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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 -
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 -
JAMA May 1979Dianhydrogalactitol was the most active of 177 agents tested against a mouse ependymoblastoma tumor. We conducted a prospectively randomized trial comparing whole-brain... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Dianhydrogalactitol was the most active of 177 agents tested against a mouse ependymoblastoma tumor. We conducted a prospectively randomized trial comparing whole-brain irradiation alone vs identical irradiation plus dianhydrogalactitol in 42 patients with grade 3 and 4 supratentorial astrocytomas. Patients receiving dianhydrogalactitol in addition to irradiation had a significantly longer median survival time (67 vs 35 weeks) than did patients receiving only irradiation. The major toxic effect of dianhydrogalactitol is hematologic suppression of a cumulative nature. Dianhydrogalactitol may play an important role (in conjunction with radiation therapy) in the initial treatment of patients with supratentorial glioma. Our data may indicate that the mouse ependymoblastoma system is a useful screen for agents to be used in the treatment of human glioma.
Topics: Adult; Aged; Brain Neoplasms; Dianhydrogalactitol; Female; Glioblastoma; Humans; Leukopenia; Male; Middle Aged; Sugar Alcohols
PubMed: 219269
DOI: No ID Found -
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 -
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 -
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 -
Pediatric Hematology and Oncology 1986The incidence of hyponatremia in 34 patients following administration of high-dose L-phenylalanine mustard (L-PAM) and dianhydrogalactitol (DAG) was determined. Two...
The incidence of hyponatremia in 34 patients following administration of high-dose L-phenylalanine mustard (L-PAM) and dianhydrogalactitol (DAG) was determined. Two consecutive daily levels of 133 mEq/l or less were observed in 12 patients. These episodes coincided with the advent of diarrhea about 10-12 days after drug administration. The hyponatremia was not due to the syndrome of inappropriate antidiuretic hormone secretion.
Topics: Diagnosis, Differential; Dianhydrogalactitol; Diarrhea; Humans; Hyponatremia; Inappropriate ADH Syndrome; Melphalan; Nervous System Neoplasms; Neuroblastoma; Prospective Studies
PubMed: 3153241
DOI: 10.3109/08880018609031229 -
Journal of the National Cancer Institute Mar 1976Dianhydrogalactitol (DAG; NSC-132313), a hexitol epoxide, was used to treat intracerebral rodent tumors. DAG was most active against the murine ependymoblastoma...
Dianhydrogalactitol (DAG; NSC-132313), a hexitol epoxide, was used to treat intracerebral rodent tumors. DAG was most active against the murine ependymoblastoma [treated/controls (T/C)greater than 440%], less active against murine glioma 26 (T/C approximately 112-150%), and least active against rat 9L gliosarcoma (T/C approximately 100%). Application of a two-compartment open model for plasma disappearance of 14C-DAG in rats gave a volume of distribution at steady state of approximately 872 ml, a clearance of approximately 9.4 ml/minute, and an elimination constant of 0.025/minute. Entry of 14C-DAG was more rapid into the 9L tumor than into the normal brain. When a two-compartment series model for brain and tumor entry was applied, the t1/2 (half-time) for compartmental equilibrium was approximately 22 and 105 minutes in the brain, and 4 and 56 minutes in the 9L tumor. The drug rapidly entered the brain and tumor intracellular compartments. Binding to RNA was linear with time, and the absolute amount of binding was approximately six times greater for RNA than for DNA.
Topics: Animals; Antineoplastic Agents; Brain; Brain Neoplasms; DNA, Neoplasm; Ependymoma; Epoxy Compounds; Glioma; Half-Life; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; RNA, Neoplasm; Rats; Rats, Inbred F344; Sugar Alcohols
PubMed: 1255783
DOI: 10.1093/jnci/56.3.535 -
Oncology 1981The drug combinations of dianhydrogalactitol and VP-16 and dianhydrogalactitol, VP-16, and triazinate were used in patients with primary brain tumors, principally...
The drug combinations of dianhydrogalactitol and VP-16 and dianhydrogalactitol, VP-16, and triazinate were used in patients with primary brain tumors, principally astrocytoma, recurrent following cranial irradiation. Tumor regressions were noted in 40% of patients treated with the 2-drug regimen and in 33% of patients treated with the 3-drug regimens. Regression were noted in all grades of tumor. Poor performance score on the patients' part did not seem to effect regression rates. Myelosuppression was the principal toxicity encountered. Dianhydrogalactitol-based combination chemotherapy seems as active as nitrosourea therapy and presents an alternative to nitrosourea therapy.
Topics: Adolescent; Adult; Astrocytoma; Brain Neoplasms; Child; Child, Preschool; Dianhydrogalactitol; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Podophyllotoxin; Sugar Alcohols; Tomography, X-Ray Computed; Triazines
PubMed: 7443176
DOI: 10.1159/000225511 -
European Journal of Cancer Jul 1979
Clinical Trial
Topics: Administration, Oral; Adult; Clinical Trials as Topic; Dianhydrogalactitol; Drug Evaluation; Gastrointestinal Neoplasms; Hematopoiesis; Humans; Lung Neoplasms; Neoplasms; Sugar Alcohols
PubMed: 385328
DOI: 10.1016/0014-2964(79)90280-9