High-throughput drug screening seeks treatment for diffuse midline glioma

Diffuse midline glioma (diffuse midline gliomas, DMG) is a type of malignant tumor that occurs in children and the central nervous system, including the thalamus, bridge brain, and spinal cordThe significant molecular characteristic of DMG is the histone H3K27M mutationPrevious studies have found that histone deacetyacese (histone deacetylase, HDAC) inhibitors panobinostat and proteaas (proteasome) inhibitors marizomib can restore H3K27 methylation levels and reduce the expression of cancer genesGrant LLin of the Department of Neurology at Stanford University School of Medicine in the United States and others used high-throughput drug screening (HTS) to obtain data on single-dose reactions of 1996 drugs in diffuse endogenous bridge glioma (DIPG) cell culturesOn this basis, after several combination screening, it was found that of the 9195 different combinations of drugs, panobinostat and marizomib are the best combination of drugs to treat DMGThe results were published in the November 2019 issue of Science Translational Medicinethe studythe study was first treated with six DIPG cell lines and found a single dose of reaction markers for 19936 drugs; These drugs target a variety of tumor-causing signaling pathways or genes, such as PI3KUsing Z-converted subcurvedin (Z-AUC) to identify the therapeutic activity of the drug, the researchers found that 371 Z-AUC drugs, named effective "hit" drugs, were identified in at least 3 DIPG cell linesAt the same time, whether the drug can penetrate the blood-brain barrier as a screening indicatorThe authors used the Central Nervous System (CNS) Multiparameter Optimization Expectation (MPO) scoring system to evaluate the drug, and found that 22 drugs had strong activity, with an average Z-AUC-2.0, and were able to enter CNS, with an MPO score of 4.4the authors then combined a single drug of interestPanobinostat has a wide range of synergies with a wide range of drugs, including protease inhibitors and signal regulators, PI3K, insulin-like growth factor receptors (IGFR), and fission-activated protein kinase (MEK) inhibitorsThe combined effect of protease inhibitor marizomib is limited and has only synergetic cytotoxicity when combined with HDAC inhibitorsThe combination of each drug and marizomib showed that pan-HDAC inhibitors such as panobinostat and romidepsin for Class I HDAC (HDAC1, HDAC2 and HDAC3) and Class II HDAC, such as panobinostat and romidepsin, produced the greatest synergyIn examining the results of single-dose screening, the authors determined that synergies could be established by one-to-many combination screening, including synergies of 45 drugs, including panobinostat and marizomib Not only confirmed the synergy between panobinostat and marizomib, but also identified synergies between the contained protease inhibitors (marizomib, carfilzomib and ixazomib) and the contained Class I HDAC inhibitors (panobinostat and vorinostat) the authors studied drug interactions with a drug dose response curve that used only 25nM of panobinostat for the candidate drug The authors measured the activity of DIPG cells in different drug doses or combinations in each culture, and the results showed that panobinostat and marizomib, panobinostat and BMS-754807, as well as panobinostat and buparlisib, had the same synergy, combined index (CI)1 To assess the proliferation and cell death of drug treatment, the authors performed flow cell analysis of EdU, Annexin V staining, and DAPI, and Panobinostat and marizomib worked together to reduce cell proliferation and increase cell death compared to any single drug application finally, the authors will screen out the drugs for inviva Panobinostat and marizomib are effective combination therapies for DMG RNA sequencing of DIPG cells after combination therapy showed that the gene expression of tumor cells in oxidation phosphorylation and cell cycles decreased significantly, while the genes of apoptosis were significantly increased The use of mass spectrometry to detect the metabolic group found that both H3K27M and H3 wild DMG cells were highly sensitive to metabolic disorders, while metabolic dysfunction of tumor cells was the main cause of cytotoxic effects in the combination of panobinostat and marizomib conclusions the authors performed continuous quantitative screening of high-throughput drugs in 2,706 FDA-approved drugs The combination of HDAC inhibitor panobinostat and protease inhibitor marizomib was the best drug treatment method, as confirmed by invival tests derived from the patient's xenotumor transplant model Transcription and myomics studies showed significant changes in oxidation phosphorylation and metabolic groups after treatment with panobinostat and marizomib, demonstrating the unstable properties of the DMG metabolic group.