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Akkaladevi, Narahari

Alvarez, Fernando

Cross, Jason

Draetta, Giulio

Geck Do, Mary

Hamilton, Matthew

Jiang, Yongying

Jones, Philip

Leonard, Paul

Mendiola, Andrea

Nair, Vinay

Pham, Nhung

Puca, Francesca

Rodriguez, C

Rogers, Norma

Soth, Mick

Thapar, Roopa

Vaccaro, Scott

Xu, Quanyun

Yu, Fei

English

OpenWorks @ MD Anderson

Nov. 17-18, 2022 1MD Anderson Cancer CenterTargeting Medium-Chain Acyl-CoA Dehydrogenase (MCAD) for Glioblastoma (GBM)MCAD as a key vulnerability unique to GBM identified by an in vivo functional genomic screen GBM is the most common and aggressive primary brain cancer, with about 12,000 new diagnoses each year.Malignant Brain Tumor Statistics, 2021Not much improvement in survival since 1975 for eldersA functional genomic screen of metabolism genes in an in vivomodel using patient-derived GBM cells (GSCs) uncovered importance of enzymes involved in fatty acid oxidation.CA: A Cancer J Clinicians, 71(5): 381-406. DOI: 10.3322/caac.21693.Cancer Discov, 11(11): 2904-2923. DOI: 10.1158/2159-8290.CD-20-1437.Elevated expression of MCAD in patient GBM samples vs. normal brain.ACADM mRNA levels in glioma subtypes vs. normal brain (TCGA data set).Relative Survival (%)Year of diagnosisImmunohistochemistry for MCAD on tissue microarray derived from normal brain and GBM tissueScale bars, 100 μm for ×4 and 25 μm for ×20.Nov. 17-18, 2022 2MD Anderson Cancer CenterTargeting Medium-Chain Acyl-CoA Dehydrogenase (MCAD) for Glioblastoma (GBM)Downregulation of MCAD resulted in severe mitochondrial failure in GBM and longer animal survival  MCAD-knockdown dramatically attenuated tumor growth using GSC8.11 and GSC6.27.GSC 8.11sh-ctrlsh-ACADM1sh-ACADM2GSC 6.274 weeks 12 weeks4 weeks 8 weeksTime (weeks)% Survival4 6 8 10 12 14050100 sh-ctrlsh-ACADM1sh-ACADM2P< 0.0001GSC 8.11MCAD-knockdown significantly extended survival time.Downregulation of MCAD impaired mitochondrial functionsh-ctrl sh-ACADM1 sh-ACADM2 0.00.51.01.5ATPATP levels(relative to ctrl)****oxygen consumption rate significantly decreased in basal respiration and reserve respiratory capacity in ACADM-deleted GSCsdecrease in ATP content in MCAD-depleted GSCsLipid accumulation and reactive oxygen species (ROS)-related damage in MCAD-knockdown GSCs- DOX + DOXish-scrish-ACADMGSC 8.11 xenograft tumor tissues showed lipid accumulation upon ACADM silencingMCAD-knockdown GSC 8.11 partially rescued in fatty acid free medium (left) and by GSH (right)GSC 8.110 2 4 6 7050000100000150000Time (Days)Number of cellssh-ctrlsh-ctrl + GSHsh-ACADM1sh-ACADM1 + GSHP= *0.0321      *0.0164**Nov. 17-18, 2022 3MD Anderson Cancer CenterTargeting Medium-Chain Acyl-CoA Dehydrogenase (MCAD) for Glioblastoma (GBM)Developing potent, selective MCAD inhibitorsOctanoyl-CoA (substrate)Flavin adenine dinucleotide (FAD, cofactor)Hits identified by high-throughput screen of 278k compounds based on RF-MS.0.0001 0.01 1 100050100Conc. (nM)MCAD activity (%)IACS-050595-000-2, IC50 = 1000 nMIACS-075710-000-1, IC50 = 55 nMIACS-135587-000-1, IC50 = 8238 nMMCAD structures with screening hits guides small molecule optimization.Crystal structure of MCAD:Octanoyl-CoACryo-EM structure of MCADRefined map at 3.3 ÅUsing 88k particles Example of a partially optimized screening hit with cellular potency < 1 µM.Properties Cmpd ID: 75915MCAD IC50 (nM) 37SCAD IC50 (nM) >5,600LCAD IC50 (nM) >5,600VLCAD IC50 (nM) >5,600MCAD CETSA IC50 (nM) ~200MCAD OCCT (nM) 540Pampa Pe (x10-6cm/s (% rec)) 11(60%)Plasma St. (m/r/d/h t1/2 min) 330/100/360/99MW/cLogP/TPSA 459/2.28/116MPO/BBB 3.83/3.16F Yu1, P Leonard1, M Hamilton1, F Puca2, N Pham2, N Rogers1, F Alvarez1, C Rodriguez1, V Nair1, N Akkaladevi1, R Thapar1, S Vaccaro1, A Mendiola1, Q Xu1, M Geck Do1, J Cross1, M Soth1, Y Jiang1, G Draetta2, and P Jones11 Institute for Applied Cancer Science2 Department of Genomic Medicine

Targeting Medium-Chain Acyl-CoA Dehydrogenase for Glioblastoma

https://openworks.mdanderson.org/cgi/viewcontent.cgi?article=1041&amp;context=leading-edge

Targeting Medium-Chain Acyl-CoA Dehydrogenase for Glioblastoma

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