Standard Of Care For Glioblastoma Research Articles

200 DWI and ADC Changes in Patients With Glioblastoma IDH-Wild Type Following Surgical Tumor Resection

INTRODUCTION: Current standard of care for glioblastoma (GBM) entails maximal tumor resection to achieve better outcomes while preserving neurological function. Early postoperative DWI has elucidated that peritumoral ischemia is common following glioma resection, but radiographic characteristics, risk factors, and outcomes have not been well described. METHODS: This retrospective cohort included 324 patients (18-86 years) who underwent surgical resection for glioblastoma IDH-wildtype between 2005 and 2022. All patients had structural MRI and DWI acquired preoperatively and within 72 hrs after resection. Areas of restricted diffusion on postoperative DWI were classified as rim, sector, mixed, or remote. RESULTS: Areas of restricted diffusion on postoperative DWI were found in 173 (53%) patients. 55 (32%) were rim-shaped, 103 (59%) sector-shaped, 10 (6%) mixed, and 5 (3%) remote. Preoperative tumor volume was positively correlated with areas of ischemia (p = 0.048), but peritumoral DWI was not correlated with decreased overall survival (OS) or Karnofsky Performance Score (KPS). In the full cohort analysis, gross total resection (GTR) correlated with improved OS compared to subtotal total resection (STR) (p = 0.016); however, subgroup analysis revealed that this survival benefit was exclusively found in patients without peritumoral infarction on DWI (21 months vs. 13 months, p = 0.043). CONCLUSIONS: Larger tumor volume was a risk factor for larger peritumoral infarction. The survival benefit of GTR was only seen in patients who did not experience postoperative peritumoral infarction, underscoring the importance of maximal safe tumor resection. Future study on specific causes of postoperative peritumoral infarctions may improve surgical management and outcomes in glioblastoma patients.

Abstract 6171: Evolution of the spatial myeloid-lymphoid engagement in glioblastoma under temozolomide treatment

Abstract The current standard of care for glioblastoma (GBM), encompassing surgery, chemotherapy, and radiation, fails to extend patient survival beyond ~12-15 months. Even advanced immunotherapies, such as checkpoint blockade and chimeric antigen receptor-armored T-cell therapies, are ineffective in GBM due to tissue-specific niche-dependent escape strategies employed by glioma cells. Immune effectiveness, a finely regulated spatial and context-dependent process, underpins such a dismal state of the present therapeutic options. Herein, we applied CO-Detection by indEXing (CODEX), a state-of-the-art multiplex imaging platform, to elucidate the immune cell networks of the tumor microenvironment. By harnessing computational tools on multiplexed regions of interest across whole-slide images, we characterize the immune repertoire of GBMs by studying intratumor heterogeneity across space-histological territories- and time, matching pre- and post-treatment tissue sections of GBMs from seven patients under treatment (Stupp protocol). We aimed to assess changes in the interactions between the two main compartments of the immune system, myeloid and lymphoid, pre- and post-treatment using spatial statistics. We designed a computational workflow for the georeferencing, classification, and phenotyping individual cells of CODEX images across 105 regions of interest, representative of a mosaic of histologically defined cellular tumor (CT) or infiltrating tumor. We defined six major immune phenotypes and evaluated their spatial association with Cd45-Nestin+Olig2+ glioma cells. We modeled the GBM ecosystem and the cells’ spatial coexistence as spatial point processes that allowed the projection of coexistence networks. After stringent quality control, we detected and phenotyped 2.3M cells. Despite interpatient heterogeneity, some patients maintained an even immune composition, while others showed an enrichment in microglia, particularly in CT. Spatial network analyses revealed an increased coexistence between myeloid and lymphoid cells after treatments despite T cells being canonically considered moderately abundant. Quantitatively, the immune meta-network displayed higher edge density and lower modularity post-treatment compared with pre-treatment, reflecting increased lymphoid-myeloid engagement. In summary, we detected an increased spatial myeloid-lymphoid engagement in GBM undergoing chemo-radiation treatments. Spatiotemporal rearrangement of tumor-immune interactions indicates mechanisms implicated in disease recurrence and resistance to standard treatment, opening the frontiers for developing new targeted immunotherapies. Citation Format: Simon P. Castillo, Afrooz Jahedi, Pravesh Gupta, Jason T. Huse, Kasthuri Kannan, Yinyin Yuan, Krishna P. Bhat. Evolution of the spatial myeloid-lymphoid engagement in glioblastoma under temozolomide treatment [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 6171.

Integrating and optimizing tonabersat in standard glioblastoma therapy: A preclinical study.

Glioblastoma (GB), a highly aggressive primary brain tumor, presents a poor prognosis despite the current standard therapy, including radiotherapy and temozolomide (TMZ) chemotherapy. Tumor microtubes involving connexin 43 (Cx43) contribute to glioma progression and therapy resistance, suggesting Cx43 inhibition as a potential treatment strategy. This research aims to explore the adjuvant potential of tonabersat, a Cx43 gap junction modulator and blood-brain barrier-penetrating compound, in combination with the standard of care for GB. In addition, different administration schedules and timings to optimize tonabersat's therapeutic window are investigated. The F98 Fischer rat model will be utilized to investigate tonabersat's impact in a clinically relevant setting, by incorporating fractionated radiotherapy (three fractions of 9 Gy) and TMZ chemotherapy (29 mg/kg). This study will evaluate tonabersat's impact on tumor growth, survival, and treatment response through advanced imaging (CE T1-w MRI) and histological analysis. Results show extended survival in rats receiving tonabersat with standard care, highlighting its adjuvant potential. Daily tonabersat administration, both preceding and following radiotherapy, emerges as a promising approach for maximizing survival outcomes. The study suggests tonabersat's potential to reduce tumor invasiveness, providing a new avenue for GB treatment. In conclusion, this preclinical investigation highlights tonabersat's potential as an effective adjuvant treatment for GB, and its established safety profile from clinical trials in migraine treatment presents a promising foundation for further exploration.

A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance.

A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence. In addition to the limited therapeutic benefit, TMZ also causes debilitating adverse events (AEs) that significantly impact the quality of life of GBM patients. Some of the most common AEs include hematologic (e.g., thrombocytopenia, neutropenia, anemia) and non-hematologic (e.g., nausea, vomiting, constipation, dizziness) toxicities. Recurrent GBMs are often resistant to TMZ and other DNA-damaging agents. Thus, there is an urgent need to devise strategies to potentiate TMZ activity, to overcome drug resistance, and to reduce dose-dependent AEs. Here, we analyze major mechanisms of the TMZ resistance-mediated intracellular signaling activation of DNA repair pathways and the overexpression of drug transporters. We review some of the approaches investigated to counteract these mechanisms of resistance to TMZ, including the use of chemosensitizers and drug delivery strategies to enhance tumoral drug exposure.

Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma.

Glioblastoma (GB) is the most lethal brain cancer in adults, with a 5-year survival rate of 5%. The standard of care for GB includes maximally safe surgical resection, radiation, and temozolomide (TMZ) therapy, but tumor recurrence is inevitable in most GB patients. Here, we describe the development of a blood-brain barrier (BBB)-penetrant tubulin destabilizer, RGN3067, for the treatment of GB. RGN3067 shows good oral bioavailability and achieves high concentrations in rodent brains after oral dosing (Cmax of 7807 ng/mL (20 μM), Tmax at 2 h). RGN3067 binds the colchicine binding site of tubulin and inhibits tubulin polymerization. The compound also suppresses the proliferation of the GB cell lines U87 and LN-18, with IC50s of 117 and 560 nM, respectively. In four patient-derived GB cell lines, the IC50 values for RGN3067 range from 148 to 616 nM. Finally, in a patient-derived xenograft (PDX) mouse model, RGN3067 reduces the rate of tumor growth compared to the control. Collectively, we show that RGN3067 is a BBB-penetrant small molecule that shows in vitro and in vivo efficacy and that its design addresses many of the physicochemical properties that prevent the use of microtubule destabilizers as treatments for GB and other brain cancers.

Tumor treating fields for the treatment of glioblastoma: Current understanding and future perspectives.

This review focuses on the recently published evidence on tumor treating fields (TTFields) administered alone or in combination with locoregional and systemic options for treating glioblastoma (GBM) in the past ten years. The aim is to critically summarize the novelty and results obtained with this innovative tool, which is becoming part of the armamentarium of neurosurgeons and neuro-oncologists. A comprehensive search and analysis were conducted on pivotal studies published in the past ten years. Furthermore, all completed clinical trials, whose results were published on clinicaltrials.gov, were examined and included in the present review, encompassing both recurrent (r) and newly diagnosed (n) GBM. Finally, an additional examination of the ongoing clinical trials was also conducted. Recent trials have shown promising results both in patients with nGBM and rGBM/progressive (rGBM), leading to Food and Drug Administration approval in selected patients and the Congress of Neurological Surgeons to include TTFields into current guidelines on the management of GBM (P100034/S001-029). Recently, different randomized trials have demonstrated promising results of TTFields in combination with standard treatment of n- and rGBM, especially when considering progression-free and overall survival, maintaining a low rate of mild to moderate adverse events. Optimal outcomes were obtained in nGBM and progressive disease. A possible future refinement of TTFields could significantly impact the treatment of rGBM and the actual standard of care for GBM, given the better safety profile and survival effects.

NIMG-35. RADIO-PATHOMIC MAPS OF TUMOR PROBABILITY IDENTIFY GLIOBLASTOMA INVASION BEYOND 5-ALA GUIDED RESECTION MARGINS THAT EVENTUALLY EXHIBIT TUMOR RECURRENCE

Abstract Current standard of care for glioblastoma includes surgery followed by chemotherapy and radiation, with extent of resection strongly correlated with survival. There is a need to improve the detection of tumor invasion beyond traditional imaging methods, as the full extent of tumor is known to be underestimated. Fluorescence-guided surgery with 5-Aminolevulinic acid (5-ALA) allows surgeons to visualize tumor cells beyond what is seen within traditional MR imaging margins. In this study, we compared tumor probability maps (TPMs) that detect tumor outside of contrast enhancement (CE) to the 5-ALA-guided resection cavity in glioblastoma patients. 3 pathologically confirmed glioblastoma patients that followed standard of care and underwent 5-ALA surgery were included. Patient 1 was a 56-year-old male with radiographic recurrence at 26 days, patient 2 was a 61-year-old male with radiographic recurrence at 130 days, and patient 3 was a 72-year-old male with cystic recurrence at 84 days, all post 5-ALA surgery. A previously published algorithm, using T1, T1C, FLAIR, and ADC as input and autopsy tissue as ground truth, was used to generate TPMs. Pre-surgical TPMs were qualitatively compared to pre-surgical CE, post-5-ALA surgical resection cavities, and radiographic recurrence seen as CE. In patients 1 and 2, TPMs identified areas suspicious of tumor that was not resected and later exhibited radiographic recurrence. Patient 3 had cystic recurrence only identified on post-resection T1C. In all patients, the extent of 5-ALA resection was greater than CE volume, but smaller than TPM identified tumor. These findings suggest that there was residual tumor that was unidentified via 5-ALA and traditional imaging but was identified by the TPMs. Future studies could utilize these maps in conjunction with 5-ALA to maximize surgical resections and prolong overall survival.

TMIC-54. RADIOTHERAPY-INDUCED REMODELING OF THE GLIOBLASTOMA MICROENVIRONMENT

Abstract Radiotherapy (RT) is included in the standard of care for glioblastoma (GBM), and while primary tumors generally respond to RT, GBMs invariably recur as incurable lesions. We have previously demonstrated that RT generates a net tumor-supportive tumor microenvironment (TME), in part by inducing remodeling of the extracellular matrix, suggesting that there are therapeutic opportunities in targeting the altered TME of recurrent GBM. Here, we have used highly multiplexed immunohistochemistry in combination with single cell RNA sequencing to characterize the cellular composition and molecular alterations to the GBM TME as tumors progress from primary to irradiated to recurrent tumors, using a genetically engineered GBM mouse model. RT resulted in a phenotypic shift suggestive of a proneural-to-mesenchymal switch of lineage-traced tumor cells immediately after treatment, but proportions of tumor cell phenotypes were largely restored at the time of recurrence. Recurrent tumors displayed an altered immune landscape, as demonstrated e.g. by an increase in the proportion of CD8+ lymphocytes coupled to a decrease in the proportion of CD4+ cells. Together, our data suggest that RT remodels the GBM TME as well as alters the phenotype of bona fide glioma cells. Ongoing studies are aimed at understanding heterotypic cell-cell interactions unique to the irradiated and recurrent GBM TME.

Spectroscopic MRI Detects Occult Glioblastoma Invasion during Chemoradiation

The standard of care for glioblastoma (GBM) includes surgical resection followed by adjuvant chemoradiation (chemoRT). Treatment margins are controversial since conventional imaging does not define the extent of infiltrating tumor cells. Whole-brain spectroscopic MRI (sMRI) allows for visualization of native metabolites in normal brain and tumor cells, and the relative choline to N-acetyl-aspartate ratio greater than 2 (rChoNAA>2) strongly correlates with the presence of occult GBM cells in otherwise normal-appearing brain. With an MRI-Linac, we are performing studies of adaptive radiotherapy to measure changes in cavity size, edema, and enhancement during chemoRT. We questioned whether rChoNAA>2 would change along with anatomical changes to inform clinical target volumes for adaptive chemoRT trials. In a prospective study, 18 patients with primary GBM underwent daily MRI-guided chemoRT with standalone 3T sMRI generation of rChoNAA>2 maps at three timepoints before, during, and after chemoradiation. Conventional treatment volumes of T1 post-contrast and cavity (GTV2, i.e., boost) with or without FLAIR hyperintensity (GTV1) were compared to rChoNAA>2 volumes. DICE similarity coefficients were calculated to assess the spatial similarity of these volumes. Hausdorff distances were calculated to identify rChoNAA>2 extending beyond GTVs throughout the course of chemoradiation. The mean GTV1 was 58.1 cc (range 0-251.4 cc), the mean GTV2 was 47.9 cc (range 0-139.9 cc), and the mean rChoNAA>2 volume was 31.1 cc (range 0-103.2 cc). rChoNAA>2 volumes did not significantly change over the course of chemoRT or correlate with measurement timepoint. The mean DICE similarity coefficient between GTV1 and rChoNAA>2 volumes was 0.39 (range 0-0.80), and the mean DICE similarity coefficient between GTV2 and rChoNAA>2 volumes was 0.29 (range 0-0.77). DICE similarity coefficients were significantly different from unity indicating spatial differences between rChoNAA>2 and conventional MRI volumes. The mean Hausdorff distances of rChoNAA>2 extending beyond GTV1 was 1.3 cm (range 0.7-2.1 cm), and the mean Hausdorff distances of rChoNAA>2 extending beyond GTV2 was 1.9 cm (range 0.8-2.9 cm), suggesting high-risk disease invading beyond what is visible on conventional MRI sequences. Whole-brain sMRI with generation of rChoNAA>2 maps suggest conventional MRI does not fully capture the extent of disease in primary GBM throughout the course of chemoradiation. rChoNAA>2 maps often extend up to approximately 2 cm beyond conventional boost radiotherapy volumes. Further studies are ongoing to determine how sMRI can be used to adapt radiation target volumes during chemoradiation and escalate dose to occult disease.

P21.04.A IMPROVEMENTS IN SURVIVAL FOR GLIOBLASTOMA IN THE POST-STUPP PROTOCOL ERA

Abstract BACKGROUND The Stupp protocol was accepted as standard of care for glioblastoma in 2005, and has led to significant increases in overall survival. Prior analyses have identified additional survival gains post-Stupp, though the source of these is unknown. In this analysis, we leveraged two large datasets to identify trends in survival and potential treatment factors associated with these improvements. MATERIAL AND METHODS Provider-side commercial claims data were obtained from IQVIA for adults (18+ years) diagnosed with malignant brain tumor (ICD-9/ICD-10:191.0-191.9/C71.0-C71.9) from 2015-2021 who received biopsy/resection and temozolomide within 60 days of diagnosis. Treatment patterns were determined using ICD-9/ICD-10 procedure and HCPCS/CPT codes. Death was determined by CPT codes or last claim followed by ≥30 days of no claims. Elixhauser comorbidity score was generated prior to diagnosis. Population-based survival data were obtained from the National Program of Cancer Registries (NPCR) from 2004-2018 for microscopically-confirmed adult (18+ years) glioblastoma cases receiving surgery and radiation. Median survival was estimated using Kaplan-Meier regression, and cox proportional hazards models were used to assess potential prognostic factors. Survival analyses were censored at 36 months. RESULTS The IQVIA dataset had 18,883 individuals and NPCR had 92,540 individuals identified as being diagnosed with glioblastoma and meeting treatment criteria. Median survival among IQVIA cases was 13.9 months (95%CI=13.7-14.1), and 14 months (95%CI=14-14) in NPCR. Median survival in NPCR increased from 11 months in 2004-2006, to 14 months in 2016-2018. Within IQVIA, 19% of individuals had ≥1 claim for Bevacizumab and 15.5% had ≥1 claim for tumor treating fields (TTFields). Use of TTFields and/or Bevacizumab in treatment were associated with significantly improved survival after adjustment for age, sex, and comorbidities. CONCLUSION s: Survival in glioblastoma continues to improve over time, which may be due to developments in therapeutic approaches. Assessment of population-level survival patterns is essential for understanding the impact of treatment advancements.

Abstract 1102: Establishing the cytotoxic benefit of Tumor Treating Fields on radiation sensitive and acquired radiation resistant glioblastoma patient derived xenograft pairs

Abstract Background: Glioblastoma (GBM) is the most common malignant primary brain tumor with very poor prognosis. The current standard of care for GBM consists of maximal safe tumor resection, chemotherapy (temozolomide) and radiotherapy followed by adjuvant temozolomide and Tumor Treating Fields (TTFields). Unfortunately, GBM displays both inherent and acquired resistance to temozolomide and radiation and is incurable. While TTFields have been found to broadly induce endoplasmic reticulum stress, autophagy, cell membrane permeability, DNA replication stress, anti-mitotic and anti-migratory effects, it is unclear how well TTFields impact radiation resistant GBM. To better understand the cytotoxic benefit of TTFields on acquired radiation resistant GBM, we tested patient-derived xenograft (PDX) brain tumor initiating cells (BTICs) that had been selected for radiation resistance and compared them to their radiation sensitive parent. Methods: PDX were developed with subcutaneous implantation of patient GBM cells into immunodeficient (nu/nu) mice. Acquired radiation resistant PDXs were generated through in vivo selection (6-8 passages) using six fractions of 2 Gray of radiation over two weeks. PDX BTICs were cultured on laminin-coated cover slips under serum free conditions. Cytotoxicity was measured on both the two-dimensional sham control and two-dimensional TTFields treatment conditions over the course of 72 hours and analyzed with crystal violet staining for both imaging and absorbance quantification. PamStation 12 Kinomic data and RNA-seq (Illumina) data was generated for each PDX. Results: Crystal violet quantification and representative imaging indicated that TTFields inhibit cell growth in both parental and acquired radiation resistant PDX-derived BTICs. There is an observed TTFields sensitivity response from the acquired radiation resistant PDX, indicating that TTFields treatment does have a cytotoxic effect on acquired radiation resistant models (seen over four reproducible experiments). Baseline kinomic and transcriptomic differences between the PDX lines suggest potential TTFields sensitivity signatures. Conclusions: Ongoing studies are focused on validation of this cytotoxic effect on larger cohort of both acquired and inherent radiation resistant PDX cells. We plan to measure TTFields -treatment induced kinomic alterations to identify downstream signaling pathways associated with TTFields treatment response, as well as the development of acquired TTFields resistant GBM PDX cells. Citation Format: Taylor L. Schanel, Amber B. Jones, Andee M. Beierle, Hasan Alrefai, Lauren C. Nassour, Patricia H. Hicks, Joshua C. Anderson, Anita B. Hjelmeland, Christopher D. Willey. Establishing the cytotoxic benefit of Tumor Treating Fields on radiation sensitive and acquired radiation resistant glioblastoma patient derived xenograft pairs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1102.

Abstract 1665: Imipramine enhances the efficacy of lomustine by regulating WNT-β-catenin signaling in glioblastoma

Abstract Background: Glioblastoma (GBM) is one of the most aggressive and difficult-to-treat brain cancers. Surgical excision followed by concurrent temozolomide (TMZ), and radiation therapy are the current standard of care for GBM. Lomustine, another alkylating regimen, has also been approved for the treatment of patients with recurrent GBM in addition to TMZ. However, the primary GBM frequently recur as therapy-resistant relapses resulting in shorter survival of patients. To date, no systemic therapies have shown proven survival benefit in recurrent GBM. In this study, we examined whether FDA approved anti-depressant drug Imipramine serve as the potent option for treating patients with recurrent GBM and to improve efficacy of approved chemotherapy. Methods: We investigated the anticancer effects of Imipramine using both established and patient-derived GBM cell lines. We tested the effect of Imipramine and Lomustine combination therapy using cell viability, colony formation, migration and apoptosis assays. Mechanistic studies were conducted using RNA-seq, western blotting, RT-PCR and reporter assays. In vivo efficacy of combination therapy was evaluated using orthotopic mouse models. Results: Our results showed that antidepressant Imipramine blocked the growth of recurrent GBM. Furthermore, Imipramine enhanced the response of Lomustine in therapy resistant GBM cells as a combination therapy and significantly reduced the cell survival and migration, and increased the apoptosis in both established and patient derived GBM cells. Further, our results demonstrated that Imipramine inhibits growth of self-renewing cancer stem cells, which contribute to drug resistance and relapse of GBM. Mechanistic studies revealed that the Imipramine treatment abrogated the WNT-β-catenin signaling, which was confirmed by TOPFLASH reporter assay. Conclusion: Collectively, the results from our study suggest that Imipramine alone and in combination with Lomustine can be used for treating recurrent GBM. Based on these results, a clinical trial is currently ongoing, where we are testing the efficacy of Imipramine for treating patients with recurrent GBM. Citation Format: Prabhakar Pitta Venkata, Arhan Rao, Santosh Timilsina, Panneerdoss Subbarayalu, Andrew Brenner, Gangadhara Reddy Sareddy, Manjeet Rao, William Kelly, Ratna Vadlamudi. Imipramine enhances the efficacy of lomustine by regulating WNT-β-catenin signaling in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1665.

STING agonist-loaded, CD47/PD-L1-targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma

As a key component of the standard of care for glioblastoma, radiotherapy induces several immune resistance mechanisms, such as upregulation of CD47 and PD-L1. Here, leveraging these radiotherapy-elicited processes, we generate a bridging-lipid nanoparticle (B-LNP) that engages tumor-associated myeloid cells (TAMCs) to glioblastoma cells via anti-CD47/PD-L1 dual ligation. We show that the engager B-LNPs block CD47 and PD-L1 and promote TAMC phagocytic activity. To enhance subsequent T cell recruitment and antitumor responses after tumor engulfment, the B-LNP was encapsulated with diABZI, a non-nucleotidyl agonist for stimulator of interferon genes. In vivo treatment with diABZI-loaded B-LNPs induced a transcriptomic and metabolic switch in TAMCs, turning these immunosuppressive cells into antitumor effectors, which induced T cell infiltration and activation in brain tumors. In preclinical murine models, B-LNP/diABZI administration synergized with radiotherapy to promote brain tumor regression and induce immunological memory against glioma. In summary, our study describes a nanotechnology-based approach that hijacks irradiation-triggered immune checkpoint molecules to boost potent and long-lasting antitumor immunity against glioblastoma.

Glioblastoma and the search for non-hypothesis driven combination therapeutics in academia.

Glioblastoma (GBM) remains a cancer of high unmet clinical need. Current standard of care for GBM, consisting of maximal surgical resection, followed by ionisation radiation (IR) plus concomitant and adjuvant temozolomide (TMZ), provides less than 15-month survival benefit. Efforts by conventional drug discovery to improve overall survival have failed to overcome challenges presented by inherent tumor heterogeneity, therapeutic resistance attributed to GBM stem cells, and tumor niches supporting self-renewal. In this review we describe the steps academic researchers are taking to address these limitations in high throughput screening programs to identify novel GBM combinatorial targets. We detail how they are implementing more physiologically relevant phenotypic assays which better recapitulate key areas of disease biology coupled with more focussed libraries of small compounds, such as drug repurposing, target discovery, pharmacologically active and novel, more comprehensive anti-cancer target-annotated compound libraries. Herein, we discuss the rationale for current GBM combination trials and the need for more systematic and transparent strategies for identification, validation and prioritisation of combinations that lead to clinical trials. Finally, we make specific recommendations to the preclinical, small compound screening paradigm that could increase the likelihood of identifying tractable, combinatorial, small molecule inhibitors and better drug targets specific to GBM.

Clinical Effects of Immuno-Oncology Therapy on Glioblastoma Patients: A Systematic Review

The most prevalent and deadly primary malignant glioma in adults is glioblastoma (GBM), which has a median survival time of about 15 months. Despite the standard of care for glioblastoma, which includes gross total resection, high-dose radiation, and temozolomide chemotherapy, this tumor is still one of the most aggressive and difficult to treat. So, it is critical to find more potent therapies that can help glioblastoma patients have better clinical outcomes. Additionally, the prognosis for recurring malignant gliomas is poor, necessitating the need for innovative therapeutics. Immunotherapy is a rather new treatment for glioblastoma and its effects are not well studied when it is combined with standard chemoradiation therapy. We conducted this study to evaluate different glioblastoma immunotherapy approaches in terms of feasibility, efficacy, and safety. We conducted a computer-assisted literature search of electronic databases for essays that are unique, involve either prospective or retrospective research, and are entirely written and published in English. We examined both observational data and randomized clinical trials. Eighteen studies met the criteria for inclusion. In conclusion, combining immunotherapy with radiochemotherapy and tumor removal is generally possible and safe, and rather effective in the prolongation of survival measures.

Injectable local drug delivery systems for glioblastoma: a systematic review and meta-analysis of progress to date.

Glioblastoma (GBM) is an aggressive malignant cancer associated with bleak prognosis and high mortality. The current standard of care for GBM is maximum surgical resection plus radiotherapy and temozolomide (TMZ) chemotherapy. The blood brain barrier (BBB) remains the main obstacle for chemotherapy and severely limits the choice of therapeutic agents. Local treatment allows drugs to circumvent the BBB and reduces systemic side effects. Despite much research effort, to date, no drug delivery system (DDS) designed to be directly injected into brain tumors has been clinically approved, and a systematic overview of the progress in this field, or lack thereof, is missing. In this review, a systematic search of pre-clinical literature was conducted which resulted in 36 original articles on injectable DDS for local treatment of GBM which met the inclusion criteria. A wide range of injectable DDS have been developed and tested pre-clinically which include nanoparticles, liposomes, microspheres, hydrogels and others. meta-Analyses of the included studies showed that, overall, local administration of injectable DDS was beneficial to increase the animal's survival time. Finally, this review summarized the therapeutic effect after local treatment and discussed the shortcomings of the experimental setting in in vivo studies.

Plasma IL13Rα2 as a novel liquid biopsy biomarker for glioblastoma.

Glioblastoma (GBM) is the most common and deadliest brain tumor with unrelenting and rapid disease progression. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Treatment failure and resistance is the rule and despite advances in imaging technology, early detection of treatment failure or impending resistance remains a challenge. There is a dire, unmet, need in clinical practice for minimally-invasive diagnostic tools to enable timely understanding of disease progression and treatment response. Here, we aim to address this clinical need by leveraging a unique characteristic of GBM: the overexpression of the α2 variant of the IL-13 receptor in over 75% of GBM tumors. In this study we examined patients with primary GBM from Penn State and Cleveland Clinic compared to healthy controls. IL13Rα2 was detectable in plasma of GBM patients using ELISA but detection could be optimized by PEG precipitation to enrich for extracellular vesicles (EVs). Patients with GBM had elevated levels of plasma IL13Rα2, which correlated to levels of this receptor in the tumor tissue. Elevated plasma levels of IL13Rα2 predicted longer overall survival (OS) (19.8 vs. 13.2 months). Similarly, detection of IL13Rα2 + cells in tumor tissue also predicted longer OS (22.1 vs. 12.2 months). These findings strongly suggest that expression of the IL13Rα2 receptor confer survival advantage in GBM patients, which can be determined through a minimally-invasive liquid biopsy. Detection of plasma IL13Rα2 can also be used to select GBM patients for targeted tumor therapy.

Glioblastoma - treatment and obstacles.

BackgroundGlioblastoma is the most common and aggressive primary tumor in adults. A narrative review of all the relevant papers known was conducted.Materials and methodsReviews, clinical trials, and randomized controlled trials published from 1981 through September 2021 and written, or at least abstracted, in English were analyzed.ResultsThe standard of care for glioblastoma is the maximum safe resection possible, followed by radiation therapy and concurrent temozolomide (TMZ) and daily TMZ and tumor treatment fields (TTFields) after irradiation. There is no evidence to date of the benefit of brachytherapy, radiosurgery (SRS), fractional stereotactic radiotherapy (FSRT), and hyperfractionated radiotherapy over conventional external beam radiation therapy (EBRT) for the primary tumor. The assessment of age and performance status before treatment in the elderly enables hypofractionated radiotherapy. The research of tumor molecular signatures contributes to the choice of the best-targeted drug therapy. In recurrent glioblastoma, it is necessary to balance the risks and benefits of re-radiation and association with bevacizumab. Solid data confirming the role of immunotherapy in the treatment of malignant glioma are still lacking.ConclusionsAlthough the treatment of glioblastoma has evolved in terms of local control, mortality remains close to 12 months after diagnosis. To obtain better results and reduce recurrence, future research needs to investigate the frontiers of knowledge, such as the elucidation of the molecular mechanisms related to the tumor, the optimization of drugs to overcome the blood-brain barrier effectively, and the discovery of new therapies aimed at the heterogeneous profile of this neoplasm.

Amphiphilic Triazine-Phosphorus Metallodendrons Possessing Anti-Cancer Stem Cell Activity.

Dendritic molecules bearing metal complexes in their structure (metallodendrimers and metallodendrons) are considered prospective therapeutic entities. In particular, metallodendrons raise interest as antitumor agents for the treatment of poorly curable or drug-resistant tumors. Herein, we have synthesized amphiphilic triazine-phosphorus dendrons bearing multiple copper (II) or gold (III) complexes on the periphery and a branched hydrophobic fragment at the focal point. Due to their amphiphilic nature, metallodendrons formed single micelles (mean diameter ~9 nm) or multi-micellar aggregates (mean diameter ~60 nm) in a water solution. We have tested the antitumor activity of amphiphilic metallodendrons towards glioblastoma, a malignant brain tumor with a notoriously high level of therapy resistance, as a model disease. The metallodendrons exhibit higher cytotoxic activity towards glioblastoma stem cells (BTSC233, JHH520, NCH644, and SF188 cell lines) and U87 glioblastoma cells (IC50 was 3–6 µM for copper-containing dendron and 11–15 µM for gold-containing dendron) in comparison with temozolomide (IC50 >100 µM)—the clinical standard of care for glioblastoma. Our findings show the potential of metallodendron-based nanoformulations as antitumor entities.

The effect of levetiracetam treatment on survival in patients with glioblastoma: a systematic review and meta-analysis

Levetiracetam (LEV) is an anti-epileptic drug (AED) that sensitizes glioblastoma (GBM) to temozolomide (TMZ) chemotherapy by inhibiting O6-methylguanine-DNA methyltransferase (MGMT) expression. Adding LEV to the standard of care (SOC) for GBM may improve TMZ efficacy. This study aimed to pool the existing evidence in the literature to quantify LEV's effect on GBM survival and characterize its safety profile to determine whether incorporating LEV into the SOC is warranted. A search of CINAHL, Embase, PubMed, and Web of Science from inception to May 2021 was performed to identify relevant articles. Hazard ratios (HR), median overall survival, and adverse events were pooled using random-effect models. Meta-regression, funnel plots, and the Newcastle-Ottawa Scale were utilized to identify sources of heterogeneity, bias, and statistical influence. From 20 included studies, 5804 GBM patients underwent meta-analysis, of which 1923 (33%) were treated with LEV. Administration of LEV did not significantly improve survival in the entire patient population (HR 0.89, p = 0.094). Significant heterogeneity was observed during pooling of HRs (I2 = 75%, p < 0.01). Meta-regression determined that LEV treatment effect decreased with greater rates of MGMT methylation (RC = 0.03, p = 0.02) and increased with greater proportions of female patients (RC = - 0.05, p = 0.002). Concurrent LEV with the SOC for GBM did not increase odds of adverse events relative to other AEDs. Levetiracetam treatment may not be effective for all GBM patients. Instead, LEV may be better suited for treating specific molecular profiles of GBM. Further studies are necessary to identify optimal GBM candidates for LEV.