tbuckley/cabot-search huggingface dataset:
CCRG-02. MICRORNA TARGETING LOGIC IN DIRECT NEURONAL REPROGRAMMING OF GLIOBLASTOMA
Authors: Luorongxin Yuan, Kitra Cates, Albert Kim, Andrew Yoo
Journal: Neuro-Oncology (2024)

Abstract microRNA (miR)-124 is one of the main drivers of mitotic exit during neurogenesis, which is recapitulated in miR-9/9* and -124 (miR-9/9*-124)-mediated direct neuronal reprogramming. In the reprogramming of various cell types, miR-9/9*-124 induce non-neuronal cell fate erasure before activating the neuronal program. Regardless of the different starting transcriptome landscapes, a core gene regulatory network (GRN) is always targeted by miR-9/9*-124, with cell cycle progression as the most significant pathway. We reason that miR-9/9*-124 can induce cell fate erasure in cancerous cells by repressing similar GRNs, using glioblastoma multiforme (GBM) as a paradigm. Mechanistic insights into GBM fate erasure by miR-9/9*-124 while inducing the postmitotic state would facilitate the understanding of GRNs that govern the tumorigenic identity of GBMs and potentially offer novel therapeutic implications. Indeed, miR-9/9*-124 readily induces mitotic exit in patient-derived GBM cell lines, represses GBM cell fates, and promotes neuronal identity over time as assessed by RNA-seq. Mice receiving GBM intracerebral xenografts with miR-9/9*-124 survived significantly longer than those receiving non-specific control miRNA. Global profiling of miRNA targeting activity by AGO2-eCLIP reveals that miR-124 binds to transcripts enriched in G1/S transition and mitogen response. Conversely, miR-506—a miR-124 homolog—despite of sharing identical seed sequences, has significantly less targeting activity and fails to stop cell cycle progression. We are currently dissecting how the difference in the miRNA 3’ sequence renders contrasting biological outcomes. Preliminary data suggests that the length of miRNA alone alters targeting specificity to cell cycle transcripts. However, different permutations of miRNA 3’ sequence, though sufficient to induce mitotic exit, are not all competent to achieve neuronal reprogramming, indicating that mitotic exit and neurogenic activities of miR-124 could be decoupled. We hope that understanding the grammar logic of miRNA targeting would provide deeper insights into how miRNAs can be leveraged to manipulate GBM identity.
CSIG-33. CERAMIDE-1-PHOSPHATE/CERK ARE REGULATORS OF ETMR GROWTH AND POTENTIAL THERAPEUTIC TARGETS
Authors: Allison Maas, Evangelos Liapis, Kelly O’Neill, Derek Hanson, Claire Carter
Journal: Neuro-Oncology (2024)

Abstract Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive CNS neoplasm which occurs almost exclusively in infants and is associated with an extremely poor prognosis. To identify functional signaling lipids that contribute to the aggressive nature of ETMR and that can be targeted therapeutically, we carried out mass spectrometry imaging on human ETMR patient samples, the patient-derived cell line BT183, and normal neural stem cells. We identified an accumulation of ceramide-1-photphate (C1P) within the rapidly proliferating embryonal tumor cells in patient samples and the cell model. We also detected high accumulation of C1P within the aberrant vascular proliferations in patient samples. Ceramide-1-phosphate is a pleiotropic bioactive signaling lipid that controls cell fate. C1P and its synthesizing enzyme, ceramide kinase (CERK), are known mitogens that have been shown to regulate cell proliferation in several non-CNS cancers. C1P is known to mediate the upregulation of PI3K/Akt/mTOR, MAPK/MEK/ERK1/2, Rho kinase, JNK, to promote cell survival and migration. After spatially mapping C1P accumulation in patient samples and our in vitro 3D models, we next carried out IHC to correlate lipid accumulation with its synthesizing enzyme, CERK. CERK was found to be abundantly accumulated in both endothelial and tumor cells within the tumor microenvironment of patient samples. Western blot analysis of CERK demonstrated a significant increase in the ETMR 3D tumorspheres compared to the NSC neurospheres. Treatment of the ETMR 3D tumorspheres with the CERK inhibitor, NVP-231, potently reduced cell growth and viability. Western blot analysis of ETMR tumorspheres at 8 and 24 hours post-treatment demonstrated a time-dependent decrease in N-MYC and a subsequent increase in p53. Studies are ongoing to validate these findings in vivo and to elucidate the signaling pathways that C1P/CERK regulate in both the vascular and tumor cells in ETMR.
RADT-31. EMBRACING HYPOFRACTIONATED RADIOTHERAPY FOR GLIOBLASTOMA IN A RESOURCE CONSTRAINED SETTING
Authors: Durgapoorna Menon, Kiron G, Dilip Panikar, Arun Warrier, Sandra Sasi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Various hypofractionated schedules of radiation have been tried in glioblastoma with limited success. Though the shorter fractionation is appealing and there is evidence (since 2017) to use the 40Gy in 15 fractions regime in the elderly, the fear of toxicity limits its use, especially in the developing nations. We have tried this regime in younger patients (not eligible for supportive care alone) who had a poor Performance status or if only a biopsy had been performed. METHODS 25 patients treated for glioblastoma from 2017 to 2023 using 4000cGy delivered in 15 fractions were included in the study. The patient details were obtained retrospectively from the medical records and the Eclipse Treatment Planning system. RESULTS There were 16 males and 9 females. Median age was 62 years (range 52 to 77 years). 56% of the patients had an ECOG performance score of 3; and the rest 2. 12 lesions were on the Right side, 9 in the left and the rest extended across the midline. Surgery was limited to biopsy alone in 8; almost as many (n=7) had a Near Total Resection; the rest underwent decompression. Surprisingly, almost half the patients were MGMT unmethylated. 16 patients were on steroids either during or after radiation. All 25 maintained their Performance Status and completed radiation as planned. The mean GTV Volume - 53.48 cc (Range 6-201). Dmax was never above 103%; Brainstem and Optic Apparatus Dmax were also kept below 100%. In the majority, 3 beams of mixed energy were used. 19 patients received both Concurrent and adjuvant temozolomide; only adjuvant was given to 6. The median overall survival was 7.7 months (range 2-60.6 months) and the Disease free survival was 7.5 months (Range 1-60.5 months). CONCLUSIONS Hypofractionated radiotherapy of 4000 cGy in 15 fractions seems to be a kinder treatment in glioblastoma patients with a poor performance status.
BIOM-42. RESPONSE TO DABRAFENIB/TRAMETINIB IN A PATIENT WITH WHO-CNS GRADE 3 BRAF V600E-MUTATED PLEOMORPHIC XANTHOASTROCYTOMA
Authors: Huda Alalami, Serguei Bannykh, Eric Vail, Chirag Patil, Jeremy Rudnick, Jethro Hu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pleomorphic xanthoastrocytoma (PXA) is a rare central nervous system tumor. Mutations in BRAF V600E are present in 60-80% of cases. While traditionally managed with surgical resection and adjuvant radiation, emerging evidence suggests targeted therapies may be effective, particularly in cases harboring the BRAF V600E mutation. CASE SUMMARY A 35-year-old male with no significant medical history presented in November 2023 with diplopia and headache leading to the discovery of a large left temporal/parietal tumor. A partial resection was performed. Initial histopathological diagnosis was glioblastoma (GBM); thus, the patient was treated with concurrent radiation and temozolomide for 6 weeks. Molecular pathological analysis demonstrated the presence of BRAF V600E mutation and CDKN2A/B copy number loss. Methylation-based tumor profiling was performed at the National Cancer Institute, with composite methylation profile indicating a consensus match to pleomorphic xanthoastrocytoma. Following chemoradiation, a repeat brain MRI in March 2024 showed tumor progression, prompting the initiation of dabrafenib and trametinib therapy. After 1 month of targeted treatment, a repeat brain MRI demonstrated a partial response with a decrease in tumor size and enhancement. In April 2024, he underwent a planned repeat resection. Symptomatically, the patient experienced intermittent headaches and nausea that were responsive to oral steroids with no serious adverse effects to targeted therapy. DISCUSSION This case highlights the therapeutic potential of double BRAF/MEK blockade with dabrafenib and trametinib in BRAF V600E-mutant anaplastic PXA. The observed partial response on imaging suggests the efficacy of targeted therapy in this molecular subtype. These findings underscore the importance of molecular profiling in guiding treatment decisions.
DDEL-14. NOVEL BLOOD BRAIN BARRIER PENETRATING BI-SPECIFIC ANTIBODY THERAPY FOR BREAST CANCER BRAIN METASTASIS
Authors: Shilpa Sharma, Afshin Ebrahimpour, Xin Ge, Balveen Kaur
Journal: Neuro-Oncology (2024)

Abstract Breast cancer is the second leading cause for brain metastasis after lung cancer. While Her2 +ve tumors respond to her2 targeted antibody therapy, these antibodies are unable to cross the blood brain tumor barrier to effectively target metastases hidden in the ‘CNS sanctuary’. To overcome this hurdle, we have modified Her2 targeting Herceptin to create a CNS penetrating antibody that is transported in a unidirectional fashion into brain tumors. The modified BBB penetrating Herceptin is processed by the tumor specific microenvironment after crossing the BBB, such that the modified antibody is then trapped in the tumor ECM. This has the potential to increase tumor retention and reduce systemic toxicity. The BBB penetrant anti Her2 antibody (Herceptin) binds to Her2 on breast cancer cells and suppresses activation of Her2 signaling in vitro. Western blot analysis shows reduction of Her2 phosphorylation and down stream signaling with both unmodified and BBB modified Herceptin. This permits recruitment and retention of the antibody into the CNS tumors. Using fluorescence imaging and IHC of intracranial tumors we have validated that the BBB modified Herceptin is localized into intracranial tumors. We are currently evaluating the safety and therapeutic benefit of this approach in mice bearing intracranial tumors.
BIOM-58. RE-INDUCTION OF INTRATHECAL CHEMOTHERAPY IN PRIOR RESPONDERS AND CORRELATION WITH CEREBROSPINAL FLUID CIRCULATING TUMOR CELLS
Authors: Skye Dawn Yazzie, Heather Orosco, Tiffany Turpin, Lyudmila Bazhenova, Rebecca Shatsky, Jessica Schulte, David Piccioni
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Leptomeningeal carcinomatosis (LMC) is an aggressive form of metastasis, with a historically poor median overall survival. Newer therapies and treatment strategies are improving outcomes, and more long-term responders exist. However, there are limited options for intrathecal (IT) chemotherapy, and re-induction in prior responders may be a reasonable treatment strategy. In addition, quantitative cerebrospinal fluid circulating tumor cells (CSF CTCs) are a valuable tool in LMC, for both surveillance of recurrence and evaluation of response. METHODS We retrospectively identified 10 patients with LMC who showed a response to IT chemotherapy and were followed with quantitative CSF CTCs on a commercially available platform. At progression, patients underwent re-induction of IT chemotherapy, on a twice a week schedule, and were evaluated for response. RESULTS All 10 patients were treated with re-induction IT chemotherapy. Six patients were re-challenged with topotecan, 3 with topotecan + trastuzumab, and 1 with pemetrexed + trastuzumab. Six patients had a primary diagnosis of breast cancer, three with lung cancer and one with ovarian cancer. The median KPS was 70. Eight were female. Prior to re-induction, all 10 had an increase in quantitative CSF CTCs. Only 1/10 had new symptoms, and 5/10 showed imaging changes on MRI. At the time of re-induction, 3/10 also received stereotactic radiosurgery to brain metastases and 2/10 had a change in systemic chemotherapy. 9/10 had improved CSF CTC counts on the next restaging, typically at 8 weeks. The median overall survival from re-challenge was 12.7 months. CONCLUSION Quantitative CSF CTCs were a more sensitive predictor of recurrence than symptoms or imaging, and were a marker of response to re-induction IT chemotherapy. Re-induction showed a durable survival benefit, and is a reasonable treatment strategy in patients who were prior responders
INNV-04. SINGLE INSTITUTION RETROSPECTIVE STUDY TO DETERMINE TIME TO FIRST PROGRESSION IN MGMT METHYLATED GLIOBLASTOMA PATIENTS WHO RECEIVED STANDARD OF CARE
Authors: Jigisha Thakkar, Isaac Ng, Ronak Jani, Abhishek Goyal, Vikram Prabhu, Douglas Anderson, Derek Wainwright, Ewa Borys, Atul Mallik, Kevin Barton
Journal: Neuro-Oncology (2024)

Abstract MGMT methylated glioblastomas respond well to standard of care with temozolomide, have a longer survival as well as increased risk of pseudo-progression as compared to unmethylated patients. Shorter survival in these patients despite effective treatments is due to misdiagnosis of true progression (in cases with pseudo-progression) that leads to overtreatment or discontinuation of effective treatments. There are limited non-invasive diagnostic tools to distinguish true progression from pseudo-progression. Knowing the expected time to first true progression will aid with interpretation of MRI changes and serve as an additional tool to distinguish true from pseudo-progression. OBJECTIVE We sought to define the time to first progression in MGMT methylated glioblastoma patients who were treated with standard of care/Stupp protocol (this has not been previously defined). METHODS We conducted a retrospective analysis of an IRB-approved database at our institution from 2019 to 2022 of all MGMT methylated glioblastoma patients who completed Stupp protocol. Time to first progression (time from initial surgery to first true progression) was determined by treating multidisciplinary team based on radiographic review +/- pathology. Eligible MGMT methylated glioblastoma patients had IDH status determined by NGS and completed standard Stupp protocol after surgery. RESULTS Approximately 30% (27) patients with IDH wild-type glioblastoma were MGMT methylated. 10 patients met eligibility criteria. 50% of MGMT methylated GBM patients had multifocal disease at presentation. Median time to first progression in MGMT methylated GBM who received standard of care was 28 months. 20% patients have not had first progression 3 years after initial surgery. CONCLUSION MRI changes on surveillance scans should be carefully interpreted in the first 28 months. Knowing time to first true progression will aid with management decisions and decrease unnecessary early aggressive interventions in MGMT methylated glioblastoma patients. We will validate these findings in a larger patient population at our institution.
DDDR-06. ENHANCING GLIOBLASTOMA TREATMENT WITH MOLYBDENUM DISULFIDE(MOS2) NANOMATERIALS AND ULTRASOUND-TRIGGERED TUMOR GROWTH INHIBITION
Authors: Tse-Yu Chen, Meng-Yin Yang
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Glioblastoma, known for its high mortality rate and limited treatment options, poses a persistent challenge in oncology. Despite advances in surgery, radiation, and chemotherapy, patient outcomes have seen only marginal improvements, with ongoing issues of high recurrence and low survival rates. The advent of nanotechnology, particularly the emergence of Molybdenum disulfide (MoS2) nanoparticles, offers new perspective in semiconductors, energy storage as well as cancer therapies. With its unique physical and chemical properties, MoS2 nanoparticles might be promising in its potential roles in the battle against cancer. We aimed to see whether ultrasound-treated MoS2 nanoparticles can interfere with growth of glioblastoma cells. METHODS MoS2 nanoparticles were added to the medium of glioblastoma cells and ultrasound treatments were given. We monitor the cell count as well as cell migration after the treatments. RESULTS MoS2 nanoparticles was found to significantly interfere with tumor cell proliferation and boost the production of reactive oxygen species (ROS). These reactive oxygen species were crucial for the apoptosis of brain tumor cells when in the right concentration. Our analysis also demonstrated that MoS2 impedes cell migration and infiltration, effectively halting tumor expansion. Additionally, Comet assay techniques confirmed extensive DNA damage in the treated cells, highlighting MoS2’s potent DNA-altering capabilities which promote programmed cell death. CONCLUSION The implications of these findings are significant, establishing a solid scientific basis for employing MoS2 nanoparticles as a targeted anti-cancer agent for brain tumors. While this study underscores the transformative potential of MoS2 nanoparticles in clinical oncology, it also acknowledges limitations such as the need for further clinical trials to evaluate efficacy and safety in humans. Key Words: MoS2 nanoparticles, Ultrasound treatment, Reactive oxygen species, Comet assay, Programmed cell death
TMET-17. LIPID METABOLIC HETEROGENEITY OF GLIOMA CELLULAR STATES REVEALS ENVIRONMENTAL DEPENDENCIES
Authors: Nicholas Bayley, Jenna Minami, Christopher Tse, Henan Zhu, Jennifer Salinas, Cassidy Andrasz, Weihong Yan, Dimitri Cadet, Amir Borujerdpur, Kevin Williams, Aparna Bhaduri, Steven Bensinger, Linda Liau, Timothy Cloughesy, Thomas Graeber, David Nathanson
Journal: Neuro-Oncology (2024)

Abstract Malignant growth and survival of cancer is supported through reprogrammed lipid metabolism. In gliomas, genetic alterations can drive lipid metabolic dysregulation revealing therapeutic opportunities to exploit lipid metabolic vulnerabilities within genetically defined subsets of glioma tumors. However, it remains unclear whether inter- and intra-tumoral transcriptomic heterogeneity in gliomas relates to distinct lipid programs and potential dependencies. Here we set out to characterize pan-glioma lipid metabolic heterogeneity through genomic, transcriptomic, and lipidomic profiling of a large and diverse cohort of patient tumor samples. We define key axes of lipid metabolic variability across gliomas and identify relationships between lipid metabolic gene expression programs and glioma lipidomic profiles. Intriguingly, intersection of lipid gene expression signatures with single cell RNA sequencing revealed patterns of lipid metabolic heterogeneity that distinguish neurodevelopmental cellular states of gliomas, mirroring patterns of lipid metabolic diversity across cell types within the normal brain. Consequently, tumors with opposing cellular state enrichment have distinct lipid metabolism and environmental dependencies. Tumors enriched for Radial Glia-like states have high capacity for de novo fatty acid synthesis while tumors enriched for oligodendrocyte progenitor-like states are dependent on exogenous sources of lipids for survival and growth. These findings connect inter- and intra-tumoral heterogeneity of cellular states to variability in lipid metabolic reprogramming to reveal future avenues for precision medicine.
TMET-19. REWIRING OF CORTICAL GLUCOSE METABOLISM FUELS HUMAN BRAIN CANCER GROWTH
Authors: Andrew Scott, Anjali Mittal, Baharan Meghdadi, Sravya Palavalasa, Abhinav Achreja, Alexandra O’Brien, Ayesha Kothari, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Donna Edwards, Zhe Wu, Jiane Feng, Anthony Andren, Li Zhang, Vijay Tarnal, Kimberly Redic, Nathan Qi, Joshua Fischer, Ethan Yang, Michael Regan, Sylwia Stopka, Gerard Baquer, Theodore Lawrence, Sriram Venneti, Nathalie Agar, Costas Lyssiotis, Wajd Al-Holou, Deepak Nagrath, Daniel Wahl
Journal: Neuro-Oncology (2024)

Abstract The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. In particular, we find that cortical tissue produces its own glucose-derived serine, whereas gliomas predominantly consume serine from the environment. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth. Combining dietary serine restriction with chemoradiation reduces brain tumor growth in mice, suggesting that such a dietary intervention could improve outcomes for patients with high grade glioma.
EPCO-22. DEEP PHENOTYPING IDENTIFIES TRUNCATING MUTATIONS IN THE NF2 LINKER DOMAIN ASSOCIATED WITH DISEASE SEVERITY IN NEUROFIBROMATOSIS TYPE II
Authors: David Asuzu, Emma Celano, Dustin Mullaney, Debjani Mandal, Abdel Elkahloun, Kory Johnson, Prashant Chittiboina
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Neurofibromatosis type 2 (NF2) is an autosomal dominant tumor syndrome with protean presentation and variable penetrance. Our objective was to perform deep phenotypic and genetic analysis of a diverse NF2 population to identify predictors of worse clinical outcome. METHODS We evaluated 167 patients with NF2 and followed them for a mean duration of 4.5 years. Detailed clinical and radiographic characteristics were collected on each patient, and Karnofsky performance scale (KPS) scores and within-study mortality were monitored. CLIA certified genotyping was supplemented with a custom sequencing panel targeting NF2 and other schwannomatosis-related genes. Outcome predictors were assessed using multivariable linear or logistic regression. RESULTS Germline mutations (nonsense 36%, splice-site 16%, and large deletions 16%) were grouped by predicted protein effect (truncating 41%, non-truncating 27%, and mosaic 33%) and mapped to the NF2chromosomal locus. Patients with truncating NF2 mutations had lower mean age of diagnosis (19.9 versus 25.7, P = 0.01) and faster tumor growth rates (2.4% versus 1.1% for all tumors, P = 0.01). Patients whose truncating mutations occurred within the NF2 linker domain (exons 8, 11 and 12) had more total tumors (adjusted coefficient 15.0, 95% CI 0.8 – 29.0, P = 0.04), and specifically more schwannomas (adjusted coefficient 7.0, 95% CI 0.2 – 13.9, P = 0.04). Presence of a-helical domain mutations predicted higher within-study mortality (adjusted OR 4.3, 95% CI 1.1 – 16.2, P = 0.03). CONCLUSIONS The NF2 linker domain functions a hinge, facilitating binding between the tail domain and the LATS binding site within the FERM domain. In our study, truncating mutations in the NF2 linker domain were associated with higher tumor burden and over four-fold within-study mortality. The linker domain may constitute a novel therapeutic target in patients with NF2.