TY - JOUR
T1 - A Potential New Treatment for High-Grade Glioma
T2 - A Study Assessing Repurposed Drug Combinations against Patient-Derived High-Grade Glioma Cells
AU - Lastakchi, Sarah
AU - Olaloko, Mary Kanyinsola
AU - McConville, Christopher
PY - 2022/5/25
Y1 - 2022/5/25
N2 - Repurposed drugs have demonstrated in vitro success against high-grade gliomas; however, their clinical success has been limited due to the in vitro model not truly representing the clinical scenario. In this study, we used two distinct patient-derived tumour fragments (tumour core (TC) and tumour margin (TM)) to generate a heterogeneous, clinically relevant in vitro model to assess if a combination of repurposed drugs (irinotecan, pitavastatin, disulfiram, copper gluconate, captopril, celecoxib, itraconazole and ticlopidine), each targeting a different growth promoting pathway, could successfully treat high-grade gliomas. To ensure the clinical relevance of our data, TC and TM samples from 11 different patients were utilized. Our data demonstrate that, at a concentration of 100µm or lower, all drug combinations achieved lower LogIC50 values than temozolomide, with one of the combinations almost eradicating the cancer by achieving cell viabilities below 4% in five of the TM samples 6 days after treatment. Temozolomide was unable to stop tumour growth over the 14-day assay, while combination 1 stopped tumour growth, with combinations 2, 3 and 4 slowing down tumour growth at higher doses. To validate the cytotoxicity data, we used two distinct assays, end point MTT and real-time IncuCyte life analysis, to evaluate the cytotoxicity of the combinations on the TC fragment from patient 3, with the cell viabilities comparable across both assays. The local administration of combinations of repurposed drugs that target different growth promoting pathways of high-grade gliomas have the potential to be translated into the clinic as a novel treatment strategy for high-grade gliomas.
AB - Repurposed drugs have demonstrated in vitro success against high-grade gliomas; however, their clinical success has been limited due to the in vitro model not truly representing the clinical scenario. In this study, we used two distinct patient-derived tumour fragments (tumour core (TC) and tumour margin (TM)) to generate a heterogeneous, clinically relevant in vitro model to assess if a combination of repurposed drugs (irinotecan, pitavastatin, disulfiram, copper gluconate, captopril, celecoxib, itraconazole and ticlopidine), each targeting a different growth promoting pathway, could successfully treat high-grade gliomas. To ensure the clinical relevance of our data, TC and TM samples from 11 different patients were utilized. Our data demonstrate that, at a concentration of 100µm or lower, all drug combinations achieved lower LogIC50 values than temozolomide, with one of the combinations almost eradicating the cancer by achieving cell viabilities below 4% in five of the TM samples 6 days after treatment. Temozolomide was unable to stop tumour growth over the 14-day assay, while combination 1 stopped tumour growth, with combinations 2, 3 and 4 slowing down tumour growth at higher doses. To validate the cytotoxicity data, we used two distinct assays, end point MTT and real-time IncuCyte life analysis, to evaluate the cytotoxicity of the combinations on the TC fragment from patient 3, with the cell viabilities comparable across both assays. The local administration of combinations of repurposed drugs that target different growth promoting pathways of high-grade gliomas have the potential to be translated into the clinic as a novel treatment strategy for high-grade gliomas.
KW - combination treatment
KW - drug repurposing
KW - primary tissue
KW - tumour core
KW - tumour margin
UR - http://www.scopus.com/inward/record.url?scp=85130995962&partnerID=8YFLogxK
U2 - 10.3390/cancers14112602
DO - 10.3390/cancers14112602
M3 - Article
C2 - 35681582
SN - 2072-6694
VL - 14
JO - Cancers
JF - Cancers
IS - 11
M1 - 2602
ER -