Abstract
Despite the use of multimodal treatment combinations, the prognosis of glioblastoma (GB) is still poor. To prevent rapid tumor recurrence, targeted strategies for the treatment of GB are widely sought. Here, we compared the efficacy of focused modulation of a set of signaling pathways in two GB cell lines, U-251 MG and T98-G, using a panel of thirteen compounds targeting cell cycle progression, proliferation, epigenetic modifications, and DNA repair mechanism. In parallel, we tested combinations of these compounds with temozolomide and lomustine, the standard chemotherapy agents used in GB treatment. Two major trends were found: within individual compounds, the lowest IC50 values were exhibited by the Aurora kinase inhibitors, whereas in the case of mixtures, the addition of DNA methyltransferase 1 inhibitor azacytidine to lomustine proved the most beneficial. The efficacy of cell cycle-targeting compounds was further augmented by combination with radiation therapy using two different treatment regimes. The potency of azacytidine and lomustine mixtures was validated using a unique assay pipeline that utilizes automated imaging and machine learning-based data analysis algorithm for assessment of cell number and DNA damage extent. Based on our results, the combination of azacytidine and lomustine should be tested in GB clinical trials.
Highlights
Despite the use of multimodal treatment combinations, the prognosis of glioblastoma (GB) is still poor
Since 1978, postoperative radiotherapy has been the mainstay of standard adjuvant treatment in G B2, which results in median overall survival of 12.1 months that can be extended to 14.6 months by administering temozolomide during and after r adiotherapy[3]
The candidates were chosen based on the available data regarding their potency, selectivity, and blood–brain barrier permeability; whenever possible, drugs that are currently used in clinics, and drug candidates that have advanced to the later stages of clinical trials were preferred[16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]
Summary
Despite the use of multimodal treatment combinations, the prognosis of glioblastoma (GB) is still poor. In patients 70 years of age or younger, additional alternating electric field therapy can be utilized in combination with radiotherapy and temozolomide that prolongs median overall survival up to 20.9 months[4]. Out of possible treatment options that include repeat surgery and chemotherapy, a nitrosourea compound lomustine is most commonly used at disease recurrence. This approach is based on several phase II and III studies that have reported median overall survival times ranging from 5.6 to 9.8 months[5,6,7,8,9]. Since chemotherapy and radiotherapy result only in temporary disease stabilization in GB patients, additional, targeted strategies for the treatment of GB are widely sought. Compound Temozolomide Lomustine Pasireotide CYN 154,806 MK-2206 ARQ 092 ARC-775 CX-4945 SAHA Azacytidine MK-1775 CC-115 MLN8237 VX 689 AZD1152-HQPA
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
