12044 Background: Advances in lung cancer therapeutics have led to a growing population of patients with lung cancer who are facing the challenges of living with the sequela of brain metastases and the therapies used to treat them. Patients experience neurocognitive deficits, difficulties with functioning, and mood symptoms. However, the mechanisms by which neurocognitive deficits contribute to mood symptoms in this patient population remain to be fully elucidated. In this study, we aimed to evaluate patient-reported functioning as a mediator between neurocognitive deficits and mood symptoms. Methods: Using a prospectively collected single-site registry, we conducted an exploratory cross-sectional study among patients with lung cancer with brain metastases at the time of evaluation for stereotactic radiosurgery. The registry included data on patient demographic and clinical characteristics, neurocognitive deficits per clinician exam (visual impairment, cranial nerve deficit, sensory deficit, motor deficit, gait impairment/incoordination, decline in ability to concentrate, decline in memory), and patient-reported functioning (self-care, usual activities, mobility) and mood symptoms (anxiety/depression) from the European Quality of Life 5-Dimensions 3-Level Version. First, we selected functional domains significantly associated with mood symptoms in a logistic regression analysis to test as potential mediators. Then, we used a regression-based path analysis to test the selected functional domain as a mediator between neurocognitive deficits and mood symptoms. The mediation model adjusted for age, performance status, tobacco use, extracranial disease status, prior brain surgery, and prior brain radiation. Results: Of 463 patients, 33.9% demonstrated any neurocognitive deficit, 38.7% self-reported any functional difficulty (self-care, usual activities, or mobility), and 15.3% reported mood symptoms. Difficulty with usual activities was associated with increased mood symptoms (OR=1.65, 95% CI=1.36, 1.97), which we then tested as a mediator. Motor deficits (OR=1.66, 95% CI=1.30, 2.38) and gait impairment/incoordination (OR=1.50, 95% CI=1.19, 2.09) had positive indirect effects on mood symptoms (i.e. increased mood symptoms) through difficulties with usual activities. No other neurocognitive deficits showed significant effects on mood symptoms. Conclusions: Among patients with lung cancer with brain metastases, the associations of motor deficits and gait impairment/incoordination with worsened mood are mediated by difficulties with engaging in usual activities. These findings underscore the potential for tailored supportive care, utilizing strategies from cognitive rehabilitation, palliative care and psychology, to improve patients’ mood by helping them adapt to and cope with difficulties in engaging in their usual activities.

BACKGROUND:The prognostic and predictive value of O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation is not well established in isocitrate dehydrogenase (IDH)-mutant gliomas. This study evaluates the survival impact of MGMTp and other clinical, molecular, and radiologic variables in low-grade and high-grade IDH-mutant gliomas. METHODS:We retrospectively evaluated 520 consecutive adult patients treated for an initial diagnosis of IDH-mutant glioma, of any histological grade, at two large academic institutions. MGMTp methylation was evaluated by methylation-specific polymerase chain reaction (PCR) analysis. Log-rank test and Cox proportional hazards model were applied to evaluate the association of clinical, molecular, and radiological characteristics with overall survival (OS) and progression-free survival (PFS). RESULTS:Median age was 36.6 years; MGMTp was methylated in 70% and unmethylated in 30%. MGMTp methylation was not significantly associated with OS (P = 0.11) or PFS (P = 0.74) on multivariate analyses. Cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion [HR = 3.26 (1.47, 7.23), P = .006] and an integrated grade 4 classification [HR = 2.08 (1.06, 4.67), P = .048] were strong predictors of OS in astrocytoma, whereas maximal resection [HR = 0.06 (0.01, 0.57), p = 0.016] and radiation [HR = 0.41 (0.18, 0.91), P = .03] were strong prognosticators for PFS in the entire cohort. Maximal resection of the enhancing disease [HR = 0.17 (0.05, 0.96), P = .014] and radiation [HR = 0.47 (0.19, 0.65), P = .046] were strongly associated with PFS in grade 2 and 3 gliomas. CONCLUSION:MGMTp methylation was not associated with a prognostic or predictive value in our IDH-mutant glioma cohort. CDKN2A/B status and extent of resection were strong predictors of outcomes.

Intracranial metastases (ICM), specifically parenchymal brain metastases, remain a major clinical challenge in solid tumor oncology, despite recent advances in cancer therapies which have led to improvements in survival for these patients. Improving outcomes even further in this patient population will require a multi-disciplinary approach, including pre-clinical and translational studies, clinical trials, and studies of patient reported outcomes and quality of life. At the 2023 and 2024 joint Society for Neuro-Oncology (SNO) and American Society of Clinical Oncology (ASCO) CNS Metastases Conferences, two ICM collaborative group think tanks convened, composed of diverse, multi-disciplinary stakeholders, including basic and translational researchers, clinical trialists, and clinicians from academia and the community setting. Here we summarize the key knowledge gaps and consensus recommendations put forth by these two think tanks. Advances in ICM research and improvements in patient outcomes will require close inter-specialty and inter-institutional collaboration between stakeholders, including pre-clinical and translational researchers, clinical investigators, industry, and regulatory bodies.

Brain metastases affect over 50% of patients with advanced lung cancer, though their impact on patients’ functioning and symptoms has not been well-described. We aimed to characterize and explore associations between neurocognitive deficits, functional difficulties, and mood. This is a cross-sectional study of patient-reported outcomes among patients with lung cancer with brain metastases at the time of stereotactic radiosurgery (SRS) evaluation, using a prospectively collected single-site registry. We summarized patients’ demographic and clinical data, neurocognitive deficits per clinician exam, and patient-reported functioning (self-care, usual activities, mobility) and mood (anxiety/depression) using the European Quality of Life 5-Dimensions 3-Level Version. We used logistical regressions to assess associations between (1) the presence of neurocognitive deficits and functional difficulties and (2) the presence of functional difficulties and mood symptoms, adjusting for age, tobacco use, performance status, and extracranial disease status. Among 463 patients, the mean age was 65.4 years at cancer diagnosis and 20.5% had controlled extracranial disease at SRS evaluation. One third (33.9%) of patients demonstrated any neurocognitive deficit, such as gait dysfunction/incoordination (14.7%), motor deficit (13.2%), sensory deficit (5.2%), memory decline (5.0%), visual deficit/double vision (3.7%), cranial nerve deficit (3.5%), or concentration decline (0.9%). Many (38.7%) self-reported any functional difficulty, including with usual activities (32.1%), mobility (28.9%), or self-care (15.8%), as well as anxiety/depression (15.3%). Motor deficits and gait dysfunction/incoordination were associated with difficulties with mobility, self-care, and usual activities (ORs=4.05-9.16, p’s<0.01). Difficulties with usual activities were associated with anxiety/depression (OR=4.81, p<0.01). Patients with lung cancer with brain metastases experience functional difficulties, particularly if they have motor deficits or gait dysfunction/incoordination. Patients also experience mood symptoms, especially if they have difficulties with usual activities. These findings highlight the need for tailored supportive care for patients with lung cancer with brain metastases.

A 57-year-old woman with a history of subarachnoid hemorrhage was admitted to the hospital because of visual disturbances involving the right visual field, as well as episodes of shaking of the right arm and leg. A diagnosis was made.

SLC1A1/EAAT3 functions as a trimeric, Na+-dependent dicarboxylic amino acids (glutamate and aspartate) transporter. Recent studies have identified SLC1A1/EAAT3 as an oncogenic dependency in several cancers, including clear cell renal cell carcinoma (ccRCC), blood-borne tumors, and lung cancer. Unfortunately, despite this transporter’s potential as a therapeutic target, pharmacological inhibition of SLC1A1 has remained elusive due to the absence of potent and selective inhibitors. In earlier studies, we investigated a previously described bicyclic imidazopyridine aniline SLC1A1 blocker (which we synthesized in-house, Compd 3e). Compd 3e bound SLC1A1 directly and promoted its thermal stability. Furthermore, Compd 3e treatment replicated the effects of genetic SLC1A1 blockade in terms of both metabolic changes and cytotoxicity of ccRCCs. Importantly, these fitness defects were rescued by supplementation of cell-permeable Asp and Glu. Here, we resolved the Cryo-EM structure of Compd 3e-bound SLC1A1. These studies showed that Compd 3e operates through a dual inhibitory mechanism. First, Compd 3e occupies a previously uncharacterized 'hidden' cholesterol-enriched pocket within the transporter, competitively disrupting Na+ binding that is critical for SLC1A1’s transport cycle. Second, Compd 3e wedges itself between the trimeric domains, thereby non-competitively arresting the 'elevator' movements necessary for substrate translocation across the membrane. Compd 3e makes several direct contacts with SLC1A1, including with the F99 residue that is not conserved in the other SLC1A family proteins. Mutating this residue into the SLC1A2/1A3-like (F99M) or the SLC1A5-like (F99L) conferred resistance to Compd 3e. These studies explain the mechanistic basis of Compd 3e’s selectivity towards SLC1A1. Compd 3e has poor pharmacological properties (solubility, bioavailability, etc.). In silico molecular docking enabled a structure-activity relationship (SAR) campaign to optimize the Compd 3e scaffold. Our biochemical, structural, and functional studies have identified improved SLC1A1 inhibitors. Our study provides an understanding of the dual mechanisms by which Compd 3e inhibits SLC1A1. These mechanistic discoveries uncover a novel therapeutic avenue for targeting ccRCC (and other SLC1A1-dependent cancers). More broadly, this work highlights the allosteric targeting of solute carriers outside their substrate-binding pocket, which can be leveraged for several other oncogenic SLCs. Pooneh Koochaki, Jesse A. Coker, Biao Qiu, Nancy Wang, Todd Romigh, Shaun R. Stauffer, Olga Boudker, Abhishek A. Chakraborty. Investigating pharmacological targeting of the SLC1A1 aspartate/glutamate transporter [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6911.

Cerebellar glioblastoma (cGBM) is a rare subtype, comprising of < 1

The significance of contrast enhancement in newly diagnosed grade 2 IDH-mutant glioma is unclear and has implications for the use of mutant IDH (mIDH) inhibitors. We evaluated its incidence, patterns, and associated survival outcomes. We retrospectively evaluated consecutive patients with grade 2 IDH-mutant glioma treated at two institutions (2010-2021). Intratumoral enhancement was identified on preoperative MRIs and classified as measurable or nonmeasurable, well- or ill-defined. Overall survival (OS) and progression-free survival (PFS) were evaluated. For patients with no postoperative treatment, time from diagnosis to progression after first-line therapy (PFS-fl) was also evaluated. Multivariate Cox models adjusted for age, Karnofsky performance status (KPS), sex, 1p/19q-codeletion, extent of resection, and receipt of adjuvant treatment. Among 327 patients median age was 37 years, median KPS was 90, 51% were male, 48% had 1p/19q-codeletion and 36% had gross-total resection (GTR). 53% received no postoperative treatment, 46% received radiation and/or chemotherapy, and 1% received mIDH inhibitor. Median OS was 21.7 years (95% CI 21.5–not estimable). On preoperative MRI, 58 (18%) tumors demonstrated enhancement, mostly ill-defined (64%) or nonmeasurable (78%). Most (81%) had GTR of enhancing disease. On multivariable analysis, presence of preoperative enhancement did not significantly impact OS (HRadjusted 0.93 [95% CI 0.50–1.73]; p =.830). Among patients with no adjuvant treatment, preoperative enhancement was associated with decreased PFS (median 2.8y vs 4.0y; HRadjusted 1.70 [1.02–2.84]; p =.044), but not with PFS-fl (HRadjusted 0.98[0.50–1.91]; p =.946) or OS (HRadjusted 0.56[0.18–1.76]; p =.324). Enhancement patterns did not predict OS. In grade 2 IDH-mutant glioma, preoperative enhancement was not associated with OS. Among patients who received no adjuvant therapy, preoperative enhancement predicted earlier PFS but not PFS-fl or OS. The role of mIDH inhibitors in this subgroup merits further study.

Figure S2. Localization of TC following Dina + MG132 treatment

Abstract Purpose: There are no effective treatment options for patients with aggressive epithelioid hemangioendothelioma (EHE) driven by the TAZ–CAMTA1 (TC) fusion gene. Here, we aimed to understand the regulation of TC using pharmacologic tools and identify vulnerabilities that can potentially be exploited for the treatment of EHE. Experimental Design: TC is a transcriptional coregulator; we hypothesized that compounds that reduce TC nuclear levels, either through translocation of TC to the cytoplasm, or through degradation, would render TC less oncogenic. TC localization was monitored using immunofluorescence in an EHE tumor cell line. Two target-selective libraries were used to identify small molecules that reduce TC localization in the nucleus. The ability of the shortlisted hits to affect cell viability, apoptosis, and tumorigenesis was also evaluated. Results: Basal TC remained “immobile” in the nucleus; administration of cyclin-dependent kinase (CDK) inhibitors such as CGP60474 and dinaciclib (Dina) mobilized TC. “Mobile” TC shuttled between the nucleus and cytoplasm; however, it was eventually degraded through proteasomes. This dramatically suppressed the levels of TC-regulated transcripts and cell viability, promoted apoptosis, and reduced the area of metastatic lesions in the allograft model of EHE. We specifically identified that the inhibition of CDK9, a transcriptional CDK, destabilizes TC. Conclusions: The CDK inhibitor Dina exhibited antitumorigenic properties both in vitro and in vivo in EHE models. Dina has been rigorously tested in clinical trials and displayed an acceptable toxicity profile. Therefore, there is a potential therapeutic window for repurposing Dina for the treatment of EHE.

Figure S1. Dose-response curves of triptonide, triptolide, and dBET6

Patients with cancer can develop neurologic deficits that frequently, but not exclusively, arise from intracranial involvement by malignancy. In this case series, we highlight 3 patients with new focal neurologic deficits in the setting of hematologic cancers without baseline intracranial disease. The first, with Waldenstrom macroglobulinemia, develops bradyphrenia, inattention, and disorientation. Patients 2 and 3 have diagnoses of chronic lymphocytic leukemia (CLL), with one experiencing a first lifetime seizure and the other right hemiparesis, rash, headache, and intermittent speech arrest. A description of the pathophysiology of the final diagnosis, suggestive imaging characteristics, and historical outcomes follows to improve future diagnostic precision.

Delays and risks associated with neurosurgical biopsies preclude timely diagnosis and treatment of central nervous system (CNS) lymphoma and other CNS neoplasms. We prospectively integrated targeted rapid genotyping of cerebrospinal fluid (CSF) into the evaluation of 70 patients with CNS lesions of unknown etiology. Participants underwent genotyping of CSF-derived DNA using a qPCR-based approach for parallel detection of single-nucleotide variants in the MYD88, TERT promoter, IDH1, IDH2, BRAF and H3F3A genes within 80 minutes of sample acquisition. Canonical mutations were detected in 42% of patients with neoplasms, including cases of primary and secondary CNS lymphoma, glioblastoma, IDH-mutant brainstem glioma and H3K27M-mutant diffuse midline glioma. Genotyping results eliminated the need for surgical biopsies in 7/33 (21.2%) cases of newly diagnosed neoplasms, resulting in significantly accelerated initiation of disease-directed treatment (median 3 vs 12 days; p = 0.027). This assay was then implemented in a Clinical Laboratory Improvement Amendments (CLIA) environment, with 2-day median turnaround for diagnosis of central nervous system lymphoma from 66 patients across 4 clinical sites. Our study prospectively demonstrates that targeted rapid CSF genotyping influences oncologic management for suspected CNS tumors.-

To assess the efficacy and tolerability of CAR-T cells in primary and secondary CNS lymphoma.

Background Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited.Methods We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period.Results Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 +/- 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1-0.7; P = .010).Conclusions CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted.

Background and Objective: Lung cancer is commonly associated with brain metastasis formation, and certain subtypes, such as anaplastic lymphoma kinase (ALK) rearranged disease, have an especially high propensity for early and frequent central nervous system (CNS) involvement for which treatment can be challenging. Historical management has centered on surgery and radiation therapy (RT), which persist as mainstays of treatment for large, symptomatic lesions and widespread CNS disease. To date, sustained disease control remains elusive, and the role for effective systemic adjunctive therapies is clear. Here we discuss the epidemiology, genomics, pathophysiology, identification, and management of lung cancer brain metastases with a particular emphasis on systemic treatment of ALK-positive disease according to the best available evidence. Methods: Review of PubMed and Google Scholar databases as well as ClinicalTrials.gov provided background and seminal trials for the local and systemic management of ALK rearranged lung cancer brain metastases. Key Content and Findings: The development of effective, CNS-penetrant systemic agents-including alectinib, brigatinib, ceritinib, and lorlatinib-has dramatically changed the management and prevention of ALK rearranged brain metastases. Most notably, there is a burgeoning role for upfront systemic therapy for both symptomatic and incidentally discovered lesions. Conclusions: Novel targeted therapies offer patients a pathway to delay, obviate, or supplement traditional local therapies while minimizing neurologic sequelae of treatment and may reduce the risk of brain metastasis formation. However, the selection of patients to whom local and targeted treatments is offered is not trivial, and the risks and benefits of both must be weighed carefully. More work is needed to establish treatment regimens that yield durable intra- and extracranial disease control.

Abstract BACKGROUND Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for systemic B-cell lymphomas; however, efficacy data for patients with CNS involvement are limited. Also, there are concerns about increased neurotoxicities (denoted by the term 'ICANS') when the target antigen is present within the CNS. METHODS We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a five-year period. RESULTS Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; one patient with two CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe ICANS (grade 3-4) after 7/45 transfusions (15.6%). No fatalities were directly attributed to ICANS. A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Similar response rates were seen in both patients with parenchymal and leptomeningeal involvement. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (HR per mg/d: 1.16, p = 0.031). If bridging therapy was warranted, the use of ibrutinib translated into favourable CNS-progression free survival (5 versus 1 month, HR 0.28, CI 0.1-0.7; p = 0.010). CONCLUSION CAR T-cells exhibit promising anti-tumor effects and a favourable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted to boost the success of such therapy.

The absence of effective therapeutic targets and aggressive nature of triple-negative breast cancer (TNBC) renders this disease subset difficult to treat. Although estrogen receptor beta (ERβ) is expressed in TNBC, studies on its functional role have yielded inconsistent results. However, recently, our preclinical studies, along with other observations, have shown the potential therapeutic utility of ERβ in the context of mutant p53 expression. The current case study examines the efficacy of the selective estrogen receptor modulator tamoxifen in p53-mutant TNBC with brain metastases. Significant increase in ERβ protein expression and anti-proliferative interaction between mutant p53 and ERβ were observed after cessation of tamoxifen therapy, with significant regression of brain metastases. This case study provides supporting evidence for the use of tamoxifen in p53-mutant, ERβ+TNBC, especially in the setting of brain metastasis.