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Cureus Jul 2021Glioblastoma multiforme (GBM) is an aggressive neoplasm of the brain that has commonly led to disappointing patient outcomes. Despite medical advancements and increasing... (Review)
Review
Glioblastoma multiforme (GBM) is an aggressive neoplasm of the brain that has commonly led to disappointing patient outcomes. Despite medical advancements and increasing research efforts, GBM studies reveal a stagnant survival rate at the global level with only sluggish improvement over time. Modern neuro-oncology research places a heavy emphasis on pharmacological therapies. Through a broad database search, we accumulated and synthesized the GBM-related neuroimmunocytological literature to create a comprehensive and contemporary review. Based on our findings, we discuss the recent neurocytological treatment strategies for GMB and the results of the studies. Regorafenib, paxalisib, and dianhydrogalactitol (VAL-083) are showing initial promise to decrease disease progression. VAL-083 is an alkylating agent that creates N7 methylation on DNA and has the ability to cross the blood-brain barrier (BBB). Selinexor, recombinant nonpathogenic polio-rhinovirus, and GBM-vaccine of autologous fibroblasts retrovirally transfected with TFG-IL4-Neo-TK vector have all also shown initial clinical benefit in terms of prolonging survival. Most trials observe modest improvement in outcomes with a positive safety profile. Nevertheless, the need for further studies is warranted, along with the trending of post-therapeutic biomarkers in order to better access future patient outcomes.
PubMed: 34405064
DOI: 10.7759/cureus.16301 -
Molecular Cancer Therapeutics Jun 2021Glioblastoma (GBM) is the most frequent and aggressive primary tumor type in the central nervous system in adults. Resistance to chemotherapy remains one of the major...
Glioblastoma (GBM) is the most frequent and aggressive primary tumor type in the central nervous system in adults. Resistance to chemotherapy remains one of the major obstacles in GBM treatment. Identifying and overcoming the mechanisms of therapy resistance is instrumental to develop novel therapeutic approaches for patients with GBM. To determine the major drivers of temozolomide (TMZ) sensitivity, we performed shRNA screenings in GBM lines with different O6-methylguanine-DNA methyl-transferase (MGMT) status. We then evaluated dianhydrogalactitol (Val-083), a small alkylating molecule that induces interstrand DNA crosslinking, as a potential treatment to bypass TMZ-resistance mechanisms. We found that loss of mismatch repair (MMR) components and MGMT expression are mutually exclusive mechanisms driving TMZ resistance Treatment of established GBM cells and tumorsphere lines with Val-083 induces DNA damage and cell-cycle arrest in G-M phase, independently of MGMT or MMR status, thus circumventing conventional resistance mechanisms to TMZ. Combination of TMZ and Val-083 shows a synergic cytotoxic effect in tumor cells , and We propose this combinatorial treatment as a potential approach for patients with GBM.
Topics: Animals; Cell Line, Tumor; Dianhydrogalactitol; Drug Resistance, Neoplasm; Glioblastoma; Humans; Mice; Temozolomide; Transfection; Xenograft Model Antitumor Assays
PubMed: 33846235
DOI: 10.1158/1535-7163.MCT-20-0319 -
Acta Neuropathologica Dec 2020Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the...
Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.
Topics: Animals; Brain Neoplasms; Glioblastoma; Glioma; Heterografts; Humans; Mice; Neoplasm Recurrence, Local; Organoids; Precision Medicine; Rats; Temozolomide
PubMed: 33009951
DOI: 10.1007/s00401-020-02226-7 -
Cell Death & Disease Jul 20201,2:5,6-Dianhydrogalactitol (DAG) is a bi-functional DNA-targeting agent currently in phase II clinical trial for treatment of temozolomide-resistant glioblastoma (GBM)....
1,2:5,6-Dianhydrogalactitol (DAG) is a bi-functional DNA-targeting agent currently in phase II clinical trial for treatment of temozolomide-resistant glioblastoma (GBM). In the present study, we investigated the cytotoxic activity of DAG alone or in combination with common chemotherapy agents in GBM and prostate cancer (PCa) cells, and determined the impact of DNA repair pathways on DAG-induced cytotoxicity. We found that DAG produced replication-dependent DNA lesions decorated with RPA32, RAD51, and γH2AX foci. DAG-induced cytotoxicity was unaffected by MLH1, MSH2, and DNA-PK expression, but was enhanced by knockdown of BRCA1. Acting in S phase, DAG displayed selective synergy with topoisomerase I (camptothecin and irinotecan) and topoisomerase II (etoposide) poisons in GBM, PCa, and lung cancer cells with no synergy observed for docetaxel. Importantly, DAG combined with irinotecan treatment enhanced tumor responses and prolonged survival of tumor-bearing mice. This work provides mechanistic insight into DAG cytotoxicity in GBM and PCa cells and offers a rational for exploring combination regimens with topoisomerase I/II poisons in future clinical trials.
Topics: Animals; Cell Cycle Checkpoints; Cell Death; Cell Line, Tumor; DNA Damage; DNA Repair; DNA Replication; Dianhydrogalactitol; Drug Synergism; G2 Phase; HEK293 Cells; Humans; Irinotecan; Male; Mice, Nude; Recombinational DNA Repair; S Phase; Topoisomerase Inhibitors; Xenograft Model Antitumor Assays
PubMed: 32709853
DOI: 10.1038/s41419-020-02780-8