Treatment Of Malignant Brain Tumors Research Articles

295 High Volume Centers Provide Superior Value of Care in the Surgical Treatment of Malignant Brain Tumor

INTRODUCTION: Improved outcomes in surgical patients have been associated with increasing volume of cases. This has led to the development of centers that facilitate care for a specific patient population. METHODS: The 2016-2020 National Inpatient Sample (NIS) was queried for patients undergoing resection of malignant brain tumors. Teaching hospitals with high case load (greater than two standrad deviations above the mean, or >140 cases) were categorized as high-volume centers (HVC). Value of care was computed by adding one point for each of the following variables: lower length of stay, lower total charges, discharge to home, and lack of major comorbidity or complication, as defined per DRG codes. RESULTS: A total of 118,390 patients underwent resection of malignant brain tumors in 3,009 hospitals. HVC criteria was met by 91 (3%) hospitals, which represented 20,230 (17.1%) of total cases. The Mid-Atlantic and South Atlantic regions had the highest percentage of cases (22.7% and 20.2%, respectively) and number of HVC (21 and 17, respectively). Value of care was higher at HVC (OR = 1.35 95%CI 1.31-1.39 p < 0.01). After controlling for baseline risk factors and high risk admissions, HVC was associated with decreased complications of intracranial hemorrhage, deep venous thrombosis, aspiration pneumonitis, acute kidney injury, and external ventricular drain requirement (p < 0.01 for all). HVC was also associated with decreased length of stay and increased rate of discharge to home (p < 0.01 for both). CONCLUSIONS: Patients undergoing craniotomy for malignant brain neoplasms have superior outcomes in HVC. Trends of centralization are likely a reflection of the benefits of multidisciplinary treatment for these patients. Improvement of access to care at these institutions may improve the efficiency of the delivery of care for these patients.

Comparison of ASL and DSC perfusion methods in the evaluation of response to treatment in patients with a history of treatment for malignant brain tumor

ObjectivePerfusion MRI is of great benefit in the post-treatment evaluation of brain tumors. Interestingly, dynamic susceptibility contrast-enhanced (DSC) perfusion has taken its place in routine examination for this purpose. The use of arterial spin labeling (ASL), a perfusion technique that does not require exogenous contrast material injection, has gained popularity in recent years. The aim of the study was to compare two different perfusion techniques, ASL and DSC, using qualitative and quantitative measurements and to investigate the diagnostic effectiveness of both. The fact that the number of patients is higher than in studies conducted with 3D pseudo-continious ASL (pCASL), the study group is heterogeneous as it consists of patients with both metastases and glial tumors, the use of 3D Turbo Gradient Spin Echo (TGSE), and the inclusion of visual (qualitative) assessment make our study unique.MethodsNinety patients, who were treated for malignant brain tumor, were enrolled in the retrospective study. DSC Cerebral Blood Volume (CBV), Cerebral Blood Flow (CBF) and ASL CBF maps of each case were obtained. In qualitative analysis, the lesions of the cases were visually classified as treatment-related changes (TRC) and relapse/residual mass (RRT). In the quantitative analysis, three regions of interest (ROI) measurements were taken from each case. The average of these measurements was compared with the ROI taken from the contralateral white matter and normalized values (n) were obtained. These normalized values were compared across events.ResultsUncorrected DSC normalized CBV (nCBV), DSC normalized CBF (nCBF) and ASL nCBF values of RRT cases were higher than those of TRC cases (p < 0.001). DSC nCBV values were correlated with DSC nCBF (r: 0.94, p < 0.001) and correlated with ASL nCBF (r: 0.75, p < 0.001). Similarly, ASL nCBF was positively correlated with DSC nCBF (r: 0.79 p < 0.01). When the ROC curve parameters were evaluated, the cut-off values were determined as 1.211 for DSC nCBV (AUC: 0.95, 93% sensitivity, 82% specificity), 0.896 for DSC nCBF (AUC; 0.95, 93% sensitivity, 82% specificity), and 0.829 for ASL nCBF (AUC: 0.84, 78% sensitivity, 75% specificity). For qualitative evaluation (visual evaluation), inter-observer agreement was found to be good for ASL CBF (0.714), good for DSC CBF (0.790), and excellent for DSC CBV (0.822). Intra-observer agreement was also evaluated. For the first observer, good agreement was found in ASL CBF (0.626, 70% sensitive, 93% specific), in DSC CBF (0.713, 76% sensitive, 95% specific), and in DSC CBV (0.755, 87% sensitive - 88% specific). In the second observer, moderate agreement was found in ASL CBF (0.584, 61% sensitive, 97% specific) and DSC CBF (0.649, 65% sensitive, 100% specific), and excellent agreement in DSC CBV (0.800, 89% sensitive, 90% specific).ConclusionIt was observed that uncorrected DSC nCBV, DSC nCBF and ASL nCBF values were well correlated with each other. In qualitative evaluation, inter-observer and intra-observer agreement was higher in DSC CBV than DSC CBF and ASL CBF. In addition, DSC CBV is found more sensitive, ASL CBF and DSC CBF are found more specific for both observers. From a diagnostic perspective, all three parameters DSC CBV, DSC CBF and ASL CBF can be used, but it was observed that the highest rate belonged to DSC CBV.

Abstract A021: Exosome delivered combinatorial treatment for malignant brain tumors

Abstract Glioblastoma (GBM), a World Health Organization (WHO) Grade IV astrocytoma, is a highly aggressive brain tumor with poor prognosis. Current therapeutic approaches, which include surgery, chemotherapy, and radiation therapy, are largely ineffective and often result in tumor recurrence. Several characteristics of the tumors make them challenging to treat, including their protection by the blood-brain barrier, which hinders effective treatment delivery. Our research addresses this issue by using exosomes, which are small cell-derived vesicles, as delivery vehicles for microRNA (miR) therapies. Dysregulation of miR expression has been implicated in tumorigenesis, and targeting these dysregulated miRs is emerging as a promising approach to tumor treatment. In particular, miR-7 and miR-124 have been identified as tumor-suppressive miRs that are downregulated in various tumors, including GBM. In this study, stem cell-derived exosomes loaded with miR-7 and miR-124 have been evaluated as a combinatorial approach for treating GBM. In our work, human adipose stem cells (ADSCs) were transduced with the target miR-7 and miR-124 plasmids and cultured in exosome-depleted FBS. The miR-containing exosomes from the ADSCs were then isolated, purified, quantified, and characterized for use in subsequent studies. Murine and human GBM cells as well as primary patient-derived primary GBM cells were treated with miR-7 and miR-124 exosomes, and the efficacy of exosome treatment was determined using cell viability assays and microscopy. The mechanisms of miR modulation of cell proliferation and cell death pathways were analyzed with time-course western blot analysis. Orthotopic animal models of GBM will be used to assess the effectiveness of our methods in vivo. Our results have demonstrated successful delivery of miR-7 and miR-124 to GBM cells via stem cell-derived exosomes. Data show that treatment with these tumor-suppressive miRs halts GBM growth in vitro by modulating multiple pathways involved in tumor growth and progression. While we await results of our in vivo studies, our preliminary data demonstrate that delivery of miR-7 and miR-124 via stem cell-derived exosomes is a promising therapeutic approach for treating GBM. Citation Format: Sydney Thomas, Karthik Gourishetti, Karthik Rangavajhula, Deepak Bhere. Exosome delivered combinatorial treatment for malignant brain tumors [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A021.

High-Volume Centers Provide Superior Value of Care in the Surgical Treatment of Malignant Brain Tumor

Improved outcomes in surgical patients have been associated with increasing volume of cases. This has led to the development of centers that facilitate care for a specific patient population. To evaluate associations of outcomes with hospital characteristics in patients undergoing resection of malignant brain tumors. The 2016-2020 National Inpatient Sample (NIS) was queried for patients undergoing resection of malignant brain tumors. Teaching hospitals with case loads greater than two standard deviations above the mean (140 cases) were categorized as high-volume centers (HVC). Value of care (VoC) was evaluated by adding one point for each of the following: short length of stay, low total charges, favorable discharge disposition, and lack of major comorbidity or complication. A total of 118,390 patients underwent resection of malignant brain tumors in 3009 hospitals. HVC criteria was met by 91 (3%) hospitals. HVC were more likely to treat patients of younger age or higher socioeconomic status (p < 0.01 for all). The Mid-Atlantic and South Atlantic regions had the highest percentage of cases and number of HVC. VoC was higher at HVC (p < 0.01). HVC was associated with decreased complications (p < 0.01 for all) and improved patient outcomes (p < 0.01 for all). Patients undergoing craniotomy for malignant brain neoplasms have superior outcomes in HVC. Trends of centralization may be a reflection of the benefits of multidisciplinary treatment, geographic preferences, publicity, and cultural impact. Improvement of access to care is an important consideration as this trend continues.

Magnetotherapy in Experimental and Clinical Neuro-Oncology: A Review

The purpose of this publication is not to state the fact of the high antitumor effectiveness of the gold standard treatment of malignant brain tumors (surgical intervention with adjuvant chemoradiotherapy), but to consider the possibility of using alternative therapeutic options, in particular, magnetotherapy, as a component of the treatment of patients with this serious pathology, as well as a method of preventing a number of postoperative adverse reactions.

Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood‒brain barrier.

Glioblastoma (GBM) is the most aggressive malignant brain tumor and has a high mortality rate. Photodynamic therapy (PDT) has emerged as a promising approach for the treatment of malignant brain tumors. However, the use of PDT for the treatment of GBM has been limited by its low blood‒brain barrier (BBB) permeability and lack of cancer-targeting ability. Herein, brain endothelial cell-derived extracellular vesicles (bEVs) were used as a biocompatible nanoplatform to transport photosensitizers into brain tumors across the BBB. To enhance PDT efficacy, the photosensitizer chlorin e6 (Ce6) was linked to mitochondria-targeting triphenylphosphonium (TPP) and entrapped into bEVs. TPP-conjugated Ce6 (TPP-Ce6) selectively accumulated in the mitochondria, which rendered brain tumor cells more susceptible to reactive oxygen species-induced apoptosis under light irradiation. Moreover, the encapsulation of TPP-Ce6 into bEVs markedly improved the aqueous stability and cellular internalization of TPP-Ce6, leading to significantly enhanced PDT efficacy in U87MG GBM cells. An invivo biodistribution study using orthotopic GBM-xenografted mice showed that bEVs containing TPP-Ce6 [bEV(TPP-Ce6)] substantially accumulated in brain tumors after BBB penetration via transferrin receptor-mediated transcytosis. As such, bEV(TPP-Ce6)-mediated PDT considerably inhibited the growth of GBM without causing adverse systemic toxicity, suggesting that mitochondria are an effective target for photodynamic GBM therapy.

P.102 Weighing the risks and benefits of perioperative steroids in the surgical treatment of malignant brain tumours

Background: Steroids are widely used in medicine because of their anti-inflammatory and immunosuppressive properties; however, they have numerous adverse effects. In neuro-oncology, dexamethasone is the first-line treatment for vasogenic edema caused by malignant brain tumours. This retrospective chart review investigated the risks and benefits of perioperative steroids in the surgical treatment of malignant brain tumours. Methods: All patients (age ≥ 18 years) who underwent a craniotomy for the treatment of a malignant brain tumour at Windsor Regional Hospital between 2012 and 2020 were assessed for eligibility for this retrospective study. Baseline patient characteristics, cumulative perioperative steroid dose, and postoperative outcomes were recorded from electronic medical records (n = 362). Statistical analysis was performed using SPSS. Results: Patients who received a higher cumulative perioperative steroid dose (≥ 80 mg) had a significantly higher rate of postoperative complications compared to those who received a lower dose. These included wound dehiscence, postoperative brain edema on imaging, unplanned return to the operating room, and readmission within 30 days. Conclusions: Steroids are important medications in neuro-oncology, but they are not without potential complications. The findings of this study highlight the need for careful consideration when using steroids in patients undergoing surgical treatment of a malignant brain tumour.

The Use of Stereotactic Radiosurgery to Treat Functional Disorders: A Topic Discussion

Stereotactic radiosurgery (SRS) is a well-known modality for the treatment of malignant brain tumors. SRS, however, can also be used to treat non-malignant functional disorders such as epilepsy, tremor, trigeminal neuralgia (TN), obsessive compulsive disorder (OCD), and intractable pain among others. Given the limited prospective data guiding treatment of these benign disorders, this article serves as a consolidated discussion of the application of SRS for functional ailments, hopefully serving as a reference for those considering application of this technique in clinical practice.

Perfusion-Weighted Imaging: The Use of a Novel Perfusion Scoring Criteria to Improve the Assessment of Brain Tumor Recurrence versus Treatment Effects.

Imaging surveillance of contrast-enhancing lesions after the treatment of malignant brain tumors with radiation is plagued by an inability to reliably distinguish between tumor recurrence and treatment effects. Magnetic resonance perfusion-weighted imaging (PWI)-among other advanced brain tumor imaging modalities-is a useful adjunctive tool for distinguishing between these two entities but can be clinically unreliable, leading to the need for tissue sampling to confirm diagnosis. This may be partially because clinical PWI interpretation is non-standardized and no grading criteria are used for assessment, leading to interpretation discrepancies. This variance in the interpretation of PWI and its subsequent effect on the predictive value has not been studied. Our objective is to propose structured perfusion scoring criteria and determine their effect on the clinical value of PWI. Patients treated at a single institution between 2012 and 2022 who had prior irradiated malignant brain tumors and subsequent progression of contrast-enhancing lesions determined by PWI were retrospectively studied from CTORE (CNS Tumor Outcomes Registry at Emory). PWI was given two separate qualitative scores (high, intermediate, or low perfusion). The first (control) was assigned by a neuroradiologist in the radiology report in the course of interpretation with no additional instruction. The second (experimental) was assigned by a neuroradiologist with additional experience in brain tumor interpretation using a novel perfusion scoring rubric. The perfusion assessments were divided into three categories, each directly corresponding to the pathology-reported classification of residual tumor content. The interpretation accuracy in predicting the true tumor percentage, our primary outcome, was assessed through Chi-squared analysis, and inter-rater reliability was assessed using Cohen's Kappa. Our 55-patient cohort had a mean age of 53.5 ± 12.2 years. The percentage agreement between the two scores was 57.4% (κ: 0.271). Upon conducting the Chi-squared analysis, we found an association with the experimental group reads (p-value: 0.014) but no association with the control group reads (p-value: 0.734) in predicting tumor recurrence versus treatment effects. With our study, we showed that having an objective perfusion scoring rubric aids in improved PWI interpretation. Although PWI is a powerful tool for CNS lesion diagnosis, methodological radiology evaluation greatly improves the accurate assessment and characterization of tumor recurrence versus treatment effects by all neuroradiologists. Further work should focus on standardizing and validating scoring rubrics for PWI evaluation in tumor patients to improve diagnostic accuracy.

Utilization of Palliative Care Services Among Patients With Malignant Brain Tumors: An Analysis of the National Inpatient Sample (2016-2019).

Recent advances in treatment of malignant brain tumors have improved outcomes. However, patients continue to experience significant disability. Palliative care helps patients with advanced illnesses improve their quality of life. There is a paucity of clinical studies examining palliative care usage among patients with malignant brain tumors. To assess if there were any patterns in palliative care utilization among patients hospitalized with malignant brain tumors. A retrospective cohort representing hospitalizations for malignant brain tumors was created from The National Inpatient Sample (2016-2019). Palliative care utilization was identified by ICD-10 code. Univariable and multivariable logistic regression models, accounting for the sample design, were built to evaluate the demographic variables associated with palliative care consultation in all patients and fatal hospitalizations. 375 010 patients admitted with a malignant brain tumor were included in this study. Over the whole cohort, 15.0% of patients used palliative care. In fatal hospitalizations, Black and Hispanic patients had 28% lower odds of receiving a palliative care consultation compared with White patients (odds ratio for both = 0.72; P = .02). For fatal hospitalizations, patients insured privately were 34% more likely to use palliative care services compared with patients insured with Medicare (odds ratio = 1.34, P = .006). Palliative care is underutilized among all patients with malignant brain tumors. Within this population, disparities in utilization are exacerbated by sociodemographic factors. Prospective studies investigating utilization disparities across race and insurance status are necessary to improve access to palliative care services for this population.

Development of prospects for adjuvant treatment of malignant brain tumors in experiments on C6 glioma

The treatment of malignant tumors and their postoperative relapses is largely limited by toxic manifestations from a large number of known chemotherapy drugs. Finding a way to reduce the toxicity of drugs while maintaining their antitumor activity is a major challenge. In this work, the highly toxic drug gemcitabine was diluted 100 and 10,000 times with ion-free water and, together with verapamil hydrochloride, at a dilution of 10,000 times, was studied for the ability, when used together, to influence the blood cell aggregation. Our previous studies with low concentrations of verapamil showed a satisfactory effect in the treatment of malignant brain gliomas. In an experiment with C6 glioma in Wistar rats, the blood cell aggregation (SPR indicators) was determined daily in vitro under the combined action of gemcitabine and verapamil at low concentrations. The daily effect of these drugs on the level of blood cell aggregation turned out to be very variable, which is an important argument against the use of chemotherapy drugs in doses that are narrowly limited by protocols. The study of the correlation coefficients between the surface plasmon resonance (SPR indicators) and the quantitative composition of cell fractions in rats after transplantation of C6 glioma made it possible to determine the scope of regenerative processes in the tumor tissue and its microenvironment, which can also make changes in the methods of tumor treatment.

Combined Effects of Focused Ultrasound and Photodynamic Treatment for Malignant Brain Tumors Using C6 Glioma Rat Model.

Glioblastoma (GBM) is an intractable disease for which various treatments have been attempted, but with little effect. This study aimed to measure the effect of photodynamic therapy (PDT) and sonodynamic therapy (SDT), which are currently being used to treat brain tumors, as well as sono-photodynamic therapy (SPDT), which is the combination of these two. Four groups of Sprague-Dawley rats were injected with C6 glioma cells in a cortical region and treated with PDT, SDT, and SPDT. Gd-MRI was monitored weekly and 18F-FDG-PET the day before and 1 week after the treatment. The acoustic power used during sonication was 5.5 W/cm² using a 0.5-MHz single-element transducer. The 633-nm laser was illuminated at 100 J/cm². Oxidative stress and apoptosis markers were evaluated 3 days after treatment using immunohistochemistry (IHC): 4-HNE, 8-OhdG, and Caspase-3. A decrease in tumor volume was observed in MRI imaging 12 days after the treatment in the PDT group (p<0.05), but the SDT group showed a slight increase compared to the 5-Ala group. The high expression rates of reactive oxygen species-related factors, such as 8-OhdG (p<0.001) and Caspase-3 (p<0.001), were observed in the SPDT group compared to other groups in IHC. Our findings show that light with sensitizers can inhibit GBM growth, but not ultrasound. Although SPDT did not show the combined effect in MRI, high oxidative stress was observed in IHC. Further studies are needed to investigate the safety parameters to apply ultrasound in GBM.

EXTH-30. PHARMACOKINETICS- AND PHARMACODYNAMICS-BASED EVALUATION OF QUISINOSTAT AS A RADIOSENSITIZER IN PRECLINICAL MODELS OF GBM

Abstract Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. Class I HDACs mediate chromatin compaction and are frequently overexpressed in GBM. Hence, there has been considerable interest in HDAC inhibitors (HDACi) for the treatment of malignant brain tumors. However, to date almost all HDACi tested clinically have failed to provide significant therapeutic benefit to primary and recurrent GBM patients. These HDACi are broad-spectrum with poor or unknown pharmacokinetic profiles and narrow therapeutic window. Isoform specificity for HDACi is important given that not all HDAC enzymes are equally expressed in GBM. Recently, we uncovered the functional importance of HDAC1 in therapy-resistant glioma stem cells, where we found that its expression increases with brain tumor grade and is correlated with decreased survival. While no class I HDAC isoform-specific inhibitors are currently available, the second-generation HDACi quisinostat harbors high specificity for HDAC1. In this study, we assessed the pharmacokinetic, pharmacodynamic and radiation-sensitizing properties of quisinostat in preclinical models of human GBM. In vitro analyses conducted in patient-derived glioma stem cell (GSC) lines revealed that quisinostat exhibited potent growth inhibition, induced global histone hyperacetylation, elevated DNA damage, cell death and cell cycle arrest. To determine the efficacy and drug distribution profile of quisinostat in vivo, athymic mice with orthotopic or flank tumors were treated with an optimized treatment schedule. At various timepoints during treatment, plasma and brain/tumor tissue were collected to measure total and unbound drug levels by liquid chromatography tandem mass spectrometry (LC-MS/MS), coupled with transcriptomic and pharmacodynamic analyses of tumor tissues. We demonstrate quisinostat is a brain-penetrant molecule that reduces tumor burden in flank and orthotopic models of GBM, and significantly extends survival when administered with radiation. Together, these results provide a rationale for developing quisinostat as a potential combination therapy with radiation for the treatment of GBM.

Patient-derived tumor organoids as a platform of precision treatment for malignant brain tumors

Malignant brain tumors consist of malignancies originated primarily within the brain and the metastatic lesions disseminated from other organs. In spite of intensive studies, malignant brain tumors remain to be a medical challenge. Patient-derived organoid (PDO) can recapitulate the biological features of the primary tumor it was derived from and has emerged as a promising drug-screening model for precision therapy. Here we show a proof-of-concept based on early clinical study entailing the organoids derived from the surgically resected tumors of 26 patients with advanced malignant brain tumors enrolled during December 2020 to October 2021. The tumors included nine glioma patients, one malignant meningioma, one primary lymphoma patient, and 15 brain metastases. The primary tumor sites of the metastases included five from the lungs, three from the breasts, two from the ovaries, two from the colon, one from the testis, one of melanoma origin, and one of chondrosarcoma. Out of the 26 tissues, 13 (50%) organoids were successfully generated with a culture time of about 2 weeks. Among these patients, three were further pursued to have the organoids derived from their tumor tissues tested for the sensitivity to different therapeutic drugs in parallel to their clinical care. Our results showed that the therapeutic effects observed by the organoid models were consistent to the responses of these patients to their treatments. Our study suggests that PDO can recapitulate patient responses in the clinic with high potential of implementation in personalized medicine of malignant brain tumors.

Cytomegalovirus infection of brain tumors and CMV immunotherapy

Objective. The article presents the literature of the last ten years and the results of our own research on the importance of cytomegalovirus (CMV) in the development of brain tumors, especially glioblastoma and medulloblastoma. Two alternative views are discussed - the pros and cons of the role of the virus in the induction and stimulation of tumor growth.Materials and methods. 256 samples of biotic material of tissues of various brain tumors were studied. Among them are histologically diagnosed: in 123 cases glial tumors of various grade of malignancy, in 51 cases meningiomas, in 25 cases medulloblastomas, in 16 cases oligodendroastrocytomas of the second grade of malignancy, in 14 cases metastatic tumors. Tumor fragments were obtained from biopsy material 1.5-2.0 hours after surgical removal. To detect the presence of CMV in the tumor tissue real-time polymerase chain reaction (PCR) using "DNA sorb A and B" kits was performed, the company "Amplisens" (Russia), according to the manufacturer’s instructions and BioRal device (USA) with standard DNA detection kits of CMV "DNA Technology" (Russia). Cytological imprints on slides were also made from tumor tissue fragments, which were examined by indirect immunofluorescence method with monoclonal antibodies to CMV pP-65 protein using the "MonoScan CMV" kit.Results. The frequency of detection of CMV antigen or its DNA in brain tissue depends on the research method - the immunofluorescence method detects pP-65 antigen by monoclonal antibodies 2-2.5 times more often than the PCR method of CMV in tumor tissue. In the tissue of different histogenesis of brain tumors both the pP-65 antigen and CMV DNA are detected with different frequencies. CMV was most often detected in tumors of glial origin and medulloblastomas. No CMV DNA was detected in the peripheral blood of patients with brain tumors at the time of admission for examination and surgical treatment, indicating an earlier contamination of the tumor focus with this virus. Data on the mechanisms of CMV induction and stimulation of tumor growth by activating cell proliferation, including nerve stem cells, are presented. Works using specific antiviral therapy and CMV specific cell immunotherapy in the treatment of gliomas have been analyzed in detail.Conclusions. The paper concludes on the important clinical and prognostic value of determining CMV infection in brain tumors and indicates the need for CMV viral and cellular immunotherapy in the combined treatment of malignant brain tumors.

Abstract 349: Pharmacokinetics- and pharmacodynamics-based evaluation of quisinostat as a radiosensitizer in preclinical models of human glioblastoma

Abstract Glioblastoma (GBM), the most common and aggressive primary brain tumor affecting adults, is characterized by an aberrant yet druggable epigenetic landscape. Class I histone deacetylases (HDACs) mediate chromatin compaction and are frequently overexpressed in GBM. Hence, over the last decade, there has been considerable interest in HDAC inhibitors (HDACi) for the treatment of malignant brain tumors. However, to date almost all HDACi tested clinically have failed to provide significant therapeutic benefit to primary and recurrent GBM patients. These HDACi are broad-spectrum with poor or unknown pharmacokinetic profiles and have narrow therapeutic window. Isoform specificity for HDACi is important given that not all HDAC enzymes are equally expressed in GBM. Recently, we uncovered the functional importance of HDAC1 in therapy-resistant glioma stem cells, where we found that its expression increases with brain tumor grade and is correlated with decreased survival. While no class I HDAC isoform-specific inhibitors are currently available, the second-generation HDACi, quisinostat harbors high specificity for HDAC1. In this study, we assessed the pharmacokinetic, pharmacodynamic and radiosensitizing properties of quisinostat in preclinical models of human GBM. In vitro analyses conducted in patient-derived glioma stem cell (GSC) lines revealed that quisinostat exhibited potent growth inhibition in multiple GSC lines (IC50 ~ 50-86 nM), and induced global histone hyperacetylation, elevated DNA damage, cell death, cell cycle arrest and decreased expression of multiple key stem cell proteins. To determine the efficacy and drug distribution profile of quisinostat in vivo, athymic mice with orthotopic or flank tumors were treated with an optimized treatment schedule. At various timepoints during treatment, plasma and brain/tumor tissue were collected to measure total and unbound drug levels by liquid chromatography tandem mass spectrometry (LC-MS/MS) and assess pharmacodynamic changes within tumor tissues. We found that quisinostat reduces tumor burden in flank and orthotopic models of GBM and extends survival when administered in combination with radiation therapy in vivo. Together, these results provide a rationale for developing quisinostat as a potential combination therapy with radiation in the treatment of GBM. Citation Format: Costanza Lo Cascio, Tigran Margaryan, Ernesto Luna Melendez, James McNamara, William Knight, Sarah Himes, Connor White, Alexis Giff, Jesus Peralta, Nader Sanai, Artak Tovmasyan, Shwetal Mehta. Pharmacokinetics- and pharmacodynamics-based evaluation of quisinostat as a radiosensitizer in preclinical models of human glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 349.

Iron Transporters and Ferroptosis in Malignant Brain Tumors.

Malignant brain tumors represent approximately 1.5% of all malignant tumors. The survival rate among patients is relatively low and the mortality rate of pediatric brain tumors ranks first among all childhood malignant tumors. At present malignant brain tumors remain incurable. Although some tumors can be treated with surgery and chemotherapy, new treatment strategies are urgent owing to the poor clinical prognosis. Iron is an essential trace element in many biological processes of the human body. Iron transporters play a crucial role in iron absorption and transport. Ferroptosis, an iron-dependent form of nonapoptotic cell death, is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism. Recently, compelling evidence has shown that inducing ferroptosis of tumor cells is a potential therapeutic strategy. In this review, we will briefly describe the significant regulatory factors of ferroptosis, iron, its absorption and transport under physiological conditions, especially the function of iron transporters. Then we will summarize the relevant mechanisms of ferroptosis and its role in malignant brain tumors, wherein the role of transporters is not to be ignored. Finally, we will introduce the current research progress in the treatment of malignant brain tumors by inducing ferroptosis in order to explain the current biological principles of potential treatment targets and treatment strategies for malignant brain tumors.

Identification and quantitative structure–activity relationship assessment of trace chemical impurities contained in the therapeutic formulation of [64Cu]Cu-ATSM

Background[64Cu]Cu-diacethyl-bis(N4-methylthiosemicarbazone) ([64Cu]Cu-ATSM) is a radioactive hypoxia-targeting therapeutic agent, and the efficacy and safety of [64Cu]Cu-ATSM in the treatment of malignant brain tumors are evaluated in clinical trials. For the clinical application of [64Cu]Cu-ATSM, we determined a drug formulation incorporating a stabilizer against radiolysis and confirmed its radiochemical stability. This study aimed to identify trace chemical impurities derived from the degradation of ATSM contained in the [64Cu]Cu-ATSM investigational drug formulation and assess their potential hazards by quantitative structure–activity relationship (QSAR) assessment. MethodsWe hypothesized that the chemical impurities contained in the [64Cu]Cu-ATSM formulation were derived from the degradation of ATSM. Therefore, we first identified the degradants of ATSM using LC-MS/MS. ATSM was dissolved with the drug formulation of [64Cu]Cu-ATSM, except for 64Cu, and analyzed by LC-MS/MS at 0 and 48 h after sample preparation. Subsequently, the chemical impurities contained in the [64Cu]Cu-ATSM formulation were measured at 0, 5, and 24 h after preparation by HPLC, and the results were compared to the degradants of ATSM. The potential hazards of the chemical impurities contained in the [64Cu]Cu-ATSM formulation were assessed using the QSAR Toolbox (ver. 4.3). ResultsSix ATSM degradants were detected and identified by LC-MS/MS analysis, indicating that the functional groups around the nitrogen and sulfur atoms of ATSM were affected. The same peaks were detected as trace chemical impurities in the [64Cu]Cu-ATSM formulation at 24 h, while no apparent peaks were detected at 0 and 5 h. The estimated LD50 values of these chemical impurities showed 4.31 mg/kg or more by QSAR assessment. In contrast, the estimated amount of each chemical impurity exposed to patients was 31.8 ng/kg or less per dose. The smallest margin between the amount of chemical impurities and smallest estimated LD50 value of the corresponding impurity was a ratio of approximately 1:700,000. ConclusionsWe identified trace chemical impurities derived from ATSM in the [64Cu]Cu-ATSM formulation. This suggests that the potential risk of the systemic exposure of patients to these chemical impurities is substantially low.

Nanomedicine in Clinical Photodynamic Therapy for the Treatment of Brain Tumors.

The current treatment for malignant brain tumors includes surgical resection, radiotherapy, and chemotherapy. Nevertheless, the survival rate for patients with glioblastoma multiforme (GBM) with a high grade of malignancy is less than one year. From a clinical point of view, effective treatment of GBM is limited by several challenges. First, the anatomical complexity of the brain influences the extent of resection because a fine balance must be struck between maximal removal of malignant tissue and minimal surgical risk. Second, the central nervous system has a distinct microenvironment that is protected by the blood–brain barrier, restricting systemically delivered drugs from accessing the brain. Additionally, GBM is characterized by high intra-tumor and inter-tumor heterogeneity at cellular and histological levels. This peculiarity of GBM-constituent tissues induces different responses to therapeutic agents, leading to failure of targeted therapies. Unlike surgical resection and radiotherapy, photodynamic therapy (PDT) can treat micro-invasive areas while protecting sensitive brain regions. PDT involves photoactivation of photosensitizers (PSs) that are selectively incorporated into tumor cells. Photo-irradiation activates the PS by transfer of energy, resulting in production of reactive oxygen species to induce cell death. Clinical outcomes of PDT-treated GBM can be advanced in terms of nanomedicine. This review discusses clinical PDT applications of nanomedicine for the treatment of GBM.

Autophagy Inhibition Reduces Irradiation-Induced Subcortical White Matter Injury Not by Reducing Inflammation, but by Increasing Mitochondrial Fusion and Inhibiting Mitochondrial Fission

Radiotherapy is an effective tool in the treatment of malignant brain tumors, but irradiation-induced late-onset toxicity remains a major problem. The purpose of this study was to investigate if genetic inhibition of autophagy has an impact on subcortical white matter development in the juvenile mouse brain after irradiation. Ten-day-old selective neural Atg7 knockout (KO) mice and wild-type (WT) littermates were subjected to a single 6-Gy dose of whole-brain irradiation and evaluated at 5 days after irradiation. Neural Atg7 deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell loss in the subcortical white matter, and Atg7 deficiency partly prevented this. There was no significant change between the KO and WT mice in the number of microglia and astrocytes in the subcortical white matter after irradiation. Transcriptome analysis showed that the GO mitochondrial gene expression pathway was significantly enriched in the differentially expressed genes between the KO and WT group after irradiation. Compared with WT mice, expression of the mitochondrial fusion protein OPA1 and phosphorylation of the mitochondrial fission protein DRP1 (P-DRP1) were dramatically decreased in KO mice under physiological conditions. The protein levels of OPA1and P-DRP1 showed no differences in WT mice between the non-irradiated group and the irradiated group but had remarkably increased levels in the KO mice after irradiation. These results indicate that inhibition of autophagy reduces irradiation-induced subcortical white matter injury not by reducing inflammation, but by increasing mitochondrial fusion and inhibiting mitochondrial fission.