Citations

Abstract GBM AGILE(NCT03970447) is a phase 2/3 Bayesian adaptive registration platform trial testing multiple therapies against a common control. Paxalisib, a PI3K/mTOR inhibitor, is the 3rd arm in the trial to conclude evaluation. METHODS Paxalisib was open to patients with newly diagnosed unmethylated (NDU) and recurrent (RD) glioblastoma, with three possible signatures: NDU, RD, and All(NDU+RD). Arm enrollment occurred Dec2020 through May2022. Control patients were enrolled from study initiation (July2019) and were treated with temozolomide(NDU) or lomustine(RD). GBM AGILE investigational arms have 1 or 2 stages, with adaptive randomization in stage 1 and fixed randomization if arms continue to stage 2. Efficacy is based on OS hazard ratio(HR) of Arm/Control. Efficacy goal is final Bayesian probability ≥ 98% for HR<1.00 in combined Stages. An Arm continues to Stage 2 if Bayesian predictive power (PP) ≥ 0.8. An Arm stops accruing in Stage 1 if it reaches maximal sample size(N) or does not meet a minimum efficacy threshold (PP<0.25 for all signatures when N>50). Clinical cut-off is 12 months after accrual stops. The maximum N for paxalisib was approximately 150(Stage 1) and 50(Stage 2). RESULTS After paxalisib reached >150 patients in Stage 1, accrual stopped [Paxalisib/control N 54/75(NDU), 100/188(RD)]. Neither PP thresholds for moving to Stage 2 nor stopping for minimum efficacy were met. Following an unplanned public disclosure that the arm did not continue to stage 2, clinical cut-off for final analysis (planned May2023) was updated to public disclosure date (August2022). At final analysis mean HRs were 0.89(NDU), 1.25(RD), 1.05(All), probabilities of HR<1.00 of 0.72(NDU), 0.076(RD), 0.398(All). Model estimated median OS paxalisib/control (months) were 14.77/13.84(NDU) and 8.58/10.06(RD). CONCLUSION Paxalisib did not show survival benefit over cumulative control in final primary analysis; additional secondary analyses are being considered. GBM AGILE continues to rapidly and efficiently assess therapies in ND and RD glioblastoma.

ImportanceExposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role.ObjectiveTo investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associated neurodegeneration.Design, Setting, and ParticipantsThis cross-sectional study was part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project, a 7-year multicenter study consisting of 4 US study sites. Data were collected from September 2016 to February 2020 and analyses were performed between May 2021 and October 2023. After controlling for magnetic resonance image (MRI) and processing quality, former American football players and unexposed asymptomatic control participants were included in analyses.ExposurePrior exposure to RHI while participating in American football was estimated using the 3 cumulative head impact indices (CHII-G, linear acceleration; CHII-R, rotational acceleration; and CHII, number of head impacts).Main Outcomes and MeasuresIndividual PVS volume was calculated in the white matter of structural MRI. Cognitive impairment was based on neuropsychological assessment. Linear regression models were used to assess associations of PVS volume with neuropsychological assessments in former American football players. All analyses were adjusted for confounders associated with PVS volume.ResultsAnalyses included 224 participants (median [IQR] age, 57 [51-65] years), with 170 male former football players (114 former professional athletes, 56 former collegiate athletes) and 54 male unexposed control participants. Former football players had larger PVS volume compared with the unexposed group (mean difference, 0.28 [95% CI, 0.00-0.56]; P = .05). Within the football group, PVS volume was associated with higher CHII-R (β = 2.71 × 10−8 [95% CI, 0.50 × 10−8 to 4.93 × 10−8]; P = .03) and CHII-G (β = 2.24 × 10−6 [95% CI, 0.35 × 10−6 to 4.13 × 10−6]; P = .03). Larger PVS volume was also associated with worse performance on cognitive functioning in former American football players (β = −0.74 [95% CI, −1.35 to −0.13]; P = .04).Conclusions and RelevanceThese findings suggest that impaired perivascular brain clearance, as indicated by larger PVS volume, may contribute to the association observed between RHI exposure and neurodegeneration.

Background:Previous reports suggest that lipid droplets (LDs) in the hepatocyte can be catabolized by a direct engulfment from nearby endolysosomes (microlipophagy). Further, it is likely that this process is compromised by chronic ethanol (EtOH) exposure leading to hepatic steatosis. This study investigates the hepatocellular machinery supporting microlipophagy and EtOH-induced alterations in this process with a focus on the small, endosome-associated, GTPase Rab5.Methods and Results:Here we report that this small Ras-related GTPase is a resident component of LDs, and its activity is important for hepatocellular LD-lysosome proximity and physical interactions. We find that Rab5 siRNA knockdown causes an accumulation of LDs in hepatocytes by inhibiting lysosome dependent LD catabolism. Importantly, Rab5 appears to support this process by mediating the recruitment of early endosomal and or multivesicular body compartments to the LD surface before lysosome fusion. Interestingly, while wild-type or a constituently active GTPase form (Q79L) of Rab5 supports LD-lysosome transport, this process is markedly reduced in cells expressing a GTPase dead (S34N) Rab5 protein or in hepatocytes exposed to chronic EtOH.Conclusions:These findings support the novel premise of an early endosomal/multivesicular body intermediate compartment on the LD surface that provides a “docking” site for lysosomal trafficking, not unlike the process that occurs during the hepatocellular degradation of endocytosed ligands that is also known to be compromised by EtOH exposure.

Abstract Brain tumor diagnostics have significantly evolved with the use of positron emission tomography (PET) and advanced magnetic resonance imaging (MRI) techniques. In addition to anatomical MRI, these modalities may provide valuable information for several clinical applications such as differential diagnosis, delineation of tumor extent, prognostication, differentiation between tumor relapse and treatment-related changes, and the evaluation of response to anticancer therapy. In particular, joint recommendations of the Response Assessment in Neuro-Oncology (RANO) Group, the European Association of Neuro-oncology, and major European and American Nuclear Medicine societies highlighted that the additional clinical value of radiolabeled amino acids compared to anatomical MRI alone is outstanding and that its widespread clinical use should be supported. For advanced MRI and its steadily increasing use in clinical practice, the Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition provided more recently an updated acquisition protocol for the widely used dynamic susceptibility contrast perfusion MRI. Besides amino acid PET and perfusion MRI, other PET tracers and advanced MRI techniques (e.g. MR spectroscopy) are of considerable clinical interest and are increasingly integrated into everyday clinical practice. Nevertheless, these modalities have shortcomings which should be considered in clinical routine. This comprehensive review provides an overview of potential challenges, limitations, and pitfalls associated with PET imaging and advanced MRI techniques in patients with gliomas or brain metastases. Despite these issues, PET imaging and advanced MRI techniques continue to play an indispensable role in brain tumor management. Acknowledging and mitigating these challenges through interdisciplinary collaboration, standardized protocols, and continuous innovation will further enhance the utility of these modalities in guiding optimal patient care.

Abstract Background PARP-1 has a well-established role in DNA repair. PARP-1 selective inhibitors are a new subclass of PARPi that offer potential for improved tolerability. NMS-03305293 (NMS-293) is an oral, brain-penetrant PARP-1 selective inhibitor with strong antitumor activity in BRCA mutated preclinical models. Furthermore, NMS-293 is synergistic with temozolomide (TMZ) in glioblastoma mouse models. Methods Two phase I/I-II dose-escalation/expansion studies assessed safety, tolerability, and preliminary antitumor activity of NMS-293. Both are actively recruiting. In PARPA-293-001 (NCT04182516), NMS-293 was administered orally, ranging from 20 mg (QD) to 160 mg (BID) for 21 or 28 days on 28-day cycle in adult patients with advanced/metastatic, relapsed/refractory solid tumors who have exhausted standard treatment options. In PARPA-293-002 (NCT04910022), NMS-293 was administered in a range of doses orally, QD or BID on days 1-7 plus TMZ 150mg/m2 QD on days 1-5 in repeated 28-day cycle in adult patients with recurrent diffuse gliomas. Tumor responses were measured by investigator-assessed RANO criteria. Results The unpooled safety database at the data-cut-off (02-AUG-23), includes 45 patients in PARPA-001 and 21 patients in PARPA-002. PARPA-001 showed an MTD of 100 mg BID for 28 days on a 28-day cycle, a dose with meaningful PK relative to preclinical activity. PARPA-002 dose finding is ongoing with no DLTs as of cutoff date. The most frequent (≥10%) any-grade treatment related adverse events (TRAEs) in PARPA-001 were reversible QTcF prolongation, nausea, asthenia, decreased appetite and vomiting, mainly mild/moderate. In PARPA-002, with discontinuous NMS-293 plus TMZ, no G≥3 TRAEs were reported. The most frequent (≥10%) any-grade TRAEs were: nausea, fatigue, vomiting, decreased appetite, and platelet count decreased, mainly G1 adverse events. Overall, no dose-dependent trends of myelosuppression have been observed. 14 recurrent glioma patients across dose levels in PARPA-002 were evaluable for tumor response. A patient with glioblastoma had confirmed partial response (PR) with duration 7.6+ weeks, remaining on treatment at cutoff date. A patient with grade 3 IDH-mutant astrocytoma had unconfirmed PR with ongoing tumor shrinkage at 16.1+ weeks. A patient with glioblastoma had complete radiological disappearance of enhancing non-target lesions, remaining on treatment at cutoff date. NMS-293 PK profiles showed an increase in exposure with the dose with approximately 5 to 13 hours half-life. Conclusion NMS-293, a PARP-1 selective, brain penetrant inhibitor was well tolerated in phase I clinical trials with no dose dependent trends of myelosuppression. Furthermore, NMS-293 showed encouraging clinical activity in combination with TMZ in difficult-to-treat recurrent glioma patients. Citation Format: Marjolein Geurts, Dorothee Gramatzki, Sara Merler, Matteo Duca, Fabio Girardi, Ugur T. Sener, Domenico Roberti, Grazia Saturno, Patrizia Crivori, Alessia Montagnoli, Lisa Mahnke, Siqing Fu, Paola Gaviani, Kurt A. Jaeckle, Jian Zhang, Yehui Shi, Valentina Guarneri, Michael Weller, Sani H. Kizilbash, Martin J. van den Bent, Michele Milella, Silvia Damian. Initial results from 2 Phase I studies of NMS-03305293, a selective PARP1 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A12.

Steatotic hepatocytes accumulate profound numbers of large neutral lipid‐storage organelles called lipid droplets (LDs). The process by which the formation or utilization of these organelles are perturbed during NAFLD and NASH is poorly defined. EtOH consumption can also exacerbate these conditions markedly by yet unknown mechanisms. Thus, there is a critical need to understand lipolytic mechanisms for LD catabolism in hepatocytes. In adipocytes, catecholamines induce lipolysis through a β‐adrenergic/cAMP pathway that activates cytosolic lipases ATGL and HSL to catabolize LD triglycerides. Importantly, β‐adrenergic induction of LD catabolism has not been demonstrated in hepatocytes. Thus, the GOAL of this study was to determine whether hepatocytes, like adipocytes, also undergo cAMP‐mediated lipolysis in response to β‐adrenergic (β‐AR) stimulation. First, treatment of primary rat hepatocytes or Hep3B human hepatoma cells with the β‐AR agonist isoproterenol caused a 20–40% reduction in total cellular LD content within 24 hours. β‐AR induced LD loss was mimicked by the cAMP agonist forskolin/IBMX and was abrogated by the cAMP‐dependent protein kinase (PKA) inhibitor H89. In correlation, PKA activation following β‐AR stimulation was confirmed by FRET biosensors and biochemical analysis. β‐AR stimulation directly activated the lipolytic pathway, as evidenced by cAMP/PKA‐mediated phosphorylation of hormone sensitive lipase (HSL) and adipose triglyceide lipase (ATGL). In addition, pharmacological inhibitors against ATGL or HSL each blocked β‐AR induced LD loss, suggesting that lipase activation is critical for this process in stimulated cells. To examine whether β‐AR/cAMP stimulation triggered lipase recruitment directly to the LD, live‐cell imaging of Hep3B cells expressing either ATGL‐EGFP or HSL‐sfGFP showed that within 60 min of stimulation, each lipase was significantly displaced from the cytosol and recruited to the LD surface. This recruitment was blocked by the PKA inhibitor H89. Finally, to test if EtOH exposure attenuates the activation of lipolysis in hepatocytes, we isolated primary hepatocytes from rats fed a 6‐week ethanol‐containing Lieber‐DeCarli diet. Compared with controls, ethanol‐exposed hepatocytes showed a drastic inhibition in lipase activation and LD breakdown following β‐AR/cAMP stimulation. Remarkably, in ethanol‐metabolizing VA13 hepatocytes, ethanol insult completely prevented isoproterenol‐induced translocation of ATGL‐EGFP to the LD. In summary , these results show that β‐adrenergic stimulation mobilizes cytosolic lipases for LD breakdown in hepatocytes, and perturbation of this pathway could be a major consequence of chronic ethanol insult leading to fatty liver. Manipulation of this regulatory cascade could be useful in developing new therapies to attenuate fatty liver disease. Support or Funding Information This study was generously supported by funding from NIAAA 5R01AA020735 (MAM and CAC) and NIDDK 5R37DK044650 (MAM), T32DK007352‐36 (MBS), and P30DK084567 (Mayo Clinic Center for Cell Signaling in Gastroenterology).

PURPOSE The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time, some limitations of these criteria were identified, and challenges emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. METHODS Informed by data from studies evaluating the different criteria, updates to the RANO criteria are proposed (RANO 2.0). RESULTS We recommend a standard set of criteria for both high- and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the postradiotherapy magnetic resonance imaging (MRI), rather than the postsurgical MRI, will be used as the baseline for comparison with subsequent scans. Since the incidence of pseudoprogression is high in the 12 weeks after radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, are required to define tumor progression. However, confirmation scans are not mandatory after this period nor for the evaluation of treatment for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (two-dimensional) but volumetric measurements are an option. For IDH wild-type glioblastoma, the nonenhancing disease will no longer be evaluated except when assessing response to antiangiogenic agents. In IDH-mutated tumors with a significant nonenhancing component, clinical trials may require evaluating both the enhancing and nonenhancing tumor components for response assessment. CONCLUSION The revised RANO 2.0 criteria refine response assessment in gliomas.

Abstract Tumor-related epilepsy (TRE) is a frequent and major consequence of brain tumors. Management of TRE is required throughout the course of disease and a deep understanding of diagnosis and treatment is key to improving quality of life. Gross total resection is favored from both an oncologic and epilepsy perspective. Shared mechanisms of tumor growth and epilepsy exist, and emerging data will provide better targeted therapy options. Initial treatment with antiseizure medications (ASM) in conjunction with surgery and/or chemoradiotherapy is typical. The first choice of ASM is critical to optimize seizure control and tolerability considering the effects of the tumor itself. These agents carry a potential for drug–drug interactions and therefore knowledge of mechanisms of action and interactions is needed. A review of adverse effects is necessary to guide ASM adjustments and decision-making. This review highlights the essential aspects of diagnosis and treatment of TRE with ASMs, surgery, chemotherapy, and radiotherapy while indicating areas of uncertainty. Future studies should consider the use of a standardized method of seizure tracking and incorporating seizure outcomes as a primary endpoint of tumor treatment trials.

Abstract BACKGROUND The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time some limitations of these criteria were identified, and uncertainty emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. MATERIAL AND METHODS Informed by data from a cohort of glioblastoma patients and other evaluations of RANO criteria that allowed evaluation of features of the different criteria, the RANO working group developed updates to the RANO criteria (RANO 2.0). RESULTS Based on the 2021 WHO classification of gliomas, we recommend a standard set of criteria for both high and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the post-radiotherapy MRI, rather than the post-surgical MRI, will be used as the baseline for future comparison. Since the incidence of pseudoprogression is high in the 12 weeks following radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, is required to define tumor progression. However, confirmation scans are not mandatory after this period nor for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (2-dimensional) but volumetric measurements are an option. For IDH-wildtype glioblastoma, the non-enhancing disease will no longer be evaluated. In IDH-mutated tumors with a significant non-enhancing component, clinical trials may require evaluating both the enhancing and non-enhancing tumor components for response assessment. CONCLUSION These criteria represent a work in progress that will hopefully improve the assessment of response in glioma trials. Future updates will incorporate novel developments, advanced imaging techniques, and endpoints as they become validated.

Abstract The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve the reliability of response assessment in glioma trials. Over time some limitations of these criteria were identified, and uncertainty emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. Informed by data from a cohort of glioblastoma patients and other evaluations of RANO criteria that allowed evaluation of features of the different criteria, we propose updates to the RANO criteria (RANO 2.0). Based on the 2021 WHO classification of gliomas, we recommend a standard set of criteria for both high and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the post-radiotherapy MRI, rather than the post-surgical MRI, will be used as the baseline for future comparison. Since the incidence of pseudoprogression is high in the 12 weeks following radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, is required to define tumor progression. However, confirmation scans are not mandatory after this period nor for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is an option. The primary measurement remains the maximum cross-sectional area of tumor (2-dimensional) but volumetric measurements are an option. For IDH-wildtype glioblastoma, the non-enhancing disease will no longer be evaluated. In IDH-mutated tumors with a significant non-enhancing component, clinical trials may require evaluating both the enhancing and non-enhancing tumor components for response assessment.