meningioma resection for octogenarian using the Surveillance, Epidemiology and End

RESULTS
(SEER), SEER-Medicare (SEER-M), National Cancer Database (NCDB), and National Readmission Database (NRD).

METHODS
Logistic regression, propensity-score matching (PSM)-method (covariates balanced using PSM: socio-demographics, facility features, and comorbidities), and accelerated failure time (AFT) models.

RESULTS
In SEER, the adjusted odds ratios of recommendation for surgery were 0.59 (95%CI=0.53-0.66, p&lt; 0.001) and 0.17 (95%CI=0.15-0.21, p&lt; 0.001) for benign meningioma patients age 60-79 and &gt; 80, relative to patients age 40-59. Expectedly, the hazard of death increased with advancing aging strata in patients who underwent meningioma resection. However, in independent analyses of NCDB and SEER-M, likelihood of death after benign meningioma resection was not significantly elevated in patients age &gt; 80 relative to age- and PSM-matched patient cohorts. In the NRD, age &gt; 80 was associated with increased odds of 90-day medical readmission after meningioma resection (OR: 1.63, 95%CI=1.33-1.99) but not 90-day neurologic readmission (OR: 1.02, 95%CI:0.76-1.37) relative to age 40-59.

CONCLUSION
We found no increased risk for patients age &gt; 80 who were selected for and underwent resection in terms of mortality and 90-day neurologic readmission risk. However, the octogenarians have a higher risk of 90-day medical readmission. These findings suggest that neurosurgeons, in general, exert sound judgment in the selection of elderly patients for benign meningioma resections.