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Biological intratumoral therapy for the high-grade glioma part I: intratumoral delivery and immunotoxins.

ABSTRACT: Management of high-grade gliomas remains a complex challenge. Standard of care consists of microsurgical resection, chemotherapy and radiation, but despite these aggressive multimodality therapies the overall prognosis remains poor. A major focus of ongoing translational research studies is to develop novel therapeutic strategies that can maximize tumor cell eradication while minimizing collateral side effects. Particularly, biological intratumoral therapies have been the focus of new translational research efforts due to their inherent potential to be both dynamically adaptive and target specific. This two-part review will provide an overview of biological intratumoral therapies and summarize key advances and remaining challenges in intratumoral biological therapies for high-grade glioma. Part I focuses on discussion of the concepts of intratumoral delivery and immunotoxin therapies.

SUBMITTER: Loya J

PROVIDER: S-EPMC6880302 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Biological intratumoral therapy for the high-grade glioma part I: intratumoral delivery and immunotoxins.

Loya Joshua J Zhang Charlie C Cox Emily E Achrol Achal S AS Kesari Santosh S

CNS oncology 20191121 3

Management of high-grade gliomas remains a complex challenge. Standard of care consists of microsurgical resection, chemotherapy and radiation, but despite these aggressive multimodality therapies the overall prognosis remains poor. A major focus of ongoing translational research studies is to develop novel therapeutic strategies that can maximize tumor cell eradication while minimizing collateral side effects. Particularly, biological intratumoral therapies have been the focus of new translatio ...[more]

PMID: 31747788

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Biological intratumoral therapy for the high-grade glioma part II: vector- and cell-based therapies and radioimmunotherapy.

Project description:Management of high-grade gliomas (HGGs) remains a complex challenge with an overall poor prognosis despite aggressive multimodal treatment. New translational research has focused on maximizing tumor cell eradication through improved tumor cell targeting while minimizing collateral systemic side effects. In particular, biological intratumoral therapies have been the focus of novel translational research efforts due to their inherent potential to be both dynamically adaptive and target specific. This two part review will provide an overview of biological intratumoral therapies that have been evaluated in human clinical trials in HGGs, and summarize key advances and remaining challenges in the development of these therapies as a potential new paradigm in the management of HGGs. Part II discusses vector-based therapies, cell-based therapies and radioimmunotherapy.

| S-EPMC6880300 | biostudies-literature

Survival after radiation therapy for high-grade glioma.

Project description:Background:High-grade gliomas (HGGs) are a heterogeneous disease group, with variable prognosis, inevitably causing deterioration of the quality of life. The estimated 2-year overall survival is 20%, despite the best trimodality treatment consisting of surgery, chemotherapy, and radiotherapy. Aim:To evaluate long-term survival outcomes and factors influencing the survival of patients with high-grade gliomas treated with radiotherapy. Materials and methods:Data from 47 patients diagnosed with high-grade gliomas between 2009 and 2014 and treated with three-dimensional radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT) were analyzed retrospectively. Results:Median survival was 16.6 months; 29 patients (62%) died before the time of analysis. IMRT was employed in 68% of cases. The mean duration of radiotherapy was 56 days, and the mean delay to the start of radiotherapy was 61.7 days (range, 27-123 days). There were no statistically significant effects of duration of radiotherapy or delay to the start of radiotherapy on patient outcomes. Conclusions:Age, total amount of gross resection, histological type, and use of adjuvant temozolomide influenced survival rate (p < 0.05). The estimated overall survival was 18 months (Kaplan-Meier estimator). Our results corroborated those reported in the literature.

| S-EPMC6187089 | biostudies-literature

Metformin as Potential Therapy for High-Grade Glioma.

Project description:Metformin (MET), 1,1-dimethylbiguanide hydrochloride, is a biguanide drug used as the first-line medication in the treatment of type 2 diabetes. The recent years have brought many observations showing metformin in its new role. The drug, commonly used in the therapy of diabetes, may also find application in the therapy of a vast variety of tumors. Its effectiveness has been demonstrated in colon, breast, prostate, pancreatic cancer, leukemia, melanoma, lung and endometrial carcinoma, as well as in gliomas. This is especially important in light of the poor options offered to patients in the case of high-grade gliomas, which include glioblastoma (GBM). A thorough understanding of the mechanism of action of metformin can make it possible to discover new drugs that could be used in neoplasm therapy.

| S-EPMC7016983 | biostudies-literature

Extracellular Vesicles from High-Grade Glioma Exchange Diverse Pro-oncogenic Signals That Maintain Intratumoral Heterogeneity.

Project description:A lack of experimental models of tumor heterogeneity limits our knowledge of the complex subpopulation dynamics within the tumor ecosystem. In high-grade gliomas (HGG), distinct hierarchical cell populations arise from different glioma stem-like cell (GSC) subpopulations. Extracellular vesicles (EV) shed by cells may serve as conduits of genetic and signaling communications; however, little is known about how HGG heterogeneity may impact EV content and activity. In this study, we performed a proteomic analysis of EVs isolated from patient-derived GSC of either proneural or mesenchymal subtypes. EV signatures were heterogeneous, but reflected the molecular make-up of the GSC and consistently clustered into the two subtypes. EV-borne protein cargos transferred between proneural and mesenchymal GSC increased protumorigenic behaviors in vitro and in vivo Clinically, analyses of HGG patient data from the The Cancer Genome Atlas database revealed that proneural tumors with mesenchymal EV signatures or mesenchymal tumors with proneural EV signatures were both associated with worse outcomes, suggesting influences by the proportion of tumor cells of varying subtypes in tumors. Collectively, our findings illuminate the heterogeneity among tumor EVs and the complexity of HGG heterogeneity, which these EVs help to maintain. Cancer Res; 76(10); 2876-81. ©2016 AACR.

| S-EPMC4873326 | biostudies-literature

Local delivery of cancer-cell glycolytic inhibitors in high-grade glioma.

Project description:Background3-bromopyruvate (3-BrPA) and dichloroacetate (DCA) are inhibitors of cancer-cell specific aerobic glycolysis. Their application in glioma is limited by 3-BrPA's inability to cross the blood-brain-barrier and DCA's dose-limiting toxicity. The safety and efficacy of intracranial delivery of these compounds were assessed.MethodsCytotoxicity of 3-BrPA and DCA were analyzed in U87, 9L, and F98 glioma cell lines. 3-BrPA and DCA were incorporated into biodegradable pCPP:SA wafers, and the maximally tolerated dose was determined in F344 rats. Efficacies of the intracranial 3-BrPA wafer and DCA wafer were assessed in a rodent allograft model of high-grade glioma, both as a monotherapy and in combination with temozolomide (TMZ) and radiation therapy (XRT).Results3-BrPA and DCA were found to have similar IC50 values across the 3 glioma cell lines. 5% 3-BrPA wafer-treated animals had significantly increased survival compared with controls (P = .0027). The median survival of rats with the 50% DCA wafer increased significantly compared with both the oral DCA group (P = .050) and the controls (P = .02). Rats implanted on day 0 with a 5% 3-BrPA wafer in combination with TMZ had significantly increased survival over either therapy alone. No statistical difference in survival was noted when the wafers were added to the combination therapy of TMZ and XRT, but the 5% 3-BrPA wafer given on day 0 in combination with TMZ and XRT resulted in long-term survivorship of 30%.ConclusionIntracranial delivery of 3-BrPA and DCA polymer was safe and significantly increased survival in an animal model of glioma, a potential novel therapeutic approach. The combination of intracranial 3-BrPA and TMZ provided a synergistic effect.

| S-EPMC4483048 | biostudies-literature

Ultrasmall Nanoparticle Delivery of Doxorubicin Improves Therapeutic Index for High-Grade Glioma.

Project description:PurposeDespite dramatic growth in the number of small-molecule drugs developed to treat solid tumors, durable therapeutic options to control primary central nervous system malignancies are relatively scarce. Chemotherapeutic agents that appear biologically potent in model systems have often been found to be marginally effective at best when given systemically in clinical trials. This work presents for the first time an ultrasmall (<8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C' dots), for the efficacious treatment of high-grade gliomas.Experimental designThis work presents first-in-kind renally clearable ultrasmall (<8 nm) multimodal C' dots with surface-conjugated doxorubicin (DOX) via pH-sensitive linkers for the efficacious treatment in two different clinically relevant high-grade glioma models.ResultsOptimal drug-per-particle ratios of as-developed nanoparticle-drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The in vivo efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in platelet-derived growth factor-driven genetically engineered mouse model, and an EGF-expressing patient-derived xenograft (EGFR PDX) model.ConclusionsUltrasmall C' dot-drug conjugates showed great translational potential over DOX for improving the therapeutic outcome of patients with high-grade gliomas, even without a cancer-targeting moiety.

| S-EPMC9250642 | biostudies-literature

MR-guided focused ultrasound increases antibody delivery to nonenhancing high-grade glioma.

Project description:BackgroundHigh-grade glioma (HGG) remains a recalcitrant clinical problem despite many decades of research. A major challenge in improving prognosis is the inability of current therapeutic strategies to address a clinically significant burden of infiltrating tumor cells that extend beyond the margins of the primary tumor mass. Such cells cannot be surgically excised nor efficiently targeted by radiation therapy. Therapeutic targeting of this tumor cell population is significantly hampered by the presence of an intact blood-brain barrier (BBB). In this study, we performed a preclinical investigation of the efficiency of MR-guided Focused Ultrasound (FUS) to temporarily disrupt the BBB to allow selective delivery of a tumor-targeting antibody to infiltrating tumor.MethodsStructural MRI, dynamic-contrast enhancement MRI, and histology were used to fully characterize the MR-enhancing properties of a patient-derived xenograft (PDX) orthotopic mouse model of HGG and to develop a reproducible, robust model of nonenhancing HGG. PET-CT imaging techniques were then used to evaluate the efficacy of FUS to increase 89Zr-radiolabeled antibody concentration in nonenhancing HGG regions and adjacent non-targeted tumor tissue.ResultsThe PDX mouse model of HGG has a significant tumor burden lying behind an intact BBB. Increased antibody uptake in nonenhancing tumor regions is directly proportional to the FUS-targeted volume. FUS locally increased antibody uptake in FUS-targeted regions of the tumor with an intact BBB, while leaving untargeted regions unaffected.ConclusionsFUS exposure successfully allowed temporary BBB disruption, localized to specifically targeted, nonenhancing, infiltrating tumor regions and delivery of a systemically administered antibody was significantly increased.

| S-EPMC7212871 | biostudies-literature

Temozolomide in paediatric high-grade glioma: a key for combination therapy?

Project description:This report describes a single-centre study with temozolomide (TMZ) (200 mg m(-2) day(-1) x 5 per cycle of 28 days) in children with (recurrent) high-grade glioma. Magnetic resonance imaging was performed every two cycles. In all, 20 patients were treated between 1998 and 2001 after the UKCCSG/SFOP TMZ phase II trial. All patients had measurable disease. Totally, 15 patients had a relapse after surgery+/-radiotherapy+/-chemotherapy. Overall, five patients received TMZ after surgery or biopsy, awaiting radiotherapy. There were one clinically malignant grade II glioma, 11 grade III and eight grade IV gliomas. Seven tumours had oligodendroglial features. Mean age at start of TMZ was 12.0 years (range 3-20.5 years). In total, eight patients had >8 cycles (range 3-30). One VGPR (currently in CR after surgery), three PRs (with a PFS of 4, 4 and 11 months, respectively) and one MR (PFS 14 months) were observed. Three out of five responses occurred after >4 courses. The overall response rate was 20%. Median progression-free survival (PFS) was 2.0 months (range 3 weeks-34+ months). PFS rate was 20% after 6 months. Median overall survival (OS) was 10 months. Nine patients showed a clinical improvement. Three patients vomitted shortly after TMZ administration, eight patients (13 cycles) experienced grade III/IV thrombocytopenia, occurring predominantly during the fourth week of the first two cycles. Five patients experienced neutropenia, and three patients febrile neutropenia. TMZ is a well-tolerated ambulatory treatment for children with malignant glial tumours. This drug warrants further study in these highly chemoresistant tumours and should be studied either as upfront therapy or in combination therapy.

| S-EPMC2409857 | biostudies-other

Radiosurgery for high-grade glioma.

Project description:BACKGROUND: For patients with newly diagnosed high-grade gliomas (HGG), the current standard-of-care treatment involves surgical resection, followed by concomitant temozolomide (TMZ) and external beam radiation therapy (XRT), and subsequent TMZ chemotherapy. For patients with recurrent HGG, there is no standard of care. Stereotactic radiosurgery (SRS) is used to deliver focused, relatively large doses of radiation to a small, precisely defined target. Treatment is usually delivered in a single fraction, but may be delivered in up to five fractions. The role of SRS in the management of patients with HGG is not well established. METHODS: The PubMed database was searched with combinations of relevant MESH headings and limits. Case reports and/or small case series were excluded. Attention was focused on overall median survival as an objective measure, and data were examined separately for newly diagnosed and recurrent HGG. RESULTS: With respect to newly diagnosed HGG, there is strong evidence that addition of an SRS boost prior to standard XRT provides no survival benefit. However, recent retrospective evidence suggests a possible survival benefit when SRS is performed after XRT. With respect to recurrent HGG, there is suggestion that SRS may confer a survival benefit but with potentially higher complication rates. Newer studies are investigating the combination of SRS with targeted molecular agents. Controlled prospective clinical trials using advanced imaging techniques are necessary for a complete assessment. CONCLUSIONS: SRS has the potential to provide a survival benefit for patients with HGG. Further research is clearly warranted to define its role in the management of newly diagnosed and recurrent HGG.

| S-EPMC3400492 | biostudies-other

Targeting neuronal activity-regulated neuroligin-3 dependency for high-grade glioma therapy

Project description:Neuronal activity promotes high-grade glioma (HGG) growth. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule and glioma mitogen neuroligin-3 (Nlgn3), but the therapeutic potential of targeting Nlgn3 in glioma remains to be defined. We demonstrate a striking dependence of HGG growth on microenvironmental Nlgn3 and determine a targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric glioblastoma, diffuse intrinsic pontine glioma and adult glioblastoma fail to grow in Nlgn3 knockout mice. Glioma exposure to Nlgn3 results in numerous signaling consequences, including early focal adhesion kinase activation upstream of PI3K-mTOR. Nlgn3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. Administration of ADAM10 inhibitors robustly blocks HGG xenograft growth. This work defines the therapeutic potential of and a promising strategy for targeting Nlgn3 secretion in the glioma microenvironment, which could prove transformative for treatment of HGG.

2017-08-11 | GSE99045 | GEO

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