tbuckley/cabot-search huggingface dataset:
PATH-42. METASTATIC ADENOID CYSTIC CARCINOMA OF BREAST WITH BRAIN METASTASES AND LEPTOMENINGEAL DISEASE
Authors: Shama Farooq, Carlos Eduardo Silva Correia
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Adenoid cystic carcinoma (ACC) of the breast rarely metastasizes to the brain and leptomeninges. ACC is a rare type of breast cancer, accounting for less than 0.1% of cases. It is usually triple negative, but has a good prognosis when it is confined to the breast. Lymph node involvement is uncommon, occurring in less than 2% of cases, and distant metastases to the brain are extremely rare. Leptomeningeal disease has not been reported yet. Case: In this case, we describe a 57-year-old woman diagnosed with triple-negative ACC of the right breast, which had spread to the axillary lymph nodes and distant metastases to the lung. The diagnosis was confirmed by biopsies of both metastatic sites. The patient received vinorelbine and cisplatin treatment for 11 cycles followed by right needle localized lumpectomy. While awaiting for the next steps in treatment she was admitted to the hospital for altered mental status, saddle anesthesia, and urinary incontinence. Neuraxis MRI revealed numerous hemorrhagic and non-hemorrhagic brain metastasis with diffuse leptomeningeal disease. Cerebrospinal fluid analysis confirmed leptomeningeal disease with positive cytology for atypical epithelioid malignant cells. The patient underwent whole brain radiation and focal radiation treatment to specific areas of leptomeningeal disease. Although she initially improved after the first month of radiation, her condition deteriorated rapidly, preventing the initiation of the next line of treatment with high-dose methotrexate or capecitabine. DISCUSSION Adenoid cystic carcinoma of the breast is exceedingly rare however with a very good overall prognosis. It is uncommon for ACC to spread to regional lymph nodes, and even rarer for distant metastasis. Brain metastasis is also infrequently reported. There are no documented cases of metastatic ACC with leptomeningeal disease, so there is no consensus on the best course of treatment.
TMET-01. LIPID METABOLIC PROGRAMS DEFINE GLIOMA STATE IDENTITY, PLASTICITY AND DEPENDENCIES
Authors: Jenna Minami, Nicholas Bayley, Christopher Tse, Cassidy Andrasz, Dimitri Cadet, Jennifer Salinas, Weihong Yan, Amir Borujerdpur, Linda Liau, Timothy Cloughesy, Kevin Williams, Steven Bensinger, Aparna Bhaduri, Thomas Graeber, David Nathanson
Journal: Neuro-Oncology (2024)

Abstract Gliomas are lethal malignancies comprised of heterogeneous and dynamic subpopulations of cell states resembling normal neurodevelopmental cell types (radial glia (RG), oligodendrocyte progenitor cell (OPC), neuron progenitor cell (NPC), neuron, etc). While both intrinsic (genetics) and extrinsic (brain environment) cues are coupled to glioma state identity, the functional programs governing glioma cell state and plasticity are unknown. Here we performed a multi-omic interrogation of a large library (n=392) of glioma patient tumors, in vivo orthotopic xenografts and in vitro gliomasphere cultures. Comparisons of matched glioma samples across environments revealed the non-native in vitro environment constrains glioma state diversity specifically enriching for stem-like glioma cell states (RG, immune, vascular). This enrichment was linked to lipid metabolic flexibility, enabling tumors enriched for stem-like states to adapt to various tumor microenvironments. By contrast, “lineage-committed” cell states (OPC, NPC, and neuron) demonstrate restricted lipid metabolism, consequently having a dependence on lipid scavenging from the brain microenvironment for survival. These results connect intra-tumoral heterogeneity and plasticity of glioma to lipid metabolism, leveraging the functional diversity of cellular states to reveal potential therapeutic opportunities.
CTNI-63. RHENIUM (186RE) OBISBEMEDA (RHENIUM NANOLIPOSOME,186RNL) FOR THE TREATMENT OF LEPTOMENINGEAL METASTASES (LM): SUMMARY OF THE PHASE 1 DOSE ESCALATION STUDY AND PHASE 2 ADMINISTERED DOSE SELECTION
Authors: Andrew Brenner, Michael Youssef, Priya Kumthekar, Ande Bao, Joel Michalek, William Phillips, Toral Patel, John Floyd, Marc Hedrick, Leonardo Juverdianu, Barbara Blouw, Norman LaFrance, Melissa Moore
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Leptomeningeal metastases (LM) is a devastating systemic cancer complication most often seen with breast, lung, and melanoma, with limited treatment options and poor survival. Rhenium (186Re) Obisbemeda (186RNL) provides the combination of effective therapeutic beta radiation, simultaneous gamma-decay for imaging, and ~90-hour physical half-life for optimal radiation delivery. A summary of the Phase 1 dose escalation study, expected to be completed, will be presented. METHODS ReSPECT-LM is a Phase 1 dose escalation study for patients with LM from any primary cancer. Adult patients are given a single dose of 186RNL via intraventricular catheter (Ommaya reservoir) in an outpatient setting to determine the maximum tolerated/feasible dose (MTD/MFD), safety, and tolerability. Seven administered dose cohorts in a 3 + 3 design, from 6.6 mCi to 109.96 mCi, were anticipated. RESULTS For the first 5 cohorts, doses were well-tolerated; most AEs were Grade 1 and 2 with 1 DLT (Cohort 5) at time of abstract submission. CSF tumor cell enumeration assays were performed with a maximum reduction over baseline seen at Day 28. Radiation absorbed doses were calculated for the ventricles, cranial subarachnoid space, and spinal fluid and showed a linear increase with administered dose, with liver and spleen remaining low. Neurological symptoms were reported to improve. We expect the Phase 1 conclusion and the RP2D to be determined for conference reporting; additionally, based on duration of benefit seen during the Phase 1, a multidose paradigm will be initiated to extend benefit. CONCLUSION A single dose of 186RNL for patients with LM has been well-tolerated, with high absorbed doses to the treatment area, acceptable organ doses, and promising clinical improvement and reductions in tumor cell count. Phase 2 is expected to begin enrollment by Q4 2024. Additionally, based on these data, a Phase 1 multidose study is planned to be initiated this year.
CTNI-64. TRIAL IN PROGRESS: DIET2TREAT -- A RANDOMIZED MULTICENTER PHASE 2 TRIAL OF A KETOGENIC DIET VS STANDARD DIETARY GUIDANCE IN COMBINATION WITH STANDARD-OF-CARE TREATMENT FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: L J Amaral, Gillian Gresham, Nicholas Butowski, Katherine Peters, Akanksha Sharma, Ekokobe Fonkem, Jen-Tsan Chi, Pao-Hwa Lin, Santosh Kesari, Stephen Shiao, Mourad Tighiouart, Sungyong You, Jeremy Rudnick, Stephen Freedland, Jethro Hu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Many glioblastoma (GBM) patients inquire about the potential therapeutic benefits of a high fat / low carbohydrate ketogenic diet (KD). Preclinical models and early-phase trials have shown encouraging results, but definitive evidence of clinical efficacy is lacking. METHODS We are conducting a multicenter randomized controlled phase 2 clinical trial (NCT05708352) of KD vs standard dietary guidance (SD) for patients with newly diagnosed GBM. All patients receive standard-of-care chemoradiation. Inclusion criteria: newly diagnosed GBM, age ≥ 18 years, Karnofsky Performance Status ≥ 70. Exclusion criteria: inability to wean steroids below 8 mg dexamethasone/day, Body Mass Index &amp;lt; 21 kg/m2, food preferences incompatible with KD. Patients are randomized 1:1 to implement either KD or SD for a study period of 18 weeks, starting alongside chemoradiation. The primary outcome is overall survival for patients randomized to the KD arm compared to those randomized to the SD arm. Secondary outcomes include progression-free survival, health-related quality-of-life (FACT-BR, FACIT-F), cognitive performance (HVLT-R, Trail-Making Test A/B), and physical activity (modified Godin leisure questionnaire, continuous activity monitoring (Fitbit)). Patients randomized to the KD arm will be provided a fingerstick monitor to check blood ketone and glucose levels twice daily. Glucose and ketone levels are also periodically monitored for patients on the SD arm. Blood, tumor, and stool samples are being collected for high throughput profiling to assess the effects of KD on metabolic markers and immune response. Target accrual is 170 patients over 5 years. Enrollment began in July 2023 and is ongoing. As of May 2024, the trial is open for enrollment at Cedars-Sinai and UCSF, and will be opening soon at Duke, St. John’s Cancer Institute, and the Medical College of Wisconsin. 13 patients have been randomized to date. Funding provided by NIH R01CA276919 and the Foundation for Metabolic Cancer Therapies.
PATH-43. MALIGNANT TRANSFORMATION OF MENINGEAL MELANOCYTOMA - GENETIC ALTERATIONS AND RESPONSE TO CHECKPOINT BLOCKADE IMMUNOTHERAPY
Authors: Carlos Eduardo Silva Correia, Viktoria Kaplan, Shama Farooq
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Meningeal melanocytomas are uncommon tumors that develop from leptomeningeal melanocytes. These tumors can exhibit aggressive behavior, leading to symptoms due to compression and potential invasion of nearby central nervous tissue. Case: In this report, we discuss the case of a 45-year-old man who was diagnosed 18 years ago with a meningeal melanocytoma in the right temporal region. He underwent complete resection with each recurrence and received focal intensity-modulated radiation therapy after a third recurrence in 2013. In May 2022, he developed progressive headaches and diplopia secondary to tumor recurrence on the right temporal region. Resection revealed that the tumor had progressed to malignant meningeal melanoma with 34 mitoses per 10 high-power fields. Next-generation sequencing (NGS) showed GNAQ mutation confirming tumor of central nervous system (CNS) origin, and also showed an SF3B1 mutation, indicating aggressive behavior. Several chromosomal abnormalities were also detected. Systemic workup revealed liver, lung, and bone metastasis. Liver biopsy confirmed meningeal melanoma of central origin. The patient received radiosurgery with a total of 30Gy over five fractions to intracranial surgical cavity, followed by three cycles of nivolumab and relatlimab. Unfortunately, the patient experienced severe intracranial and systemic progression, leading to his death six months after the malignant transformation. DISCUSSION Meningeal melanocytomas are rare however these tumors have a high recurrence rate with potential malignant transformation over time. NGS is a valuable tool for confirming the CNS origin of the tumor and predicting its aggressive behavior. Despite microscopic similarity with cutaneous melanomas, meningeal melanocytomas have different pathogenesis and do not seem to respond to immunotherapy, as observed in this case.
EXTH-12. POTENTIATING THE EFFICACY OF IMMUNE CHECK-POINT INHIBITORS IN GLIOBLASTOMA BY INHIBITION OF CXCL12
Authors: Chen Cam-El Makranz, Caitlin Huguely, Tuesday Haynes, Nicole Briceno, Meili Zhang, Dionne Davis, Hua Song, Wei Zhang, Mark Gilbert, Masashi Watanabe
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The tumor immune microenvironment (TIME) in glioblastoma (GBM) is rich in CXCL12, a chemokine known for stimulating angiogenesis. CXCL12 also controls immune cell trafficking and promotes polarization to an immunosuppressive phenotype. We postulated that inhibiting CXCL12 will modulate the immunosuppressive TIME in GBM, thereby augmenting the efficacy of immunotherapy agents like immune checkpoint inhibitors (ICIs). We examined the immunomodulatory and therapeutic efficacy of CXCL12 inhibition, using a small molecule NOX-A12, with and without ICIs in pre-clinical murine GBM models. METHODS B6 immunocompetent mice bearing intracranial (i.c.) or subcutaneous (s.c.) SB28 tumors received either vehicle, NOX-A12, anti-PD1 and anti-CTLA4 (dual ICI) or NOX-A12 + dual ICI (combination). Tumor growth was measured by IVIS imaging and immune cells in brain were analyzed using high dimensional flow cytometry. Survival was analyzed using Kaplan-Meier curves and log rank test. RESULTS Combination treatment resulted in tumor regression and long-term survival in 40% of s.c. tumor bearing mice compared to 10% treated with dual ICI only. Three of 4 mice rechallenged with contralateral s.c. tumor remained tumor free while all naive mice reached endpoint. TIME from treated s.c. tumors revealed increase in CD4 and effector memory CD8 T cells by combination treatment compared to dual ICI. In i.c. GBM tumors, while no survival benefit or growth inhibition was seen, combination treatment induced an early increase in effector memory CD8 T cells and PD-L1+ B cells, and a later increase in MHC-II+ microglia compared to dual ICI. CONCLUSION Inhibition of CXCL12 enabled the increase of effector cytotoxic T cells by ICI, improving survival in the s.c. GBM model, but not in i.c. GBM model. This might be due to differences in CXCL12 effect between extra and intra-CNS tumor or due to robust immune response causing excessive brain edema and death. These will be further explored in ongoing and future studies.
EXTH-11. PEDIATRIC GLIOMA IMMUNE PROFILING IDENTIFIES TIM3 AS A THERAPEUTIC TARGET IN BRAF-FUSION PILOCYTIC ASTROCYTOMA
Authors: Shashwat Tripathi, Hinda Najem, Corey Dussold, Sebastian Pacheco, Ruochen Du, Moloud Sooreshjani, James Chandler, Roger Stupp, Adam Sonabend, Craig Horbinski, Rimas Lukas, Joanne Xiu, Theodore Nicolaides, Valerie Brown, Nitin Wadhwani, Sandi Lam, Charles James, Ganesh Rao, Maria Castro, Amy Heimberger, Michael DeCuypere
Journal: Neuro-Oncology (2024)

Abstract Despite being the leading cause of childhood mortality, pediatric gliomas have been relatively understudied. Repurposing of adult brain tumor immunotherapies in pediatric patients has not been successful, highlighting the need for pediatric-specific immunotherapies. Pilocytic astrocytomas (PA) are the most common pediatric glioma. While surgical resection of PA is the first-line treatment, the ten-year progression-free survival rate for patients with residual tumors is &amp;lt;50%. Notably, some PAs undergo spontaneous regression after partial resection, suggesting potential baseline tumor immunoreactivity. Whole transcriptome sequencing performed on a commercial platform of pediatric gliomas (n=250) showed that MAPK-driven gliomas have higher interferon signatures compared to other molecular subgroups. Single-cell sequencing identified a unique activated and cytotoxic microglia population designated MG-Act in BRAF-fused MAPK-activated PA (n=13; p &amp;lt; 0.05), but not in pediatric high-grade gliomas (n=5) or normal brain (n=3). TIM3 was expressed on the luminal side of endothelial cells and MG-Act, but not in the surrounding normal brain based on sequential multiplex imaging. Flow cytometry showed that TIM3 intensity is upregulated on immune cells in the PA tumor microenvironment (TME) relative to matched peripheral blood immune cells (n=6; p &amp;lt; 0.01). Anti-TIM3 reprogrammed fresh ex vivo immune cells from the TME of human PAs (n=3) to a pro-inflammatory cytotoxic phenotype. In a genetically engineered murine model of MAPK-driven low-grade gliomas, median survival (MS) was 252 days in mice treated with anti-TIM3 (n=21; p&amp;lt;0.01) relative to IgG control (MS: 110 days; n=20) or anti-PD-1 (MS: 134 days; n=20). The therapeutic activity of anti-TIM3 was abrogated in the CX3CR1 microglia knockout background. ScRNA sequencing data during the therapeutic window of anti-TIM3 in wild-type mice demonstrated enrichment of the MG-Act population within low-grade gliomas at two different longitudinal time points but not in IgG-treated controls. Together, these data indicate that anti-TIM3 should be considered for clinical trials in pediatric low-grade MAPK-driven gliomas.
PATH-45. TREATMENT OF FGFR1 – ALTERED WHO GRADE 1 GLIONEURONAL TUMORS WITH FGFR INHIBITOR ERDAFITINIB
Authors: Marina Kushnirsky, Bradley Gampel, Sakir Humayun Gultekin, Michael E Ivan, Ricardo J Komotar, Hilda Capo, Basil Williams, Macarena I de la Fuente
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Low-grade mitogen-activated protein kinase (MAPK) pathway-altered glioneuronal tumors carry distinct molecular alterations, which may represent therapeutic opportunities to avoid or delay toxic treatments like radiation. Erdafitinib is a pan-FGFR tyrosine kinase inhibitor, regulatorily approved in recurrent urothelial carcinoma, and is under clinical investigation for recurrent FGFR-altered gliomas (NCT05859334). METHODS We report two patients with FGFR1-altered rosette-forming glioneuronal tumors (RGNT) treated with erdafitinib. RESULTS Patient 1 is a 32-year-old woman who presented with obstructive hydrocephalus and a non-enhancing pineal tumor. She underwent a subtotal resection, with histopathology initially consistent with a low grade dysembryoplastic neuroepithelial tumor. She was under observant management for 7 years, and developed worsening symptoms with slow non-enhancing growth, although stable per RANO low grade criteria. The initial tissue was sent for next-generation sequencing (NGS) and DNA methylation profiling, revealing an FGFR1 pathogenic variant with DNA methylation profiling matching with RGNT. Patient began Erdafitinib 8 mg daily, and had stable disease per RANO at 6 months. She developed CTCAE grade 1 toxicities of subretinal fluid, fatigue, dry skin, and paronychia. Patient 2 is a 34-year-old man diagnosed 1 year prior with a tectal tumor, who underwent biopsy due to non-measurable/ non-enhancing progression. Histopathology was consistent with RGNT. NGS revealed FGFR1 mutation, PIK3CA mutation, and NF1 pathogenic variant, described in the literature as characteristic of RGNT. There was insufficient tissue for DNA methylation profiling. Patient started erdafitinib 8 mg daily and remains clinically stable for 1 month. He developed asymptomatic hyperphosphatemia (CTCAE grade 1). Both patients have tolerated treatment without interruptions or dose reductions. CONCLUSION Erdafitinib is a well-tolerated and potentially efficacious treatment of FGFR1- altered RGNT, and may avoid the need for radiation. Diagnosis of MAPK- altered low-grade glioneuronal tumors, specifically RGNT, is increasingly reliant on molecular data, and can significantly impact treatment options.
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: Xiaohua Chen, Nazanin Esmaeili Anvar, Medina Colic, Jihong Xu, Jiyong Liang, Pratibha Sharma, Longfei Huo, Harsha S Sugur, Traver Hart, Vinay K Puduvalli
Journal: Neuro-Oncology (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.
CTNI-09. TYPE II RAF INHIBITOR TOVORAFENIB IN RELAPSED/REFRACTORY (R/R) PEDIATRIC LOW-GRADE GLIOMA (PLGG): RESULTS FROM PATIENTS ON A DRUG HOLIDAY (DH) IN THE PHASE 2 FIREFLY-1 TRIAL
Authors: Sébastien Perreault, Dong-Anh Khuong-Quang, Lindsay B Kilburn, Daniel B Landi, Sarah E S Leary, Simon Bailey, Valérie Larouche, Karsten Nysom, Pablo Hernáiz Driever, Patricia A Baxter, Olaf Witt, Michal Yalon Oren, Mohamed S Abdelbaki, Cassie Kline, Nicholas S Whipple, David S Ziegler, Jasper van der Lugt, Timothy E Hassall, Nicolas U Gerber, Devorah Segal, Jordan R Hansford, Geoffrey McCowage, Hyoung Jin Kang, Jung Woo Han, Darren Hargrave, Andrea T Franson, Helen Toledano, Nada Jabado, Nicholas G Gottardo, Susan N Chi, Liat Oren, Enrica E K Tan, Sabine Mueller, Molly E Hoke, Yeonhee Kim, Ashley Walter, Daniel Da Costa, Peter Manley, Angela J Waanders
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tovorafenib, a selective, CNS-penetrant, type II RAF inhibitor, received US FDA accelerated approval for r/r BRAF-altered pLGG. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) in this population showed clinically meaningful tumor responses and a manageable safety profile. METHODS Patients in FIREFLY-1 treated for ≥26 cycles (~24 months) who entered a DH period were routinely assessed every 3 cycles; once-weekly tovorafenib 420 mg/m2 (not to exceed 600 mg) could be restarted if there was radiographic and/or clinical evidence of new disease progression. RESULTS As of the April 19, 2024 data cutoff, 26 patients (BRAF fusion: 22; BRAF V600E mutation: 4) (33.8%) of 77 patients in arm 1 (pLGG registrational) had completed 2 years of treatment and started a DH. No patients on a DH withdrew. Twenty-four patients (92.3%) remain on a DH, of which 22 were evaluable for response (duration range: 0.6-10.9 months); duration of response off-treatment ranged from 0.0-8.5 months. (Ranges exclude 2 non-evaluable patients treated beyond radiographic progression who remained on treatment in first 26 cycles due to ongoing clinical benefit; both remain on DH without clinical progression.) Two patients had tumor progression while on a DH and restarted treatment; 1 patient with a BRAF V600E mutation progressed (≥25% in tumor size) after 1 month (rebound growth per O’Hare P., et al. Neuro-Oncol. 2024: ≥25% increase [per RANO-LGG] w/in 6 months of stopping treatment) and has been on retreatment for 4 months; 1 patient with a BRAF fusion progressed after 9 months and has been on retreatment for 3 months. Treatment-related adverse events of any grade experienced by patients on retreatment were alopecia and rash (1 each). Independent radiographic analysis for response during retreatment is ongoing. CONCLUSIONS Tovorafenib provided durable tumor responses off-treatment in patients with r/r pLGG on a DH in FIREFLY-1.