Treatment Of Malignant Gliomas Research Articles

An Update on the Clinical Status, Challenges, and Future Directions of Oncolytic Virotherapy for Malignant Gliomas.

Malignant gliomas are common central nervous system tumors that pose a significant clinical challenge due to the lack of effective treatments. Glioblastoma (GBM), a grade 4 malignant glioma, is the most prevalent primary malignant brain tumor and is associated with poor prognosis. Current clinical trials are exploring various strategies to combat GBM, with oncolytic viruses (OVs) appearing particularly promising. In addition to ongoing and recently completed clinical trials, one OV (Teserpaturev, Delytact®) received provisional approval for GBM treatment in Japan. OVs are designed to selectively target and eliminate cancer cells while promoting changes in the tumor microenvironment that can trigger and support long-lasting anti-tumor immunity. OVs offer the potential to remodel the tumor microenvironment and reverse systemic immune exhaustion. Additionally, an increasing number of OVs are armed with immunomodulatory payloads or combined with immunotherapy approaches in an effort to promote anti-tumor responses in a tumor-targeted manner. Recently completed oncolytic virotherapy trials can guide the way for future treatment individualization through patient preselection, enhancing the likelihood of achieving the highest possible clinical success. These trials also offer valuable insight into the numerous challenges inherent in malignant glioma treatment, some of which OVs can help overcome.

388 The First Endovascular Rat Glioma Model for Pre-clinical Evaluation of Intra-arterial Therapeutics

INTRODUCTION: Several translational animal models have been described assessing intra-arterial (IA) treatments for malignant gliomas. We describe the first endovascular animal model that allows testing of IA drug delivery as first-line treatment, which is difficult to do in actual patients. METHODS: Wistar rats underwent left femoral artery catherization with a Balt Magic 1.2F catheter or Marathon Flow directed 1.5F Microcatheter with an Asahi Chikai 0.008 micro-guidewire which was navigated to the left internal carotid artery under x-ray. 25% mannitol was administered to test blood brain barrier breakdown (BBBB). Additional rats were implanted with C6 glioma cells in the left frontal lobe. C6 Glioma-Implanted Rats were monitored for overall survival and tumor growth. Tumor volumes from MRI images were calculated utilizing 3D slicer. Additional rats underwent femoral artery catheterization with Bevacizumab, carboplatin, or irinotecan injected into the left internal carotid artery to test feasibility and safety. RESULTS: A successful endovascular access and BBBB protocol was established. BBBB was confirmed with positive Evans-blue staining. 10 rats were successfully implanted with C6 gliomas with confirmed growths on MRI. Overall survival was 19.75 ± 2.21 days. 5 rats were utilized for development of our femoral catheterization protocol and BBBB testing. With regards to IA chemotherapy dosage testing, control rats tolerated targeted 10 mg/kg of bevascizumab, 2.4 mg/kg of carboplatin, and 15 mg/kg of irinotecan IA ICA injections without complications. CONCLUSIONS: We present the first endovascular IA rat glioma model that allows selective catheterization of the intracranial vasculature and assessment of IA therapies for gliomas without need for access and sacrifice of proximal cerebrovasculature.

Survival Analysis of Patients Undergoing Intraoperative Contrast-enhanced Ultrasound in the Surgical Treatment of Malignant Glioma.

Complete resection of malignant gliomas is often challenging. Our previous study indicated that intraoperative contrast-enhanced ultrasound (ICEUS) could aid in the detection of residual tumor remnants and the total removal of brain lesions. This study aimed to investigate the survival rates of patients undergoing resection with or without the use of ICEUS and to assess the impact of ICEUS on the prognosis of patients with malignant glioma. A total of 64 patients diagnosed with malignant glioma (WHO grade HI and IV) who underwent surgery between 2012 and 2018 were included. Among them, 29 patients received ICEUS. The effects of ICEUS on overall survival (OS) and progression-free survival (PFS) of patients were evaluated. A quantitative analysis was performed to compare ICEUS parameters between gliomas and the surrounding tissues. The ICEUS group showed better survival rates both in OS and PFS than the control group. The univariate analysis revealed that age, pathology and ICEUS were significant prognostic factors for PFS, with only age being a significant prognostic factor for OS. In multivariate analysis, age and ICEUS were significant prognostic factors for both OS and PFS. The quantitative analysis showed that the intensity and transit time of microbubbles reaching the tumors were significantly different from those of microbubbles reaching the surrounding tissue. ICEUS facilitates the identification of residual tumors. Age and ICEUS are prognostic factors for malignant glioma surgery, and use of ICEUS offers a better prognosis for patients with malignant glioma.

Abstract 5959: Targeting TRIM11 is a potential therapeutic strategy for malignant gliomas

Abstract Background: TRIM11 (tripartite motif-containing protein 11) belongs to the TRIM/RBCC (the RING B-box coiled-coil) family of E3 ubiquitin ligases. Emerging evidence has demonstrated that TRIM11 is a novel target against cancer and neurodegenerative diseases as it plays vital role in cellular proliferation, differentiation, tumor progression, and apoptosis. Our previous work demonstrated that TRIM11 is over-expressed in high-grade gliomas and promotes proliferation, invasion, migration and tumor growth, suggesting that TRIM11 may be used as a target for malignant glioma treatment. The tumor suppressor p53 plays critical roles in tumor prevention, and deregulated p53 pathway has been found in a majority of glioblastomas (GBMs). Recent studies have shown that TRIM proteins are involved in the regulation of p53, and TRIM proteins are also regulated by p53. Methods: To evaluate the effect of TRIM11 on GBM progression in vivo, we intracranially implanted GBM cells over-expressing TRIM11 in immunocompromised mice, and the animal survival was monitored. We have synthesized a series of TRIM11 inhibitors and evaluated their anti-GBM potential in vitro. Furthermore, we tested the crosstalk between TRIM11 and p53 by knocking down TP53 through RNA interference. Results: Our in vivo data showed that the control group mice (GL261 parent line) survived longer than the mice bearing TRIM11 over-expressing GL261 tumors (p<0.05), suggesting TRIM11 enhances tumor progression in vivo. In vitro data showed that the oncogenic effect of TRIM11 may be related to its influence on the apoptosis pathway since a robust induction of poly (ADP-ribose) polymerase (PARP) was observed in TRIM11 over-expressing GBM cells. When treated with Temozolomide (TMZ), TRIM11 over-expressing cells were more resistant and showed a higher survival rate compared to parental cells. We screened a small library of TRIM11 inhibitors (~ 25 compounds), and identified several compounds which significantly inhibited the growth of both established and primary GBM cells in a dose-dependent manner, implicating that TRIM11 inhibitors may serve as novel agents for GBM treatment. We found that inactivation of p53 by siRNA increased the expression of TRIM11 and modulated the sensitivities of GBM cells to chemotherapy drugs. Conclusion: Despite remarkable advances in the prognosis and multidisciplinary treatment strategies, GBM is still the most lethal primary brain tumor, and there is a pressing need for newer anti-GBM agents with novel targets and mode of action. Our preclinical studies demonstrate a significant anti-tumor effect of TRIM11 inhibitors on malignant glioma cells. Our finding that TRIM11 may be modulated by p53 adds a new layer of regulation to this complicated signaling pathway. A better understanding of the crosstalk between p53 and TRIM11 will benefit the clinical application of targeting p53 and TRIM11 signaling pathways for therapeutical indications in GBM. Citation Format: Kaijun Di, Bhaskar C. Das, Daniela Alexandru Abrams, Daniela A. Bota. Targeting TRIM11 is a potential therapeutic strategy for malignant gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5959.

Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis

Temozolomide (TMZ) represents a standard-of-care chemotherapeutic agent in glioblastoma (GBM). However, the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma. Although specific innovative approaches, such as immunotherapy, have shown favorable clinical outcomes, the inherent invasiveness of most gliomas continues to make them challenging to treat. Consequently, there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development. This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors. A total of 648 proteins exhibiting significant differential expression were identified. Gene Set Enrichment Analysis (GSEA) unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups. Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate (IP3) kinase B (ITPKB) in the recurrence group, correlating with poor survival in glioma patients. In TMZ-resistant cells, the depletion of ITPKB led to an increase in reactive oxygen species (ROS) related to NADPH oxidase (NOX) activity and restored cell sensitivity to TMZ. Mechanistically, the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination. This, in turn, elevated ITPKB stability and impaired ROS production. Furthermore, ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model. These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target for TMZ-resistant GBM.

Intranasal Delivery of Perillyl Alcohol (NEO100) as a New Treatment Strategy for Glioma

Background: Perillyl alcohol (POH) is a naturally occurring monoterpene that is being developed as an intranasally delivered agent for the treatment of brain-localized malignancies. Clinical trials with glioma patients in Brazil have yielded preliminary evidence that this approach might be able to achieve therapeutic activity and result in prolonged survival of patients. Methods: NEO100, a highly pure, current good manufacturing practice-produced version of POH, is being evaluated in a Phase I/IIa clinical trial with recurrent glioblastoma patients in the United States. Patients self-administer POH/NEO100 as a mist with a nasal mask over the course of 15 minutes, four times a day, every day. Results: The treatment regimen is well tolerated, even if maintained over several years. It correlated with improved survival when compared to historical controls. Conclusion: There is human data demonstrating that this novel approach could become useful for the treatment of malignant glioma. Clinical Trial Registration Number:: NCT02704858

SYSTEMIC INFLAMMATORY INDICES IN PATIENTS WITH MALIGNANT GLIOMAS AND EFFECTS OF PLATELET SECRETOME IN VITRO.

To date, no significant clinical progress has been achieved in the treatment of brain malignant gliomas (MG), and the active search for non-invasive circulating biomarkers continues. The prognostic significance of the ratio of the main peripheral blood cell populations of patients with MG is evaluated. Considerable attention is paid to the secretome of platelets (Pt) of peripheral blood. To evaluate the indicators of the peripheral blood cell population ratios in patients with brain MG and to study the influence of the secretome of Pt (SPt) of the peripheral blood of patients with brain MG in cell cultures in vitro. We studied samples of peripheral blood from patients with glioma CNS WHO grade G2 (n = 5), G3 (n = 12), and G4 (n = 20). The peripheral blood cell counts were analyzed in the preoperative period on an automatic hematology analyzer. The in vitro study of SPt was performed on the U251 human glioblastoma cell line cultured with SPt from MG patients or SPt pre-incubated with anti-TGF-β1 antibody. Cell cultures were observed for 72 h, and mitotic index (MI) was calculated. In MG patients, the count of peripheral blood leukocytes and neutrophils increased (p < 0.05). The neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) increased by 2-3 times compared to control. Nevertheless, correlation analysis did not reveal significant relationships between quantitative indicators of peripheral blood cells and the tumor malignancy degree in MG patients. The MI in U251 cells increased under the influence of SPt from patients with MG (p < 0.021), correlated with the tumor degree of malignancy (r = 0.246, p = 0.014). Pre-incubation of SPt with anti-TGF-β1 antibody tends to neutralize this promitotic effect. In MG patients, the integral indicators of NLR and SII increased but no significant relationship with the degree of tumor malignancy was found. In U251 cells, promitotic effects of SPt of MG patients partially decreased by anti-TGF-β1 antibody.

Nonclinical pharmacodynamics of boron neutron capture therapy using direct intratumoral administration of a folate receptor targeting novel boron carrier.

Boron neutron capture therapy (BNCT) is a precise particle radiation therapy known for its unique cellular targeting ability. The development of innovative boron carriers is crucial for the advancement of BNCT technologies. Our previous study demonstrated the potential of PBC-IP administered via convection-enhanced delivery (CED) in an F98 rat glioma model. This approach significantly extended rat survival in neutron irradiation experiments, with half achieving long-term survival, akin to a cure, in a rat brain tumor model. Our commitment to clinical applicability has spurred additional nonclinical pharmacodynamic research, including an investigation into the effects of cannula position and the time elapsed post-CED administration. In comprehensive in vivo experiments conducted on an F98 rat brain tumor model, we meticulously examined the boron distribution and neutron irradiation experiments at various sites and multiple time intervals following CED administration. The PBC-IP showed substantial efficacy for BNCT, revealing minimal differences in tumor boron concentration between central and peripheral CED administration, although a gradual decline in intratumoral boron concentration post-administration was observed. Therapeutic efficacy remained robust, particularly when employing cannula insertion at the tumor margin, compared to central injections. Even delayed neutron irradiation showed notable effectiveness, albeit with a slightly reduced survival period. These findings underscore the robust clinical potential of CED-administered PBC-IP in the treatment of malignant gliomas, offering adaptability across an array of treatment protocols. This study represents a significant leap forward in the quest to enhance BNCT for the management of malignant gliomas, opening promising avenues for clinical translation.

Immunotherapy with autologous dendritic cells in the complex treatment of malignant gliomas - results.

Malignant gliomas are the most common primary brain tumor. Despite the variety of modern treatments, it is still a fatal disease with an extremely poor prognosis. The use of immunotherapy as a technique for the treatment of malignant tumors has great promise, retraining and exploiting the patient's immune response against tumors. Evaluation of the effectiveness of dendritic cell vaccine in patients with malignant brain gliomas in the structure of complex treatment in comparison with the control group of patients without immunotherapy in the structure of treatment. In a single-center, prospective, cohort study, taking place on the basis of the RNSI named after prof. A.L. Polenov, 91 patients with morphologically established malignant glial tumor (glioblastoma) took part. The main group of 41 patients who, in addition to standard treatment (surgical, radiation and chemotherapy), underwent specific antitumor immunotherapy. 50 patients received only standard treatment, without immunotherapy. Median survival was 21.7 months in the immunotherapy group (95% CI 4-37 months) and 15.8 months (95% CI 3-22 months) in the non-immunotherapy group (p = 0.002). The median relapse-free period in the group with immunotherapy was 13.8 months (95% CI 1-20 months), and in the group without immunotherapy 7.9 months (95% CI 1-12 months) (p = 0.003). In general, the use of immunotherapy in the structure of complex treatment of patients with malignant gliomas demonstrates a clear positive trend in terms of overall survival and median relapse-free period. But nevertheless, immunotherapy requires further development as a therapeutic tool, study and improvement, which will take into account immunosuppression in malignant gliomas and means of overcoming it, optimization in terms of target antigen selection, cell preparation and integration of dendritic vaccines into other treatment regimens.

The Father of Wisdom: "The Influence of Surgical Experience on Overall Survival in Patients with Malignant Gliomas".

The role of surgery in the management of malignant gliomas has been feverishly deliberated after the publication of the first expansive case series, the last two decades reinvigorating the discussion regarding the value of total removal in improving survivability. Despite numerous technologies being implemented to increase the resection rates of malignant gliomas, the role of surgical experience has been largely overlooked. This article aims to discuss the importance of a single surgeon's experience in treating high-grade gliomas over a period of 20years. In order to demonstrate the role of surgical experience, we divided the patients operated by a single neurosurgeon into two distinct intervals: between 2000 and 2009 and between 2012 and 2020, respectively. Only cases with subsequent adjuvant radio-chemotherapy were included. For objective reasons, no technologies that could assist the extent of resection (EOR) such as intraoperative MRI (iMRI) or 5-ALA could be used in the country of our study. Gross total resection was the main goal whenever possible, whereas subtotal removal was defined as a clear remnant on contrasted MRI or CT performed 24-48h postoperatively. Using the Kaplan-Meier method, we analyzed the survival and disease-free interval of our patients according to age, pathology, and degree of resection. In the 20-year interval of our retrospective study, the main author (ISF) operated 1591 cases of gliomas in a total of 1878 surgeries, including recurrences. The number of high-grade glioma (HGG) patients was 909 (57.10%), 495 of which were male (54.5%) and 414 (45.5%) female. The mean age of the HGG population was 51.9years. The most common type of HGG subtype were glioblastomas with a total number 620 cases (68.2%). Regarding overall survival (OS), average survival at 12months was better by 1.6%, and 12.1% improved at 18months and 17.8% longer at 24months in the 2012-2020 interval. The mean OS in the earlier interval was 11.00months compared to the second when it reached 13.441months (CI, 12.642-14.24). Surgical treatment represents a critical step in the multimodal treatment of malignant gliomas. According to our results, surgical experience improves not only overall survival in a manner equivalent to adjuvant chemotherapy but also the quality of life. As such, a special qualification in neurooncology may prove necessary in offering these patients a second chance at life.

10103-GMC-7 RETROSPECTIVE ANALYSIS ABOUT BEVACIZUMAB THERAPY FOR 10 YEARS AFTER AUTHORIZATION FOR MALIGNANT GLIOMAS IN OUR DEPARTMENT

Abstract In the treatment of malignant gliomas, drug therapy options are limited, and the Stupp regimen is still the standard treatment, In 2013, bevacizumab (BEV) was approved and became an option. Although BEV is not considered to prolong survival, it is currently used in many cases. We conducted a retrospective review of the use of BEV in our department 10 years after its approval. Of the 83 cases treated at our department, 70 were treated from the initial treatment to death or transfer to BSC. 70 cases consisted of 39 males and 31 females with a mean age of 63 years. Pathology was obtained in 69, and the diagnosis was made according to the WHO classification at each treated time. In the 21 cases where BEV was initially used, biopsy was performed in 13 cases and partial excision in 3 cases, indicating that BEV tended to be used from the time of initial presentation if there was residual disease. Of the 38 cases used at recurrence, 29 were treated with BEV alone, 8 with surgery followed by BEV for residual disease, and 6 of the 70 cases were still being followed. Of the remaining 64 patients, 55 died and 9 were transferred to BSC. The average number of times was 9.6 times, and the reasons for termination were invalidity in 45 cases, side effects in 10 cases, BSC transfer in 6 cases, patient request in 2 cases, and unknown in 1 case. In the 55 patients who died, the average overall survival was 21.4 months, the average survival time from the start of BEV to death was 8.9 months, and the average survival time from the end of BEV to death was 3.3 months. Based on 10 years of experience, it is necessary to find more efficient ways to use BEV.

Safety and feasibility of intra-arterial delivery of teniposide to high grade gliomas after blood-brain barrier disruption: a case series.

This case series describes the safety and efficacy of superselective intra-arterial (IA) cerebral infusion of teniposide for the treatment of patients with glioma, to provide new ideas and methods for the treatment of high grade gliomas. 12 patients with glioma who were previously treated with standard therapy were treated with superselective IA cerebral infusion of teniposide. Patients received at least two cycles of treatment (one cycle: 150 mg/time, used for 1 day, repeated at 28 day intervals) after blood-brain barrier disruption. Patients received individualized treatment on the tumor location. The ophthalmic artery was bypassed during the super-selective arterial infusion. No significant differences in biochemical indexes and Karnofsky performance status (KPS) score were observed before and after treatment, and no evident adverse events occurred (P>0.05). In a recent response evaluation (August 2023), two (8%) patients presented with a complete response (16.7%), four had a partial response (33.3%), four had stable disease (33.3%), and two showed progressive disease (16.7%). The overall response rate and disease control rate were 50.0% and 83.3%, respectively. In addition, we described the detailed course of treatment in two patients. Case No 1 (recurrent tumor) and case No 2 (primary tumor) received six and three cycles of teniposide infusion, respectively. After treatment, the tumors of the patients were significantly reduced without evident adverse effects. This small series suggests that superselective IA cerebral infusion of teniposide may be a safe and effective therapy in the multimodal treatment of malignant glioma and warrants further study in larger prospective investigations.

Photodynamic therapy in brain cancer: mechanisms, clinical and preclinical studies and therapeutic challenges

Cancer is a main cause of death and preferred methods of therapy depend on the type of tumor and its location. Gliomas are the most common primary intracranial tumor, accounting for 81% of malignant brain tumors. Although relatively rare, they cause significant mortality. Traditional methods include surgery, radiotherapy and chemotherapy; they also have significant associated side effects that cause difficulties related to tumor excision and recurrence. Photodynamic therapy has potentially fewer side effects, less toxicity, and is a more selective treatment, and is thus attracting increasing interest as an advanced therapeutic strategy. Photodynamic treatment of malignant glioma is considered to be a promising additional therapeutic option that is currently being extensively investigated in vitro and in vivo. This review describes the application of photodynamic therapy for treatment of brain cancer. The mechanism of photodynamic action is also described in this work as it applies to treatment of brain cancers such as glioblastoma multiforme. The pros and cons of photodynamic therapy for brain cancer are also discussed.

EXTH-54. GB13 IS A POTENT TREATMENT FOR IL13RA2-EXPRESSING GBM AND DMG AND IMPROVES STANDARD-OF-CARE THERAPY

Abstract GB13 is a novel biologic therapy in the final stages of preclinical development for the treatment of glioblastoma (GBM) and H3 K27-altered diffuse midline glioma (DMG) that has received Orphan Drug Designation by the Food and Drug Administration for treatment of malignant gliomas. GB13 targets a specific tumor-restricted receptor of interleukin 13 called interleukin 13 receptor alpha 2 (IL13Rα2). IL13Rα2 is highly expressed in malignant gliomas and, importantly, is not expressed on non-cancerous cells of the brain. GB13 consists of an engineered proprietary mutant of IL13, which binds exclusively to IL13Rα2, and is fused to a highly cytotoxic exotoxin molecule. In vitro data demonstrate that GB13 potently kills IL13Rα2+ cancer cells while sparing non-cancerous cells. These characteristics make GB13 an attractive agent for safe and efficacious targeting of tumor cells expressing IL13Rα2 in upcoming clinical trials. In the current studies, we employed patient-derived GBM and DMG cell and animal models to provide key conclusions that support GB13 as an effective treatment option for gliomas in the clinic. First, we demonstrated that single acute infusions of GB13 by enhanced delivery (CED) is effective at decreasing orthotopic tumor volumes and increasing animal survival and that a long-term infusion can more significantly extend animal survival. Second, we determined that IL13Rα2 is requisite for GB13 activity as tumors that do not express the receptor are insensitive to the cytotoxic effects of GB13, demonstrating a precise and clear biomarker for clinical trial patient selection. Finally, we determined that GB13 works in concert with clinical standard-of-care radiation therapy to increase cell death, compared to radiation alone. Based on this work, we and our clinical collaborators are confident that the current work confirms GB13 has many important characteristics as an exciting therapy, which continues development towards a Phase I clinical trial for both GBM and pediatric DMG.

Investigation of the effect and prediction factors of bevacizumab on immunoregulation in glioblastoma

Glioblastoma (GB) is one of the most common and malignant tumours that originates in the brain. It has a high likelihood of recurrence and a poor survival rate. Professor Toshihide Tanaka, Chief Medical Officer, Jikei University School of Medicine, conducts translational research based on clinical samples of glioblastoma tumours obtained from brain tumour surgery procedures as well as animal studies. He heads up a multidisciplinary team focused on the design and selection of personalised treatments for hypervascular malignant gliomas. In their current project, the researchers are investigating the use of Bevacizumab (Bev), a monoclonal antibody that targets vascular endothelial growth factor (VEGF). VEGF enhances tumour growth by changing the surrounding environment to one more favourable for tumour growth. The effect of Bev on cancers is transient and the mechanisms of resistance to Bev are yet to be investigated in detail. The researchers are therefore seeking to discover predictive biomarkers of microenvironment-targeted therapy for GB. In order to investigate the effect and prediction factors of Bev on immunoregulation in GB, Tanaka and the team perform in situ observations using histological techniques including immunohistochemistry using tumour tissues from patients who have undergone surgical resection. The researchers have been able to demonstrate a decrease in microvascular density and an improvement in the tumour microenvironment after treatment with Bev.

Enhancement of Microglia Functions by Developed Nano-Immuno-Synergist to Ameliorate Immunodeficiency for Malignant Glioma Treatment.

Resident microglia are key factors in mediating immunity against brain tumors, but the microglia in malignant glioma are functionally impaired. Little immunotherapy is explored to restore microglial function against glioma. Herein, oleanolic acid (OA) (microglia "restorer") and D PPA-1 peptide (immune checkpoint blockade) are integrated on a nano-immuno-synergist (D PAM@OA) to work coordinately. The self-assembled OA core is coated with macrophage membrane for efficient blood-brain barrier penetration and microglia targeting, on which D PPA-1 peptide is attached via acid-sensitive bonds for specific release in tumor microenvironment. With the enhanced accumulation of the dual drugs in their respective action sites, D PAM@OA effectively promotes the recruitment and activation of effector T cells by inhibiting aberrant activation of Signal transducer and activator of transcription (STAT-3) pathway in microglia, and assists activated effector T cells in killing tumor cells by blocking elevated immune checkpoint proteins in malignant glioma. Eventually, as adjuvant therapy, the rationally designed nano-immuno-synergist hinders malignant glioma progression and recurrence with or without temozolomide. The work demonstrates the feasibility of a nano-formulation for microglia-based immunotherapy, which may provide a new direction for the treatment of brain tumors.

GDNF triggers proliferation of rat C6 glioma cells via the NF-κB/CXCL1 signaling pathway.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor that is characterized by its high proliferative and migratory potential, leading to a high invasiveness of this tumor type. However, the underlying mechanism of GBM proliferation and migration has not been fully elucidated. In this study, at first, we used RNA-seq together with bioinformatics technology to screen for C-X-C motif ligand 1 (CXCL1) as a proliferation-related gene. And exogenous glial cell line-derived neurotrophic factor (GDNF) induced proliferation and up-regulated the level of CXCL1 in rat C6 glioma cells determined by sqPCR and ELISA. Then, we manipulated the CXCL1 expression by using a lentiviral vector (CXCL1-RNAi) approach. By this, the proliferation of C6 cells was decreased, suggesting that CXCL1 plays a key role in proliferation in these cells. We hypothesized that exogenous GDNF promoted NF-κB nuclear translocation and therefore, analyzed the interaction of CXCL1 with NF-κB by Western Blot and immunofluorescence. Additionally, we used BAY 11-7082, a phosphorylation inhibitor of NF-κB, to elucidate NF-κB mediated the effect of GDNF on CXCL1. These results demonstrated that GDNF enhanced the proliferation of rat C6 glioma cells through activating the NF-κB/CXCL1 signaling pathway. In summary, these studies not only revealed the mechanism of action of exogenous GDNF in promoting the proliferation of C6 glioma cells but may also provide a new biological target for the treatment of malignant glioma.

SYST-12 LP-184, A NOVEL ACYLFULVENE-DERIVED TUMOR SITE ACTIVATED SMALL MOLECULE INHIBITS ADULT AND PEDIATRIC CNS TUMOR CELL GROWTH

Abstract Blood-brain barrier (BBB) permeable agents effective against recurrent, chemotherapy-resistant central nervous system (CNS) tumors are urgently needed, particularly in Glioblastoma multiforme (GBM) and atypical teratoid/rhabdoid tumors (ATRT). These represent extremely aggressive and lethal types of CNS malignancies. LP-184 is a next-generation acylfulvene class drug candidate and has received FDA orphan drug designations for the treatment of malignant gliomas and ATRT. LP-184 creates covalent DNA adducts that are selectively repaired via nucleotide excision repair (NER). Repair of LP-184-induced DNA damage is mediated by ERCC complexes. Consistent with this, we observed 3-6X decreased cancer cell viability in U87, M1123 and Mayo39 GBM cells treated with LP-184 in combination with the ERCC3 degrader Spironolactone (SP) relative to LP-184 alone. Mice bearing pre-established subcutaneous U87 xenografts were treated with SP alone, LP-184 alone or their combination. Tumors recurred after initial regression in 5/5 animals treated with LP-184 alone whereas tumors showed durable complete regression without recurrence in 4/5 animals treated with LP-184 + SP. Thus, LP-184 likely functions as a synthetically lethal agent in the presence of DNA repair deficiencies. LP-184 inhibited cell growth in CHLA06 and BT37 ATRT cell lines, with IC50s in the 20-25nM range. LP-184 induced apoptosis 96 hours after treatment in these ATRT cell lines as measured by immunofluorescence for cleaved caspase-3 and Western blot for c-PARP. LP-184 intravenous treatment at 4 mg/kg twice weekly for 2 weeks showed tumor regression in mice implanted with CHLA06 ATRT subcutaneous xenografts, with 112% tumor growth inhibition and 2/10 treated mice being tumor-free at study termination. LP-184 further showed favorable intracranial tumor bioavailability along with in vivo BBB permeability comparable to other CNS cancer drugs. These findings identify LP-184 as a promising new agent and support its further development for treating CNS tumors in adult and pediatric populations.

Low-parameter supervised learning models can discriminate pseudoprogression and true progression in non-perfusion-based MRI.

Discrimination of pseudoprogression and true progression is one challenge to the treatment of malignant gliomas. Although some techniques such as circulating tumor DNA (ctDNA) and perfusion-weighted imaging (PWI) demonstrate promise in distinguishing PsP from TP, we investigate robust and replicable alternatives to distinguish the two entities based on more widely-available media. In this study, we use low-parametric supervised learning techniques based on geographically-weighted regression (GWR) to investigate the utility of both conventional MRI sequences as well as a diffusion-weighted sequence (apparent diffusion coefficient or ADC) in the discrimination of PsP v TP. GWR applied to MRI modality pairs is a unique approach for small sample sizes and is a novel approach in this arena. From our analysis, all modality pairs involving ADC maps, and those involving post-contrast T1 regressed onto T2 showed potential promise. This work on ADC data adds to a growing body of research suggesting the predictive benefits of ADC, and suggests further research on the relationships between post-contrast T1 and T2.Clinical relevance- Few studies have investigated predictive potential of conventional MRI and ADC to detect PsP. Our study adds to the growing research on the topic and presents a new perspective to research by exploiting the utility of ADC in PsP v TP distinction. In addition, our GWR methodology for low-parametric supervised computer vision models demonstrates a unique approach for image processing of small sample sizes.

Advances in computational and translational approaches for malignant glioma.

Gliomas are the most common primary brain tumors in adults and carry a dismal prognosis for patients. Current standard-of-care for gliomas is comprised of maximal safe surgical resection following by a combination of chemotherapy and radiation therapy depending on the grade and type of tumor. Despite decades of research efforts directed towards identifying effective therapies, curative treatments have been largely elusive in the majority of cases. The development and refinement of novel methodologies over recent years that integrate computational techniques with translational paradigms have begun to shed light on features of glioma, previously difficult to study. These methodologies have enabled a number of point-of-care approaches that can provide real-time, patient-specific and tumor-specific diagnostics that may guide the selection and development of therapies including decision-making surrounding surgical resection. Novel methodologies have also demonstrated utility in characterizing glioma-brain network dynamics and in turn early investigations into glioma plasticity and influence on surgical planning at a systems level. Similarly, application of such techniques in the laboratory setting have enhanced the ability to accurately model glioma disease processes and interrogate mechanisms of resistance to therapy. In this review, we highlight representative trends in the integration of computational methodologies including artificial intelligence and modeling with translational approaches in the study and treatment of malignant gliomas both at the point-of-care and outside the operative theater in silico as well as in the laboratory setting.