-
Biomedicine & Pharmacotherapy =... Sep 2023Glioblastoma (GBL) is the most common (60-70% of primary brain tumours) and the most malignant of the glial tumours. Although current therapies remain palliative, they... (Review)
Review
Glioblastoma (GBL) is the most common (60-70% of primary brain tumours) and the most malignant of the glial tumours. Although current therapies remain palliative, they have been proven to prolong overall survival. Within an optimal treatment regimen (incl. surgical resection, radiation therapy, and chemotherapy) temozolomide as the current anti-GBL first-line chemotherapeutic has increased the median overall survival to 14-15 months, and the percentage of patients alive at two years has been reported to rise from 10.4% to 26.5%. Though, the effectiveness of temozolomide chemotherapy is limited by the serious systemic, dose-related side effects. Therefore, the ponderation regarding novel treatment methods along with innovative formulations is crucial to emerging the therapeutic potential of the widely used drug simultaneously reducing the drawbacks of its use. Herein the complex temozolomide application restrictions present at different levels of therapy as well as, the currently proposed strategies aimed at reducing those limitations are demonstrated. Approaches increasing the efficacy of anti-GBL treatment are addressed. Our paper is focused on the most recent developments in the field of nano/biomaterials-based systems for temozolomide delivery and their functionalization towards more effective blood-brain-barrier crossing and/or tumour targeting. Appropriate designing accounting for the physical and chemical features of formulations along with distinct routes of administration is also discussed. In addition, considering the multiple resistance mechanisms, the molecular heterogeneity and the evolution of tumour the purposely selected delivery methods, the combined therapeutic approaches and specifically focused on GBL cells therapies are reviewed.
Topics: Humans; Temozolomide; Dacarbazine; Brain Neoplasms; Glioblastoma; Glioma; Antineoplastic Agents, Alkylating
PubMed: 37459661
DOI: 10.1016/j.biopha.2023.115174 -
Science Translational Medicine Sep 2023The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle to the advancement of therapy for high-grade gliomas, particularly glioblastoma...
The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle to the advancement of therapy for high-grade gliomas, particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial (number NCT04135807), we provide first-in-human evidence that drug-releasing intratumoral microdevices (IMDs) can be safely and effectively used to obtain patient-specific, high-throughput molecular and histopathological drug response profiling. These data can complement other strategies to inform the selection of drugs based on their observed antitumor effect in situ. IMDs are integrated into surgical practice during tumor resection and remain in situ only for the duration of the otherwise standard operation (2 to 3 hours). None of the six enrolled patients experienced adverse events related to the IMD, and the exposed tissue was usable for downstream analysis for 11 out of 12 retrieved specimens. Analysis of the specimens provided preliminary evidence of the robustness of the readout, compatibility with a wide array of techniques for molecular tissue interrogation, and promising similarities with the available observed clinical-radiological responses to temozolomide. From an investigational aspect, the amount of information obtained with IMDs allows characterization of tissue effects of any drugs of interest, within the physiological context of the intact tumor, and without affecting the standard surgical workflow.
Topics: Humans; Glioma; Glioblastoma; Drug Delivery Systems; Drug Liberation; Temozolomide
PubMed: 37672566
DOI: 10.1126/scitranslmed.adi0069 -
Bulletin Du Cancer Oct 2023Pheochromocytomas and paragangliomas are rare neuroendocrine tumors, developed respectively in the adrenal medulla and in extra-adrenal locations. Their malignancy is...
Pheochromocytomas and paragangliomas are rare neuroendocrine tumors, developed respectively in the adrenal medulla and in extra-adrenal locations. Their malignancy is defined by the presence of distant metastases. Forty percent of them are inherited and can be part of different hereditary syndromes. Their management is ensured in France by the multidisciplinary expert centers of the ENDOCAN-COMETE national network "Cancers of the Adrenal gland", certified by the National Cancer Institute and discussed within multidisciplinary team meetings. The diagnostic and therapeutic work-up must be standardized, based on an expert analysis of clinical symptoms, hormonal biological secretions, genetics, morphological and specific metabolic imaging. In the context of a heterogeneous survival sometimes beyond seven to ten years, therapeutic intervention must be justified. This is multidisciplinary and relies on surgery, interventional radiology, external or internal radiotherapy and medical treatments such as sunitinib or dacarbazine and temodal chemotherapy. The personalized approach based on functional imaging fixation status and genetics is progressing despite the extreme rarity of this disease.
PubMed: 37573200
DOI: 10.1016/j.bulcan.2023.06.002 -
International Journal of Circumpolar... Dec 2023Glioblastoma (GBM), WHO grade IV, is the most common primary malignant brain tumour among adults with a devastating overall survival of 14-22 months. Standard...
Glioblastoma (GBM), WHO grade IV, is the most common primary malignant brain tumour among adults with a devastating overall survival of 14-22 months. Standard treatment of GBM includes maximum safe resection, radiotherapy plus concomitant and adjuvant temozolomide (TMZ), given over a period of approximately 9 months. Treatment and follow-up for Greenlandic patients with GBM are managed at Rigshospitalet (RH), Copenhagen. Greenlandic GBM patients, therefore, travel back and forth to RH, often unaccompanied, and challenged by cognitive failure or other symptoms from their disease and/or treatment. Few Greenlandic patients are diagnosed with GBM annually, but considering the poor prognosis and short remaining lifespan, it would be preferable to limit their travels. TMZ is administrated as capsules. Health personnel at Queen Ingrid's Hospital (DIH), Nuuk, are trained in treating other oncological diseases and handling side effects. Hence, it could be investigated whether administration of adjuvant TMZ at DIH could be feasible after personnel education as well as economic consideration and compensation, in close collaboration with neuro oncologists at RH. In this article, we describe the Greenlandic cancer treatment, and the typical workflow from diagnosis of GBM to treatment to progression.
Topics: Adult; Humans; Glioblastoma; Antineoplastic Agents, Alkylating; Dacarbazine; Chemotherapy, Adjuvant; Brain Neoplasms; Temozolomide
PubMed: 37992407
DOI: 10.1080/22423982.2023.2285077 -
Acta Neurochirurgica Apr 2024Glioblastoma is the most common primary malignant brain tumor. Despite advances in multimodal concepts over the last decades, prognosis remains poor. Treatment of... (Review)
Review
Glioblastoma is the most common primary malignant brain tumor. Despite advances in multimodal concepts over the last decades, prognosis remains poor. Treatment of patients with glioblastoma remains a considerable challenge due to the infiltrative nature of the tumor, rapid growth rates, and tumor heterogeneity. Standard therapy consists of maximally safe microsurgical resection followed by adjuvant radio- and chemotherapy with temozolomide. In recent years, local therapies have been extensively investigated in experimental as well as translational levels. External stimuli-responsive therapies such as Photodynamic Therapy (PDT), Sonodynamic Therapy (SDT) and Radiodynamic Therapy (RDT) can induce cell death mechanisms via generation of reactive oxygen species (ROS) after administration of five-aminolevulinic acid (5-ALA), which induces the formation of sensitizing porphyrins within tumor tissue. Preliminary data from clinical trials are available. The aim of this review is to summarize the status of such therapeutic approaches as an adjunct to current standard therapy in glioblastoma.
Topics: Humans; Glioblastoma; Aminolevulinic Acid; Fluorescence; Temozolomide; Reactive Oxygen Species
PubMed: 38563988
DOI: 10.1007/s00701-024-06049-3 -
Postepy Biochemii Sep 2023Malignant melanoma is a dangerous skin cancer, accounting for the majority of skin cancer-related deaths. Many patients with this cancer have the V600E mutation in the...
Malignant melanoma is a dangerous skin cancer, accounting for the majority of skin cancer-related deaths. Many patients with this cancer have the V600E mutation in the BRAF gene. This mutation causes constitutive activation of the MAPK/ERK signaling pathway, significantly contributing to the process of carcinogenesis. We discuss the drug design process on the example of a specific BRAF V600E inhibitor, vemurafenib. We begin with the most commonly used drug design methods. The second part of the article focuses on vemurafenib. We analyze the invention of this BRAF V600E inhibitor and its analogue as well as the course of three stages of clinical trials. Then we provide information about other popular drugs for malignant melanoma, i.e. dacarbazine, ipilimumab and dabrafenib, and about the advantages of therapy with the simultaneous use of two inhibitors. Finally, we briefly discuss the role of artificial intelligence in the future of drug design.
Topics: Humans; Vemurafenib; Antineoplastic Agents; Proto-Oncogene Proteins B-raf; Artificial Intelligence; Indoles; Sulfonamides; Melanoma; Skin Neoplasms; Protein Kinase Inhibitors; Mutation; Drug Resistance, Neoplasm; Melanoma, Cutaneous Malignant
PubMed: 38019740
DOI: 10.18388/pb.2021_498 -
Neuro-oncology Nov 2023Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) has been limited by resistance. The level of O-6-methylguanine-DNA methyltransferase (MGMT) and intrinsic DNA...
BACKGROUND
Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) has been limited by resistance. The level of O-6-methylguanine-DNA methyltransferase (MGMT) and intrinsic DNA damage repair factors are important for the TMZ response in patients. Here, we reported a novel compound, called EPIC-0307, that increased TMZ sensitivity by inhibiting specific DNA damage repair proteins and MGMT expression.
METHODS
EPIC-0307 was derived by molecular docking screening. RNA immunoprecipitation (RIP), and chromatin immunoprecipitation by RNA (ChIRP) assays were used to verify the blocking effect. Chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) assays were performed to explore the mechanism of EPIC-0307. A series of in vivo and in vitro experiments were designed to evaluate the efficacy of EPIC-0307 in sensitizing GBM cells to TMZ.
RESULTS
EPIC-0307 selectively disrupted the binding of PRADX to EZH2 and upregulated the expression of P21 and PUMA, leading to cell cycle arrest and apoptosis in GBM cells. EPIC-0307 exhibited a synergistic inhibitory effect on GBM when combined with TMZ by downregulating TMZ-induced DNA damage repair responses and epigenetically silencing MGMT expression through modulating the recruitment of ATF3-pSTAT3-HDAC1 regulatory complex to the MGMT promoter. EPIC-0307 demonstrated significant efficacy in suppressing the tumorigenesis of GBM cells, restoring TMZ sensitivity.
CONCLUSION
This study identified a potential small-molecule inhibitor (SMI) EPIC-0307 that selectively disrupted the PRADX-EZH2 interaction to upregulate expressions of tumor suppressor genes, thereby exerting its antitumor effects on GBM cells. EPIC-0307 treatment also increased the chemotherapeutic efficacy of TMZ by epigenetically downregulating DNA repair-associate genes and MGMT expression in GBM cells.
Topics: Humans; Temozolomide; Glioblastoma; Antineoplastic Agents, Alkylating; Molecular Docking Simulation; DNA Repair; DNA Repair Enzymes; O(6)-Methylguanine-DNA Methyltransferase; DNA Modification Methylases; RNA; Cell Line, Tumor; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Tumor Suppressor Proteins
PubMed: 37279651
DOI: 10.1093/neuonc/noad102 -
Expert Opinion on Investigational Drugs 2023Glioblastoma, isocitrate dehydrogenase wildtype (IDHwt), remains an incurable disease despite considerable research effort. The current standard of care since 2005... (Review)
Review
INTRODUCTION
Glioblastoma, isocitrate dehydrogenase wildtype (IDHwt), remains an incurable disease despite considerable research effort. The current standard of care since 2005 comprises maximal safe resection followed by radiation with concurrent and adjuvant temozolomide; more recently, the addition of tumor treating fields was approved in the newly diagnosed and recurrent disease settings.
AREAS COVERED
Searches of PubMed, Cochrane Library, and ClinicalTrials.gov provided a foundation for this review. We first describe early research including carmustine wafers, brachytherapy, anti-angiogenesis, and immune checkpoint inhibition for glioblastoma. Next, we discuss challenges precluding the translation of preclinical successes. This is followed by a description of promising treatments such as chimeric antigen receptor T-cell therapy as well as the recent qualified successes of cancer vaccinations. Non-immunotherapy trials are also highlighted, and ongoing or pending phase 2 and 3 clinical trials are codified in study tables.
EXPERT OPINION
Unfortunately, hundreds of trials, including of agents effective in systemic malignancy, have not drastically changed management of glioblastoma. This may reflect unique resistance mechanisms and highlights a need for multimodality treatments beyond surgery, radiation, and conventional chemotherapy. Novel techniques, such as those in the emerging field of cancer neuroscience, may help uncover tolerable and effective regimens for this lethal malignancy.
Topics: Humans; Glioblastoma; Brain Neoplasms; Temozolomide; Combined Modality Therapy; Therapies, Investigational
PubMed: 37796104
DOI: 10.1080/13543784.2023.2267982 -
Cells Jul 2023Glioblastoma (GBM) is the most common and aggressive primary brain tumor. GBM contains a small subpopulation of glioma stem cells (GSCs) that are implicated in treatment...
Glioblastoma (GBM) is the most common and aggressive primary brain tumor. GBM contains a small subpopulation of glioma stem cells (GSCs) that are implicated in treatment resistance, tumor infiltration, and recurrence, and are thereby considered important therapeutic targets. Recent clinical studies have suggested that the choice of general anesthetic (GA), particularly propofol, during tumor resection, affects subsequent tumor response to treatments and patient prognosis. In this study, we investigated the molecular mechanisms underlying propofol's anti-tumor effects on GSCs and their interaction with microglia cells. Propofol exerted a dose-dependent inhibitory effect on the self-renewal, expression of mesenchymal markers, and migration of GSCs and sensitized them to both temozolomide (TMZ) and radiation. At higher concentrations, propofol induced a large degree of cell death, as demonstrated using microfluid chip technology. Propofol increased the expression of the lncRNA BDNF-AS, which acts as a tumor suppressor in GBM, and silencing of this lncRNA partially abrogated propofol's effects. Propofol also inhibited the pro-tumorigenic GSC-microglia crosstalk via extracellular vesicles (EVs) and delivery of BDNF-AS. In conclusion, propofol exerted anti-tumor effects on GSCs, sensitized these cells to radiation and TMZ, and inhibited their pro-tumorigenic interactions with microglia via transfer of BDNF-AS by EVs.
Topics: Humans; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Extracellular Vesicles; Glioblastoma; Glioma; Microglia; Neoplastic Stem Cells; Propofol; RNA, Long Noncoding; Temozolomide
PubMed: 37566001
DOI: 10.3390/cells12151921 -
Cell Death & Disease Nov 2023Aggressiveness and drug resistance are major challenges in the clinical treatment of glioblastoma (GBM). Our previously research reported a novel candidate oncogene...
Aggressiveness and drug resistance are major challenges in the clinical treatment of glioblastoma (GBM). Our previously research reported a novel candidate oncogene ribosomal protein L22 like 1 (RPL22L1). The aim of this study was to elucidate the potential role and mechanism of RPL22L1 in progression and temozolomide (TMZ) resistance of GBM. Online database, tissue microarrays and clinical tissue specimens were used to evaluate the expression and clinical implication of RPL22L1 in GBM. We performed cell function assays, orthotopic and subcutaneous xenograft tumor models to evaluate the effects and molecular mechanisms of RPL22L1 on GBM. RPL22L1 expression was significantly upregulated in GBM and associated with poorer prognosis. RPL22L1 overexpression enhanced GBM cell proliferation, migration, invasion, TMZ resistance and tumorigenicity, which could be reduced by RPL22L1 knockdown. Further, we found RPL22L1 promoted mesenchymal phenotype of GBM and the impact of these effects was closely related to EGFR/STAT3 pathway. Importantly, we observed that STAT3 specific inhibitor (Stattic) significantly inhibited the malignant functions of RPL22L1, especially on TMZ resistance. RPL22L1 overexpressed increased combination drug sensitive of Stattic and TMZ both in vitro and in vivo. Moreover, Stattic effectively restored the sensitive of RPL22L1 induced TMZ resistance in vitro and in vivo. Our study identified a novel candidate oncogene RPL22L1 which promoted the GBM malignancy through STAT3 pathway. And we highlighted that Stattic combined with TMZ therapy might be an effective treatment strategy in RPL22L1 high-expressed GBM patients.
Topics: Humans; Temozolomide; Glioblastoma; Cell Line, Tumor; Brain Neoplasms; Oncogenes; Drug Resistance, Neoplasm; Antineoplastic Agents, Alkylating; Xenograft Model Antitumor Assays; STAT3 Transcription Factor; Ribosomal Proteins
PubMed: 37985768
DOI: 10.1038/s41419-023-06156-6