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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 -
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 -
Biomedicine & Pharmacotherapy =... Jul 2017The complexity of cancer has led to single-target agents exhibiting lower-than-desired clinical efficacy. Drugs with multiple targets provide a feasible option for the...
The complexity of cancer has led to single-target agents exhibiting lower-than-desired clinical efficacy. Drugs with multiple targets provide a feasible option for the treatment of complex tumors. Multitarget anti-angiogenesis agents are among the new generation of anticancer drugs and have shown favorable clinical efficacy. Dianhydrogalactitol (DAG) is a chemotherapeutic agent for chronic myeloid leukemia and lung cancer. Recently, it has been tested in phase II trials of glioblastoma treatment; however, mechanisms of DAG in glioblastoma have not been elucidated. Here we show that DAG could inhibit the migration and invasion of U251 cell line by inhibiting matrix metalloproteinase-2 (MMP2) expression. Furthermore, DAG could also inhibit tumor angiogenesis in vitro as well as in the zebrafish model. Mechanistic studies reveal that DAG inhibited both VEGFR2 and FGFR1 pathways. Our results suggest that DAG may be a potential multitarget agent that can inhibit tumor migration, invasion, and angiogenesis, and the anti-angiogenic effects may be involved in dual-suppression VEGF/VEGFR2 and FGF2/FGFR1 signal pathways.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dianhydrogalactitol; Glioblastoma; Human Umbilical Vein Endothelial Cells; Humans; Matrix Metalloproteinase 2; Neoplasm Invasiveness; Neovascularization, Pathologic; Proto-Oncogene Proteins; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Zebrafish
PubMed: 28525947
DOI: 10.1016/j.biopha.2017.05.025 -
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 -
Cell Death & Disease Oct 20181,2:5,6-Dianhydrogalactitol (DAG) is a bifunctional DNA-targeting agent causing N-guanine alkylation and inter-strand DNA crosslinks currently in clinical trial for...
1,2:5,6-Dianhydrogalactitol (DAG) is a bifunctional DNA-targeting agent causing N-guanine alkylation and inter-strand DNA crosslinks currently in clinical trial for treatment of glioblastoma. While preclinical studies and clinical trials have demonstrated antitumor activity of DAG in a variety of malignancies, understanding the molecular mechanisms underlying DAG-induced cytotoxicity is essential for proper clinical qualification. Using non-small cell lung cancer (NSCLC) as a model system, we show that DAG-induced cytotoxicity materializes when cells enter S phase with unrepaired N-guanine DNA crosslinks. In S phase, DAG-mediated DNA crosslink lesions translated into replication-dependent DNA double-strand breaks (DSBs) that subsequently triggered irreversible cell cycle arrest and loss of viability. DAG-treated NSCLC cells attempt to repair the DSBs by homologous recombination (HR) and inhibition of the HR repair pathway sensitized NSCLC cells to DAG-induced DNA damage. Accordingly, our work describes a molecular mechanism behind N-guanine crosslink-induced cytotoxicity in cancer cells and provides a rationale for using DAG analogs to treat HR-deficient tumors.
Topics: A549 Cells; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; DNA Replication; Dianhydrogalactitol; Guanine; Homologous Recombination; Humans; Lung Neoplasms; S Phase
PubMed: 30283085
DOI: 10.1038/s41419-018-1069-9 -
The Biochemical Journal Mar 1980DNA was alkylated in neutral solution at 37 degrees C with 1,2:5,6-dianhydrogalactitol and hydrolysed to yield two principal products, identified as 7-galactitylguanine...
DNA was alkylated in neutral solution at 37 degrees C with 1,2:5,6-dianhydrogalactitol and hydrolysed to yield two principal products, identified as 7-galactitylguanine and 1,6-dideoxy-1,6-di(guanin-7-yl)galactitol. The reaction products were separated by chromatography on Sephadex G-10 and Dowex 50 (H+ form). The two compounds were also obtained by reaction between dianhydrogalactitol and guanosine in acetic acid. The products were characterized from their u.v.-spectral data by comparison with those of the 7-alkylguanines and were also identified by mass spectrometry.
Topics: Alkylation; DNA; Dianhydrogalactitol; Guanosine; Mass Spectrometry; Spectrophotometry, Ultraviolet; Sugar Alcohols
PubMed: 7387628
DOI: 10.1042/bj1850659 -
Acta Pharmacologica Sinica Apr 20171,2:5,6-dianhydrogalactitol (DAG) is a hexitol epoxide with marked antitumor activity against multiple types of cancer cells, but the molecular mechanisms by which DAG...
1,2:5,6-dianhydrogalactitol (DAG) is a hexitol epoxide with marked antitumor activity against multiple types of cancer cells, but the molecular mechanisms by which DAG functions as an antitumor agent is largely unknown. In this study, we investigated the inhibitory effects of DAG on human glioma cell growth in vitro and in vivo and uncovered the underlying molecular mechanisms. Treatment with DAG (120 μmol/L) dose-dependently inhibited the proliferation and colony formation in human glioma cell lines LN229, U251, and U87MG in vitro. DAG (1, 2, 5 μmol/L) induced cell cycle arrest at G/M phase in the 3 glioma cell lines in a dose-dependent manner. The signaling pathways involved in DAG-caused cell cycle arrest was further analyzed in LN229 cells, which revealed that DAG dose-dependently activated two parallel signaling cascades, ie, the p53-p21 cascade and the CDC25C-CDK1 cascade. DAG also significantly enhanced the radiosensitivity of LN229 cells as shown in the clonogenic assay. In nude mice bearing subcutaneously xenografted LN229 glioma, administration of DAG (5 mg/kg, iv, twice per week for 6 weeks) effectively suppressed the growth of xenografted tumors: the relative tumor growth rate (T/C) was reduced to 22.38%, and the tumor growth inhibitory rate (TGI) was 83.58% (P<0.01). In addition, DAG administration significantly activated the CDC25C-CDK1 cascade in the xenografted tumors. In conclusion, DAG inhibited human glioma cell growth in vitro and in vivo by inducing cell cycle arrest at G/M phase. Two parallel cascades are activated and involved in the cell cycle arrest.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; CDC2 Protein Kinase; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; G2 Phase Cell Cycle Checkpoints; Glioma; Heterografts; Humans; Mice, Nude; Neoplasm Transplantation; Signal Transduction; Tumor Suppressor Protein p53; cdc25 Phosphatases
PubMed: 28216618
DOI: 10.1038/aps.2016.154 -
Zhongguo Yao Li Xue Bao = Acta... Dec 1980
Topics: Animals; Bone Marrow; Dianhydrogalactitol; Dose-Response Relationship, Drug; Hematopoietic Stem Cells; Melanoma; Mice; Sugar Alcohols
PubMed: 6461181
DOI: No ID Found -
Acta Pharmacologica Sinica May 2002To investigate the roles of caspases in diacetyldianhydrogalactitol (DADAG)-induced apoptosis in human leukemia HL-60 cells.
AIM
To investigate the roles of caspases in diacetyldianhydrogalactitol (DADAG)-induced apoptosis in human leukemia HL-60 cells.
METHODS
Inhibition of proliferation was measured by MTT assay. DADAG-induced apoptosis in HL-60 cells was observed by electron microscopy, flow cytometry, and DNA fragmentation assay. Caspase-3 activity was determined by ApoAlert CPP32 colorimetric assay kit. The cleavage of substrates of caspases was detected by Western blot.
RESULTS
DADAG exhibited potent antiproliferative activity and induced apoptosis in HL-60 cells. After treatment with DADAG 8 mg/L for 24 h, caspase-3 activity increased markedly and the cleavage of poly-(ADP-ribose) polymerase (PARP), lamin B, and DFF45 appeared. All of the apoptotic signals were suppressed by z-VAD fmk (a general inhibitor of caspase activities), whereas z-DEVD fmk, a selective inhibitor of caspase-3 activity, only induced partial reversion of the apoptotic effects.
CONCLUSION
DADAG induced apoptosis in HL-60 cells by activating caspases. Caspases promoted apoptosis through the cleavage of substrates of PARP, lamin B, and DFF45.
Topics: Apoptosis; Caspase 3; Caspases; Cell Division; Dianhydrogalactitol; HL-60 Cells; Humans; Leukemia
PubMed: 11978198
DOI: No ID Found