Treatment Of Malignant Gliomas Research Articles

ECOA-2. Immuno-sensitization of Glioblastoma to NY-ESO-1 Targeting via Promoter Demethylation

Abstract Introduction The immunotherapeutic targeting of New York-esophageal squamous cell carcinoma (NY-ESO-1) and other cancer/testis antigens (CTA) is an appealing strategy for the treatment of malignant gliomas because CTA are not expressed in most normal adult tissues and their expression can be induced in tumors for targeting by T-cells. Basally, NY-ESO-1 is often poorly expressed in glioblastoma (GBM), presumably through promoter methylation. Mechanisms governing the expression of CTA have been explored in other cancers; however, neither the prevalence of NY-ESO-1 downregulation in GBM patient tumors nor the presumed mechanism of downregulation by promoter methylation in GBM has been formally established. Methods We characterized baseline CpG methylation of NY-ESO-1 in 30 bulk patient GBM samples, 10 patient-derived gliomaspheres, and three established tumor cell lines using bisulfite sequencing. We induced NY-ESO-1 expression in vitro in U251 human GBM cells using the hypomethylating agent decitabine (DAC). We investigated the epigenetic response of DAC-treated U251 with bisulfite sequencing and NY-ESO-1 expression with quantitative real-time PCR. Lastly, we performed single-cell RNA sequencing on DAC-treated GBM U251 to evaluate tumor subpopulations that upregulate NY-ESO-1 and other co-expressed CTA after DAC treatment. Results Baseline NY-ESO-1 expression is associated with promoter methylation in the majority of GBM. Treatment of cells with 1 µM DAC every day for 4 days explicitly demethylated the promoter region of NY-ESO-1 and resulted in a 1000-fold increase in mRNA expression. DAC treatment upregulates NY-ESO-1 coordinately with other cancer/testis antigens CTAG2 and MAGEA4 as demonstrated by single-cell RNA sequencing. Conclusion Exposure of U251 to DAC results in promoter demethylation in NY-ESO-1 and increased expression of CTA. DAC treatment may therefore render GBM susceptible to targeting of these antigens by T-cells, revealing a feasible strategy of NY-ESO-1 and co-expressed CTA promoter demethylation to sensitize GBM to immunotherapy.

Abstract 1948: Investigation of the effect of LLLT on glioblastoma multiforme

Abstract Low-level Laser Treatment (LLLT) has a potential to alter tumor behavior such as proliferation in addition to therapeutic effects such as wound healing, inflammation reduction. Studies indicate that, different tumor cells respond distinctly to LLLT based on laser dose (J/sq. cm). GBM is an aggressive and invasive primary brain tumor which is heterogenic in nature and any treatment that could have a potential to kill or change tumor behavior or tumor microenvironment by making GBM sensitive to available treatments can help improve the survival rate. In this study, we investigated the effect of LLLT on human malignant glioma (U251) cells using He-Ne Laser (632.8 nm). The He-Ne laser parameters used for the treatment are power (14.87±0.3 mW), beam diameter (0.68 cm), and varying laser exposure times of 5 mins and 10 mins leading to variable doses of 12.28 J/sq.cm and 24.56 J/sq. cm respectively. The dose response of LLLT on U251 cells revealed that the dose 12.28 J/sq. cm lead to cell death of 17%, 24 hrs post treatment while the dose 24.56 J/sq. cm achieved cell death of 30%, 6 hrs post treatment along with some morphological changes such as vacuole formation in the heterogenic malignant glioma. Also, a biphasic response was observed post treatment with the dose of 24.56 J/sq. cm, as we observed increase in cell viability 18hrs post treatment along with neurite formation. Western analysis suggests the involvement of PARP and caspase 9 in killing LLL treated U251 cells. Thus, upon further study, LLLT could have a potential to be used as an adjunctive treatment when used with conventional treatments for malignant glioma. Citation Format: Rohini Atluri, Parsa Afkhami, Tae-Youl Choi, Denise P. Simmons. Investigation of the effect of LLLT on glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1948.

Role of Polymeric Local Drug Delivery in Multimodal Treatment of Malignant Glioma: A Review.

Malignant gliomas (MGs) are the most common and devastating primary brain tumor. At present, surgical interventions, radiotherapy, and chemotherapy are only marginally effective in prolonging the life expectancy of patients with MGs. Inherent heterogeneity, aggressive invasion and infiltration, intact physical barriers, and the numerous mechanisms underlying chemotherapy and radiotherapy resistance contribute to the poor prognosis for patients with MGs. Various studies have investigated methods to overcome these obstacles in MG treatment. In this review, we address difficulties in MG treatment and focus on promising polymeric local drug delivery systems. In contrast to most local delivery systems, which are directly implanted into the residual cavity after intratumoral injection or the surgical removal of a tumor, some rapidly developing and promising nanotechnological methods—including surface-decorated nanoparticles, magnetic nanoparticles, and focused ultrasound assist transport—are administered through (systemic) intravascular injection. We also discuss further synergistic and multimodal strategies for heightening therapeutic efficacy. Finally, we outline the challenges and therapeutic potential of these polymeric drug delivery systems.

Radiation-induced YAP activation confers glioma radioresistance via promoting FGF2 transcription and DNA damage repair

Although radiotherapy is a well-known effective non-surgical treatment for malignant gliomas, the therapeutic efficacy is severely limited due to the radioresistance of tumor cells. Previously, we demonstrated that Yes-associated protein (YAP) promotes glioma malignant progression. However, whether YAP plays a role in radioresistance and its potential value in cancer treatment are still unclear. In this study, we found that high YAP expression is associated with poor prognosis in malignant glioma patients undergoing radiotherapy. Research in immortalized cell lines and primary cells from GBM patients revealed that YAP exhibited a radioresistant effect on gliomas via promoting DNA damage repair. Mechanistically, after radiation, YAP was translocated into the nucleus, where it promoted the expression and secretion of FGF2, leading to MAPK–ERK pathway activation. FGF2 is a novel target gene of YAP. Inhibition of YAP–FGF2–MAPK signaling sensitizes gliomas to radiotherapy and prolongs the survival of intracranial cell-derived and patient-derived xenograft models. These results suggest that YAP–FGF2–MAPK is a key mechanism of radioresistance and is an actionable target for improving radiotherapy efficacy.

Effect of temozolomide combined with radiotherapy on survival and MGMT protein expression in recurrent malignant glioma patients

Purpose: To investigate the effect of temozolomide (TMZ) combined with radiotherapy (RT) on O-6- methylguanine-DNA methyltransferase (MGMT) protein and survival of recurrent malignant glioma patients.
 Methods: Ninety-two patients with malignant glioma in our hospital from January 2014 to January 2015 were assigned to study and control groups using the random table method. Subjects in the control group received radiotherapy (total dose in the range of 60 – 75 Gy), while those in the study group were given TMZ orally (75 mg/m2) daily in addition to radiotherapy, as well as TMZ at 150 – 200 mg/m2. After treatment, clinical effectiveness was compared for the two groups. Changes in methylation of MGMT gene were determined in the two groups. The patients were followed up for 3 years, and the degrees of survival and recurrence were recorded.
 Results: Total effectiveness of clinical treatment was markedly higher in the study group (76.09 %) than in the control group (45.65 %; p < 0.05). One month after radiotherapy, significant decrease in MGMT gene methylation was seen in patients in the study group, relative to control patients (p < 0.05). Patients in the study group had lower median recurrence but higher degree of survival in the 2nd and 3rd years, relative to control patients (p < 0.05).
 Conclusion: The combination of temozolomide and radiotherapy is more effective than radiotherapy in the treatment of recurrent malignant glioma. The combined treatment significantly inhibits tumor recurrence in patients, and improves their prognosis and standard of life.

Chemotherapy for Glioma

Chemotherapeutic treatment of malignant gliomas is extremely challenging. Tumor accumulation of systemically-administrated chemotherapy is always hindered by the blood-brain barrier(BBB). Although temozolomide administered orally or intravenously represents the standard of care for malignant gliomas, its efficacy is unsatisfactory. Local chemotherapy bypasses the BBB and, therefore, achieves a high drug concentration at the site the drug is administered. Carmustine wafers are clinically available local chemotherapeutic agents. However, their efficacy is limited because of limited drug penetration into the tumor. Combined with the highly chemoresistant features of glioma itself, ongoing chemotherapy is far from satisfactory in terms of efficacy. This review covers several important issues regarding temozolomide chemotherapy, including the reactivation of hepatitis B virus, assessment of MGMT promoter methylation, and pseudo-progression. Local chemotherapy for newly diagnosed resectable glioblastoma cases using carmustine wafers is currently under investigation with a randomized phase 3 trial (JCOG 1703), which will also be discussed. In addition, recent progress in convection-enhanced delivery of chemotherapeutics against gliomas has also been reported. Development of an alternative strategy to effectively deliver drugs to the tumor site may improve the efficacy of chemotherapy against gliomas in the near future.

Targeting the Complement Pathway in Malignant Glioma Microenvironments

Malignant glioma is a highly fatal type of brain tumor, and its reoccurrence is largely due to the ordered interactions among the components present in the complex microenvironment. Besides its role in immune surveillance and clearance under physiological conditions, the complement system is expressed in a variety of tumor types and mediates the interactions within the tumor microenvironments. Recent studies have uncovered the broad expression spectrum of complement signaling molecules in the tumor microenvironment and various tumor cells, in particular, malignant glioma cells. Involvement of the complement system in tumor growth, immunosuppression and phenotype transition have also been elucidated. In this review, we enumerate the expression and function of complement molecules in multiple tumor types reported. Moreover, we elaborate the complement pathways in glioma cells and various components of malignant glioma microenvironments. Finally, we summarize the possibility of the complement molecules as prognostic factors and therapeutic targets in the treatment of malignant glioma. Specific targeting of the complement system maybe of great significance and value in the future treatment of multi-type tumors including malignant glioma.

Inflammatory tumor microenvironment responsive neutrophil exosomes-based drug delivery system for targeted glioma therapy

Clinical treatment of malignant glioma remains a major challenge due to high infiltrative growth and chemotherapeutic resistance of tumors and the presence of the blood brain barrier (BBB). Advanced nanoplatforms that can efficiently cross the BBB and target to brain tumor are urgently needed. Encouraged by the intrinsic inflammatory chemotaxis and excellent BBB-crossing capability of neutrophils, a bioinspired neutrophil-exosomes (NEs-Exos) system for delivering loaded doxorubicin (DOX) drug for glioma treatment is proposed and systematically investigated. In vivo zebrafish and C6-Luc glioma-bearing mice models show that NEs-Exos carrying the drug rapidly penetrate the BBB and migrate into the brain. Additionally, a transwell BBB model and mouse brain inflammatory study show that NEs-Exos can respond chemotactically to inflammatory stimuli and target infiltrating tumor cells in inflamed brain tumors. Moreover, intravenous injection of NEs-Exos/DOX efficiently suppress tumor growth and prolong survival time in a glioma mouse model. On the basis of these results, NEs-Exos are confirmed to have neutrophil-like chemotactic function and BBB penetration. This novel NEs-Exos/DOX delivery platform represents a promising chemotherapeutic approach for clinical treatment of glioma and other solid tumor or brain diseases.

Commentary on "Regulatory Science and Innovation Programme for Europe (ReScIPE): A proposed model".

Commentary on "Regulatory Science and Innovation Programme for Europe (ReScIPE): A proposed model".

Mifepristone Repurposing in Treatment of High-Grade Gliomas.

Glioma is the most common and aggressive primary tumor of the central nervous system. The standard treatment for malignant gliomas is surgery followed by chemoradiotherapy. Unfortunately, this treatment has not produced an adequate patient response, resulting in a median survival time of 12–15 months and a 5-year overall survival of <5%. Although new strategies have been sought to enhance patient response, no significant increase in the global survival of glioma patients has been achieved. The option of developing new drugs implies a long and costly process, making drug repurposing a more practical alternative for improving glioma treatment. In the last few years, researchers seeking more effective cancer therapy have pursued the possibility of using anti-hormonal agents, such as mifepristone. The latter drug, an antagonist for progesterone and glucocorticoid receptors, has several attractive features: anti-tumor activity, low cytotoxicity to healthy cells, and modulation of the chemosensitivity of several cancer cell lines in vitro. Hence, the addition of mifepristone to temozolomide-based glioblastoma chemotherapy may lead to a better patient response. The mechanisms by which mifepristone enhances glioma treatment are not yet known. The current review aims to discuss the potential role of mifepristone as an adjuvant drug for the treatment of high-grade gliomas.

Double-targeting CDCA8 and E2F1 inhibits the growth and migration of malignant glioma

High-grade glioma is the most common and aggressive primary brain tumor in adults with poor therapeutic efficiency and survival prognosis. Cell division cycle associated 8 (CDCA8) has been well known as a cell cycle regulator and tumor promotor in various malignant tumors. However, its biological role in glioma still remains unclear. Our results showed that high level of CDCA8 was significantly correlated with advanced WHO grade and poor overall survival and disease-free survival prognosis. In vitro and in vivo investigations demonstrated that CDCA8 promoted the glioma malignancy by promoting cell proliferation, cell migration, and inhibiting cell apoptosis. Moreover, we found its synergetic biological protein—E2F1 by the gene microarray chip. In this study, we revealed that CDCA8 synergized with E2F1 facilitated the proliferation and migration of glioma. In conclusion, our study provides a novel promising therapeutic targets and prognostic biomarkers for malignant glioma treatment.

The potential value of dequalinium chloride in the treatment of cancer: Focus on malignant glioma.

Dequalinium chloride has been known as one kind of antibiotic that displays a broad antimicrobial spectrum and has been clinically proven to be very safe. In recent years, studies have shown that dequalinium chloride can inhibit the growth of malignant tumours, and reports were mainly used for solid tumours. Glioblastoma is the most common malignant neuroepithelial tumour of the central nervous system in adults, and the prognosis of glioblastoma is poor as it has a high resistance to apoptosis. This review summarizes the current understanding of dequalinium chloride-induced cancer cell apoptosis and its potential role in glioblastoma resistance and progression. Particularly, we focus on dequalinium chloride as it exerts a wide range of anti-cancer activity through its ability to target and accumulate in the mitochondria, and it effectively inhibits the growth of glioblastoma cells in vitro and vivo. Dequalinium chloride is an inhibitor of XIAP and can also act as a mitochondrial targeting agent, which gives it an interesting perspective regarding recent advances in the treatment of malignant glioma.

Hippo Signaling Pathway in Gliomas.

The Hippo signaling pathway is a highly conserved pathway involved in tissue development and regeneration that controls organ size through the regulation of cell proliferation and apoptosis. The core Hippo pathway is composed of a block of kinases, MST1/2 (Mammalian STE20-like protein kinase 1/2) and LATS1/2 (Large tumor suppressor 1/2), which inhibits nuclear translocation of YAP/TAZ (Yes-Associated Protein 1/Transcriptional co-activator with PDZ-binding motif) and its downstream association with the TEAD (TEA domain) family of transcription factors. This pathway was recently shown to be involved in tumorigenesis and metastasis in several cancers such as lung, breast, or colorectal cancers but is still poorly investigated in brain tumors. Gliomas are the most common and the most lethal primary brain tumors representing about 80% of malignant central nervous system neoplasms. Despite intensive clinical protocol, the prognosis for patients remains very poor due to systematic relapse and treatment failure. Growing evidence demonstrating the role of Hippo signaling in cancer biology and the lack of efficient treatments for malignant gliomas support the idea that this pathway could represent a potential target paving the way for alternative therapeutics. Based on recent advances in the Hippo pathway deciphering, the main goal of this review is to highlight the role of this pathway in gliomas by a state-of-the-art synthesis.

Regulation of temozolomide resistance in glioma cells via the RIP2/NF-κB/MGMT pathway.

BackgroundTemozolomide (TMZ) is a first‐line chemotherapy drug for the treatment of malignant glioma and resistance to it poses a major challenge. Receptor‐interacting protein 2 (RIP2) is associated with the malignant character of cancer cells. However, it remains unclear whether RIP2 is involved in TMZ resistance in glioma.MethodsRIP2 expression was inhibited in TMZ‐resistant glioma cells and normal glioma cells by using small interfering RNA (siRNA) against RIP2. Plasmid transfection method was used to overexpress RIP2. Cell counting kit‐8 assays were performed to evaluate cell viability. Western blotting or immunofluorescence was performed to determine RIP2, NF‐κB, and MGMT expression in cells. Flow cytometry was used to investigate cell apoptosis. TMZ‐resistant glioma xenograft models were established to evaluate the role of the RIP2/NF‐κB/MGMT signaling pathway in drug resistance.ResultsWe observed that RIP2 expression was upregulated in TMZ‐resistant glioma cells, whereas silencing of RIP2 expression enhanced cellular sensitivity to TMZ. Similarly, upon the induction of RIP2 overexpression, glioma cells developed resistance to TMZ. The molecular mechanism underlying the process indicated that RIP2 can activate the NF‐κB signaling pathway and upregulate the expression of O6‐methylguanine‐DNA methyltransferase (MGMT), following which the glioma cells develop drug resistance. In the TMZ‐resistant glioma xenograft model, treatment with JSH‐23 (an NF‐κB inhibitor) and lomeguatrib (an MGMT inhibitor) could enhance the sensitivity of the transplanted tumor to TMZ.ConclusionWe report that the RIP2/NF‐κB/MGMT signaling pathway is involved in the regulation of TMZ resistance. Interference with NF‐κB or MGMT activity could constitute a novel strategy for the treatment of RIP2‐positive TMZ‐resistant glioma.

Anti-tumour activity of deer growing antlers and its potential applications in the treatment of malignant gliomas

A recent study showed that antlers have evolved a high rate of growth due to the expression of proto-oncogenes and that they have also evolved to express several tumour suppressor genes to control the risk of cancer. This may explain why deer antler velvet (DAV) extract shows anti-tumour activity. The fast growth of antler innervation through the velvet in close association to blood vessels provides a unique environment to study the fast but non-cancerous proliferation of heterogeneous cell populations. We set out to study the anti-cancer effect of DAV in glioblastoma (GB) cell lines in comparison with temozolomide, a chemotherapeutic drug used to treat high-grade brain tumours. Here we report, for the first time, that DAV extract from the tip, but not from mid-parts of the antler, exhibits an anti-tumour effect in GB cell lines (T98G and A172) while being non-toxic in non-cancerous cell lines (HEK293 and HACAT). In T98G cells, DAV treatment showed reduced proliferation (37.5%) and colony-formation capacity (84%), inhibited migration (39%), induced changes in cell cycle progression, and promoted apoptosis. The anticancer activity of DAV extract as demonstrated by these results may provide a new therapeutic strategy for GB treatment.

Dosimetric Comparison: Volumetric Modulated Arc Therapy (VMAT) and 3D Conformal Radiotherapy (3D-CRT) in High Grade Glioma Cancer—Experience of Casablanca Cancer Center at the Cheikh Khalifa International University Hospital

Background: Intensity Modulated Radiation Therapy (IMRT) is currently employed as a major arm of treatment in multiforme glioblastoma (GBM). The present study aimed to compare 3D-CRT with IMRT to assess tumor volume coverage and OAR sparing for the treatment of malignant gliomas. Materials and methods: We assessed 22 anonymized patients datasets with High Grade Glioblastoma who had undergone post-operative Intensity Modulated Radiotherapy (IMRT) and 3D Conformal Radiotherapy (3D-CRT), This study will compare and contrast treatment plans Rapidarc and 3D-CRT to determine which technology improves significantly dosimetric parameters. Results: Plans will be assessed by reviewing the coverage of the PTV using mean, maximum and minimum doses while the OAR doses will be compared using the maximal doses for each, as set out in the QUANTEC dose limits. Conclusion: The use of IMRT seems a superior technique as compared to 3D-CRT for the treatment of malignant gliomas having the potential to increase the dose to the PTV while sparing OARs optimally.

Dosimetric Comparison: Volumetric Modulated Arc Therapy (VMAT) and 3d Conformal Radiotherapy (3d-CRT) in High Grade Glioma Cancer Experience of Casablanca Cancer Center at the Cheikh Khalifa International University Hospital

Background: Intensity Modulated Radiation Therapy (IMRT) is currently employed as a major arm of treatment in multiforme glioblastoma (GBM). The present study aimed to compare 3D-CRT with IMRT to assess tumor volume coverage and OAR sparing for treatment of malignant gliomas. Materials and Methods: We assessed 22 anonymized patients datasets with High Grade Glioblastoma who had undergone post-operative Intensity Modulated Radiotherapy (IMRT) and 3D Conformal Radiotherapy (3D-CRT), This study will compare and contrast treatment plans Rapidarc and 3D-CRT to determine which technique improves significantly dosimetric parameters. Results: Plans will be assessed by reviewing the coverage of the PTV using mean, maximum and minimum doses while the OAR doses will be compared using the maximal doses for each, as set out in the QUANTEC dose limits. Conclusion: The use of IMRT seems a superior technique as compared to 3D-CRT for the treatment of malignant gliomas having the potential to increase dose to the PTV while sparing OARs optimally

Acute toxicity of temozolomide for the treatment of anaplastic astrocytoma: A case report

Temozolomide is an orally administered chemotherapeutic drug that has become a standard treatment for malignant gliomas. Severe toxicity of temozolomide is rare, especially shortly after administration. We report a 37-year-old male patient diagnosed with anaplastic astrocytoma following tumor resection. He was treated postoperatively with cranial radiation and adjuvant temozolomide 150 mg/m2 for six planned cycles. However, 3 days after finishing the first cycle of temozolomide, the patient's condition deteriorated. Laboratory results showed thrombocytopenia and lymphopenia, and chest X-ray revealed an infiltrate in the right segment of the lung, suggesting pneumonia. These conditions were thought to be caused by temozolomide. Although temozolomide is generally well tolerated by glioma patients, several adverse effects have been reported. In addition, malignancy, corticosteroids, and chemotherapy are known to increase the risk of immunosuppression. Close monitoring of patients treated with temozolomide is warranted, especially brain tumor patients, due to the risk of myelosuppression and severe infection. The work was approved by the Health Research Ethics Committee of DR Mohammad Hoesin Hospital (No. 130/kepkrsmh/2020) on December 15, 2020.

Convection Enhanced Delivery of Topotecan for Gliomas: A Single-Center Experience.

A key limitation to glioma treatment involves the blood brain barrier (BBB). Convection enhanced delivery (CED) is a technique that uses a catheter placed directly into the brain parenchyma to infuse treatments using a pressure gradient. In this manuscript, we describe the physical principles behind CED along with the common pitfalls and methods for optimizing convection. Finally, we highlight our institutional experience using topotecan CED for the treatment of malignant glioma.

Understanding the glioblastoma tumor biology to optimize photodynamic therapy: From molecular to cellular events.

Photodynamic therapy (PDT) has recently gained attention as an alternative treatment of malignant gliomas. Glioblastoma (GBM) is the most prevalent within tumors of the central nervous system (CNS). Conventional treatments for this CNS tumor include surgery, radiation, and chemotherapy. Surgery is still being considered as the treatment of choice. Even so, the poor prognosis and/or recurrence of the disease after applying any of these treatments highlight the urgency of exploring new therapies and/or improving existing ones to achieve the definitive eradication of tumor masses and remaining cells. PDT is a therapeutic modality that involves the destruction of tumor cells by reactive oxygen species induced by light, which were previously treated with a photosensitizing agent. However, in recent years, its experimental application has expanded to other effects that could improve overall performance against GBM. In the current review, we revisit the main advances of PDT for GBM management and also, the recent mechanistic insights about cellular and molecular aspects related to tumoral resistance to PDT of GBM.