bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDDR-29. MATRIX STIFFNESS INDUCED PHENOTYPE IN BRAIN METASTATIC BREAST CANCER CELLS DETERMINES RESPONSE TO THERAPY
Authors: Yakati Venu , Shevde Lalita A , Rao* Shreyas S 
Published: November 2024

Abstract
Breast cancer is the most prevalent form of cancer, representing 12.5% of all cancer cases diagnosed worldwide. Breast cancer cells can metastasize to distant organs (i.e., brain) and remain dormant for extended periods of time. This aspect makes it very difficult to treat these cells as they exhibit reduced growth as well as resistance to therapy. Despite advances in our understanding of breast cancer metastasis, the specific mechanisms that enable dormant cancer cells to resist therapeutics, particularly in brain metastatic breast cancer (BMBC), remain unclear. Herein, we employed brain tissue mimetic hyaluronic acid (HA) hydrogels of varying stiffness (i.e., ~0.4 kPa vs. ~4.5 kPa) to investigate the response to chemo or targeted therapy in dormant versus proliferative BMBC cells. It was revealed that BMBC cells grown on soft HA hydrogels (~0.4 kPa) displayed a non-proliferative (i.e., dormant) phenotype and exhibited resistance to Paclitaxel (PTX) or Lapatinib (LAP). However, BMBC cells grown on stiff HA hydrogels (~4.5 kPa) displayed a proliferative phenotype and sensitivity to PTX or LAP. Furthermore, we found that resistance to therapy was due to the enhanced expression of the serum/glucocorticoid regulated kinase 1 (SGK1) gene, mediated, in part, via the p38 mitogen-activated protein kinase (MAPK) pathway. Consequently, SGK1 inhibition using a SGK inhibitor in BMBC cells cultured on soft HA hydrogels resulted in a dormant-to-proliferative switch as well as response to PTX or LAP. In sum, our study demonstrated that matrix stiffness plays a major role in the dormancy-associated therapy response, mediated, in part, via the p38/SGK1 pathway.
DDDR-33. TRANSCRIPTOMICS-BASED NOVEL DRUG DISCOVERY IN DIFFUSE MIDLINE GLIOMA
Authors: Kaur Savneet , Leshchiner Dmitry , Watanabe Jun , Uchida Eita , Mineji Kentaro , Chen Bin , Hashizume Rintaro 
Published: November 2024

Abstract
Introduction. Pediatric high-grade gliomas are the most common cause of cancer-related death in children, of which the most malignant and devastating tumors include diffuse midline glioma (DMG). Recent availability of tumor samples and advances in next-generation sequencing enable the profiling of thousands of molecular features in DMG. We employ a system-based approach that uses gene expression as a representation of the molecular state, providing an avenue for therapeutic discovery. Previously, we used this approach to identify repurposed candidates for DMG; however, the final candidate had poor brain penetration, prompting us to discover novel compounds with better brain penetration. To apply it to novel compound discovery, we need the expression profiles of all library compounds, which is impractical for millions of compounds. To overcome this, we have developed a platform, Gene expression profiles Predictor on chemical Structures (GPS), that incorporates machine learning algorithms which leverage existing drug-induced gene expression profiles to predict gene expression based on compound structure. methods. DMG RNA-Seq samples were acquired from St. Jude Children’s Research Hospital and Children’s Brain Tumor Network (CBTN). We developed deep learning autoencoder to search reference normal tissues from Genotype-Tissue Expression (GTEx). A DMG meta-signature was created and fed into GPS to predict drug candidates from the Enamine CNS library, seven of which were experimentally tested in vitro and the most promising one subsequently validated in vivo. Results. Cell proliferation analyzed by MTS assay showed three compounds with IC50&lt; 50 µM in K27M-mutant DMG cell lines (SF8628, DIPG007, SU-DIPG36). Toxicity study showed no adverse effects in the mice treated with 100-200 mg/kg of the most promising compound (IC50 = 1.9 µM in DMG cells). Conclusion. Our novel computational framework leverages deep learning to fill the gap in drug discovery in DMG. Work is underway to determine antitumor activity, brain penetration (via HPLC) and survival benefit in the mice bearing DMG PDX treated with the lead compound.
DDDR-34. A SYSTEMS MEDICINE PLATFORM FOR INDIVIDUALIZED TREATMENT OF GLIOBLASTOMA
Authors: Skaga Erlend , Naderi Pourya , Halldorsson Skarphedinn , Sandberg Cecilie J , Hide Winston , Vik-Mo Einar O 
Published: November 2024

Abstract
Glioblastoma is an aggressive brain cancer characterized by complex intertumoral heterogeneity. Yet, no methods have successfully stratified patients for effective individualized treatments. We aimed to use a systems medicine approach to individualize treatments for patients. From 27 patients undergoing surgery for either a newly diagnosed or a progressive glioblastoma, we collected biopsies and cultured the cells as spheroids. Drug sensitivity testing for &gt;500 drugs from the FDA-approved oncology collection was performed. Drug efficacy was quantified using a modified area under the dose-response curve (Drug Sensitivity Score, DSS), and individualized by normalizing the DSS to the drug response in bone marrow cells from healthy donors (selective DSS, sDSS). All samples were assayed by WES, WGS, and RNA-sequencing. We found that glioblastomas can be stratified into three DSS groups. These were associated with expression of genes both known (e.g. ALDH1A1), and not known (e.g. VRK2) to be linked to drug resistance. By unsupervised clustering of sDSS, we found a robust patient stratification primarily driven by drug sensitivity to four groups of targets: i) EGFR, ii) FGFR/PDGFR/VEGFR, iii) MDM2 and iv) MEK/ERK. We found differentially expressed genes (N = 20-90 genes, varying by group) between the responders and non-responders in each group. We explored differential pathway activity between the responders and non-responders in each group to correlate drug responses to transcriptional networks to inform underlying disease mechanisms. The transcriptional networks further provide a molecular basis for drug predictions for additional treatment prioritizations. We conclude that our platform can stratify glioblastomas into subgroups, inform the underlying biology of drug sensitivity, and prioritize treatments for patients. Clinical utility is currently under evaluation in a formal trial.
DDDR-35. THERAPEUTIC STRATEGIES FOR DIFFUSE MIDLINE GLIOMA: INSIGHTS FROM HIGH-THROUGHPUT COMBINATION DRUG AND RADIATION SENSITIZATION SCREENING
Authors: Faisal Syed M , Yadav Monika , Gibson Garrett R , Klinestiver Adora T , Roy Anuradha , Koschmann Carl , Weir Scott J , Bossmann Stefan H , Yadav Viveka Nand 
Published: November 2024

Abstract
Diffuse midline gliomas (DMGs) are the most aggressive pediatric high-grade gliomas. Over 85% DMGs harboring the H3K27M mutation in histone genes H3F3A (H3.3) and H3C2 (H3.1). H3K27M mutation disrupts epigenetic regulation by inhibiting PRC2, causing loss of H3K27 trimethylation and oncogenic gene expression. Presently, there are no effective therapies for DMG, and 95% of the patients die within 1.5 years of diagnosis. Thus, there is an urgent need to identify novel therapeutic strategies targeting H3K27M oncohistone. To assess the H3K27M mutation’s vulnerability, we used paired isogenic H3K27M-mutated and CRISPR-corrected H3M27K (H3-WT) primary DMG cell lines derived from thalamus (BT-245) and pons (DIPGXIIIP). We performed comprehensive single-agent high-throughput screens (HTS) with 1,520 FDA-approved drugs and further assessed drug combinations of ONC201 with the 86 most promising drugs from the HTS. A third combination experiment evaluated radio-sensitizing potential, where most effective top-six drugs (A-F) were tested in combination with radiation therapy across an expanded panel of patient-derived DMG cell cultures. To test drug efficacy in vivo, we developed a genetically engineered isogenic mouse model (GEMM) of DMGs using intrauterine electroporation (IUE) with DNp53/PDGFRA/H3.3K27M (PPK) and DNp53/PDGFRA/H3.3WT (PPW) genetic alterations. Our initial single-agent HTS screening identified 86 drugs with significantly higher cytotoxicity, specifically against H3K27M-mutated DMG cell lines. Combination HTS of the top six drugs revealed that drug E displayed significantly synergistic cytotoxicity with ONC201. We also evaluated drugs A-E in combination with radiation in both human and mouse H3K27M-mutated DMG cell lines. Drugs D and E showed selective radiosensitivity in both human and mouse H3K27M-mutated DMG cell lines. Preliminary findings also suggested drug D acts as an anti-invasive agent. Our findings identify novel drugs via HTS that enhance ONC201 efficacy and act as radiation sensitizers in DMGs. Future studies will test these compounds with ONC201 and radiation in our in vivo IUE-mediated H3K27M mouse model.
DDDR-45. INVESTIGATING TEMOZOLOMIDE RESISTANCE IN GLIOBLASTOMA USING A CLINICALLY RELEVANT DOSING REGIMEN
Authors: Kumar Harshita , Dhawan Andrew 
Published: November 2024

Abstract
The standard of care of management for glioblastoma, the most common primary malignant brain tumor in adults, involves maximal safe surgical resection followed by adjuvant chemoradiotherapy and six cycles of adjuvant temozolomide (TMZ). Approximately half of all treated patients develop chemoresistance to TMZ. The evolution of chemoresistance to temozolomide in vitro has historically involved continuous exposure to drug, as opposed to clinical dosing schedules, which involve five days of treatment followed by 23 days of recovery. Thus, in this study, we examined the emergence of chemoresistance to TMZ in vitro, using a clinical dosing regimen. Temozolomide dose response to RN1, an MGMT promoter unmethylated, IDH-wildtype, patient-derived glioblastoma cell line, was determined using cell titer glo. Cells were treated with TMZ for five days, followed by 23 days of recovery, in cycles. In each subsequent cycle, the dose of TMZ used was adjusted to previous cycle’s IC50, the concentration at which 50% of cell growth is inhibited. This protocol was repeated over three rounds. Cells treated with TMZ, as compared to the DMSO-treated control population, gradually acquired chemoresistance with a continuous increase in IC50. Our protocol therefore highlights how a clinically relevant dosing regimen may help capture the trajectory by which chemoresistance emerges, also allowing for the exploration of the molecular mechanisms underlying this phenomenon.
DDDR-46. TARGETING TRANSGLUTAMINASE 2 (TGM2) ENHANCES SENSITIVITY OF GLIOBLASTOMA CELL LINES TO RADIOTHERAPY AND TEMOZOLOMIDE
Authors: Lan Katherine , Jamali Fatemeh , April Vincent , Sabri Siham , Abdulkarim Bassam 
Published: November 2024

Abstract
Glioblastoma (GBM), the most aggressive and common primary brain tumor in adults, remains highly resistant to conventional therapeutics, including radiation therapy (RT), largely due to its molecular heterogeneity. Few biomarkers have been identified that successfully guide or predict treatment response. Transglutaminase 2 (TGM2), a ubiquitous multifunctional enzyme involved in numerous signal transduction pathways related to tumorigenesis, has recently been suggested to drive chemoradioresistance. Here, we investigate the effects of disrupting TGM2 by pharmacologic inhibition or CRISPR knockout (TGM2-KO) on GBM cell’s response to RT and Temozolomide (TMZ) chemotherapy. Using western blotting and clonogenic assays, we show that the allosteric TGM2 inhibitor, GK921, stabilizes p53 expression and impedes reproductive ability at IC50 and IC25 concentrations. TGM2-KO and GK921 (at IC10 and lower) sensitized GBM cell lines to RT with almost equivalent efficacy, resulting in a 2- to 3-fold suppression of clonal expansion compared to scramble controls or irradiation alone. We also demonstrate increased sensitivity of GBM cell lines to TMZ upon inhibition of TGM2 by GK921. Our findings indicate that the use of TGM2 inhibitors, such as GK921, could enhance the efficacy of RT and the potency of TMZ, positioning TGM2 as a promising therapeutic target that may improve standard treatment of GBM cells expressing TGM2.
EOLP-02. END-OF-LIFE CHALLENGES IN NEURO-ONCOLOGICAL PATIENT CARE: A YOUNGNOA SURVEY
Authors: Lazaridis Lazaros , Pepper Niklas , Agkatsev Sarina , Bodensohn Raphael , Berg Rebecca , Seliger Corinna , Hau Peter , Platten Michael , Combs Stephanie , Mildenberger Iris , Müther Michael , Kebir Sied 
Published: November 2024

Abstract

BACKGROUND
Malignant brain tumors inevitably relapse, almost always causing significant functional and neurological impairments. Thus, palliative care is crucial in managing individuals with malignant brain tumors. It is essential for neuro-oncologists to be well-prepared to openly communicate about and meet the palliative needs of these patients. With this survey, we sought to evaluate palliative care practices in Germany and their impact on the treatment of neuro-oncological patients.

METHODS
We conducted an anonymous, interdisciplinary survey targeting palliative care practices among neuro-oncologists in Germany, all members of the Neuro-oncology Working Group of the German Cancer Society. The questionnaire, designed in close coordination with board-certified palliative care specialists, was distributed to 450 physicians. It collected personal information and assessed respondents’ knowledge of and access to palliative care structures. The survey was conducted online from March 31 to April 30, 2023.

RESULTS
Ninety-two physicians completed the survey. Of these, 81 (88%) reported feeling comfortable with end-of-life conversations, while 11 (12%) did not. No significant differences were observed between the two subgroups regarding their level of medical education (p=0.7140), workplace (p=0.4966), sex (p=0.9999), medical specialty (p=0.5478), or region of practice (p=0.9999). However, those comfortable with end-of-life discussions had significantly more palliative care training either during specialty training (p=0.0475) or through active participation in palliative care courses (p=0.0254). Further detailed analysis is in progress.

CONCLUSIONS
The survey indicates that while the majority of participants are comfortable with end-of-life discussions, a clear correlation exists between their comfort level and the extent of palliative care training received. This highlights the critical need for enhanced and targeted palliative care education within neuro-oncology training programs to prepare physicians for the complex communication and care challenges in neuro-oncological palliation. Further analysis will continue to explore additional educational and systemic factors that could increase the quality of palliative care in neuro-oncology.
EPID-01. PEDIATRIC BRAIN TUMORS IN SUB-SAHARAN AFRICA:A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Nyalundja Arsene Daniel , Kanmounye Ulrick Sidney , Karekezi Claire , Laeke Tsegazeab , Thango Nqobile , Balogun James A 
Published: November 2024

Abstract

OBJECTIVE
brain tumors are a global problem, leading to higher cancer-related morbidity and mortality rates in children. Despite the progressive though slow advances in neuro-oncology care, research, and diagnostics in sub-Saharan Africa (SSA), the epidemiological landscape of pediatric brain tumors (PBTs) remains underestimated. This study aimed to systematically analyze the distribution of PBT types in SSA.

METHODS
major databases and grey literature were searched for literature on PBTs in SSA published before October 29, 2022. A proportional meta-analysis was performed.

RESULTS
forty-nine studies, involving 2360 children, met the inclusion criteria for review; only 20 (40.82%) were included in the quantitative analysis. South Africa and Nigeria were the countries with the most abundant data. Glioma not otherwise specified (NOS) was the common PBT in the 4 SSA regions combined. However, medulloblastoma was more commonly reported in Southern-SSA(p=0.01) than in other regions. The prevalence and the overall pooled proportion of the 3 common PBTs was estimated at 46.27% and 0.41 (95%CI 0.32–0.50, 95% prediction interval [PI] 0.11–0.79), 25.34% and 0.18 (95%CI 0.14–0.21, 95%PI 0.06–0.40), and 12.67% and 0.12 (95%CI 0.09–0.15, 95%PI 0.04–0.29) for glioma-NOS, medulloblastoma, and craniopharyngioma, respectively. Sample size moderated the estimated proportion of glioma-NOS (p = 0.02). The highest proportion of craniopharyngiomas was in Western-SSA, and medulloblastoma and glioma-NOS in Central-SSA.

CONCLUSION
these findings provide insight into the trends of PBT types and the proportion of the top 3 most common tumors across SSA. Although statistical conclusions are difficult due to the inconsistency in the data. We identify critical areas for policy development and collaborations that can facilitate improved outcomes in PBTs in SSA. More accurate epidemiological studies are needed to better understand the burden of the disease and the geographic variation in their distribution, and to raise awareness in their subsequent management.
EPID-04. VESTIBULAR SCHWANNOMA IN PREGNANCY: A SYSTEMATIC REVIEW
Authors: Bartman Mason , Barake Carole 
Published: November 2024

Abstract

INTRODUCTION
Vestibular Schwannomas (VS) are intracranial tumors of the nervous system originating from peripherally myelinating Schwann cells. There are sparse reports of this tumor presenting in pregnant patients but many of the cardinal symptoms of pregnancy overlap with the presentation of VS. For this reason, we systematically reviewed reports of VS in pregnant patients to identify the most specific clinical symptoms to aid diagnosis of and address management considerations for this population.

METHODS
Our systematic review was performed according to PRISMA guidelines. The data extracted includes study characteristics, symptom presence and onset relative to tumor diagnosis, tumor size, treatment modality, complications, and maternal/fetal health outcomes. This data was analyzed for overlap with commonly presenting symptoms and current management trends.

RESULTS
Sixteen papers between 1967 and 2018 reported a total of 26 pregnant patients who met criteria for inclusion. The most common presenting symptoms were hearing loss (76.9%), ataxia (42.3%), headache (38.5%), and vomiting (38.5%). The symptoms that presented with the longest duration were dizziness/vertigo (145.33 weeks), tinnitus (155 weeks), and hearing loss (145.67 weeks). The most common complications were post-op facial paralysis (46.2%), hydrocephalus (23.1%), and post-op hearing loss (19.2%).

CONCLUSIONS
A heightened clinical suspicion for VS in pregnant patients is needed due to the large overlap of cardinal symptoms of pregnancy and VS presentation. The way pregnancy changes patients’ normal physiology should be considered when determining optimal management. We hope that this review will improve diagnostic accuracy and prevent complications in pregnant patients with VS.
EPID-22. MUTATIONAL SIGNATURE ASSOCIATED WITH HALOALKANE EXPOSURE ENRICHED IN FIREFIGHTERS IN THE ADULT GLIOMA STUDY
Authors: Cannataro Vincent , Bracci Paige , Taylor Jennie , McCoy Lucie , Rice Terri , Hansen Helen , Heffernan Annie , Wiemels Joe , Wiencke John , Wrensch Margaret , Claus Elizabeth 
Published: November 2024

Abstract
Using data from The Cancer Genome Atlas (TCGA) and Glioma Longitudinal Analysis (GLASS), we identified specific environmentally related mutational signatures in glioma including a signature associated with haloalkane exposure (SBS42) from the Catalogue of Somatic Mutational Signatures (COSMIC). Haloalkanes are widely used commercially including in flame retardants and fire extinguishants and are an intriguing finding given an observed increased glioma risk in firefighters. To validate our findings, we use new study participants with data on occupation (not available in either TCGA/GLASS) from the University of California, San Francisco Adult Glioma Study (AGS) to compare mutational signatures in tumors from 17 persons with glioma and documented occupational exposure to firefighting with those of 18 matched glioma patients without history of firefighting. Using whole exome sequencing, we identified environmental exposure signatures in tumor tissue from firefighters as well as in non-firefighters who had other relevant occupational exposure (e.g. auto/truck mechanic work). In these data, glioma is largely associated with aging and mutational signatures relating to endogenous mutational processes that correlate with age, such as spontaneous or enzymatic deamination of 5-methylcytosine. However, some gliomas have detectable signatures associated with exogenous mutational processes, such as SBS42 haloalkanes. Thus, we confirm detection of haloalkane signatures in persons likely highly exposed, i.e. long-term firefighters. Identifying exogenous mutational processes in cancers are important as they may inform public health intervention strategy to reduce mutagenesis and prevent cancer inception. Identifying occupational correlates with SBS42, associated with occupational exposure to haloalkanes, will pinpoint occupational hazards that may be avoidable. This is especially important for glioma and other cancers where exogenous mutagenesis is not well established.
EPID-24. OPTIMIZING PATIENT RECRUITMENT FOR BRAIN TUMOR STUDIES: LEVERAGING THE POWER OF GOOGLE ADS TO CONNECT WITH AFFECTED FAMILIES
Authors: Kakaizada Sofia , Bainbridge Matthew , Armstrong Georgina , Bondy Melissa 
Published: November 2024

Abstract

OBJECTIVE
We assessed the effectiveness of using Google Ads to recruit individuals with familial glioma into a genetic research study.

METHODS
We conducted a comparative analysis between two periods: March 1 to June 30, 2023 (with Google Ads) and March 1 to June 30, 2021 (without Google Ads). We targeted individuals searching for brain tumor information using Google Ads, directing them to a study landing page. We analyzed metrics such as advertisement clicks, impressions, click-through rate, and cost per click. Our eligibility criteria included families with at least two members having glioma, with one currently living with the condition, aged 18 or older, and residing in the United States.

RESULTS
The 2023 Google Ads campaign generated 7,228 clicks, 82,242 impressions, an 8.79% click-through rate, and a cost per click of $0.62. The number of interested individuals increased from 13 in 2021 (without Google Ads) to 35 in 2023 (with Google Ads), with 20 indicating they found the study through Google Ads. However, the increase lacked statistical significance (x2=1.48, p=0.22).

CONCLUSION
Google Ads enhanced our participant outreach and recruitment for the glioma study, although the results were not statistically significant. This approach shows promise for recruiting participants for rare disease research. We recommend that future studies consider longer durations and larger sample sizes to better assess its impact. Additionally, due to the prevalence of misinformation about familial glioma, we submitted and conducted a survey to the Society of NeuroOncology to evaluate the attitudes and beliefs of physicians and other healthcare professionals towards familial glioma. This survey aims to address misconceptions and improve understanding within the healthcare community.