Targeting 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.
A functional genomic screen of metabolism genes in an in vivo model using patient-derived GBM cells (GSCs) uncovered importance of enzymes involved in fatty acid oxidation.
Elevated expression of MCAD in patient GBM samples vs. normal brain.
Malignant Brain Tumor Statistics, 2021
ACADM mRNA levels in glioma subtypes vs. normal brain (TCGA data set).
Immunohistochemistry for MCAD on tissue microarray derived from normal brain and GBM tissue
Not much improvement in survival since 1975 for elders
Scale bars, 100 μm for × 4 and 25 μm for × 20.
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.
Year of diagnosis
Nov. 17-18, 2022
1
MD Anderson Cancer Center
Targeting 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.
Downregulation of MCAD impaired mitochondrial function
Lipid accumulation and reactive oxygen species (ROS)-related damage in MCAD-knockdown GSCs
GSC 6.27
GSC 8.11
oxygen consumption rate significantly decreased in basal respiration and reserve respiratory capacity in ACADM -deleted GSCs
GSC 8.11 xenograft tumor tissues showed lipid accumulation upon ACADM silencing
12 weeks
4 weeks
4 weeks
8 weeks
- DOX
+ DOX
MCAD-knockdown significantly extended survival time.
MCAD-knockdown GSC 8.11 partially rescued in fatty acid free medium (left) and by GSH (right)
decrease in ATP content in MCAD-depleted GSCs
GSC 8.11
P= *0.0321 *0.0164
sh-ctrl
ATP
100
1.5
GSC 8.11
sh-ACADM1
sh-ctrl sh-ctrl + GSH sh-ACADM1 sh-ACADM1 + GSH
150000
**
**
sh-ACADM2
100000
1.0
50
50000
0.5
*
*
P< 0.0001
0
0
2
4
6
7
0
Time (Days)
0.0
Time (weeks) 4 6 8 10 12 14
sh-ctrl
sh-ACADM1 sh-ACADM2
Nov. 17-18, 2022
2
MD Anderson Cancer Center
Targeting Medium-Chain Acyl-CoA Dehydrogenase (MCAD) for Glioblastoma (GBM)
Developing potent, selective MCAD inhibitors
Hits identified by high-throughput screen of 278k compounds based on RF-MS.
MCAD structures with screening hits guides small molecule optimization.
Example of a partially optimized screening hit with cellular potency < 1 µM.
Crystal structure of MCAD:Octanoyl-CoA
Properties
CmpdID: 75915
MCAD IC 50 (nM)
37
Octanoyl-CoA (substrate)
SCAD IC 50 (nM)
>5,600
LCAD IC 50 (nM)
>5,600
VLCAD IC 50 (nM)
>5,600
Flavin adenine dinucleotide (FAD, cofactor)
MCAD CETSA IC 50 (nM)
~200
MCAD OCCT (nM)
540
Pampa Pe (x10 -6 cm/s (% rec))
11(60%)
100
Plasma St. (m/r/d/h t 1/2 min)
330/100/360/99
Cryo-EM structure of MCAD
MW/cLogP/TPSA
459/2.28/116
50
MPO/BBB
3.83/3.16
0
Refined map at 3.3 Å Using 88k particles
F Yu 1 , P Leonard 1 , M Hamilton 1 , F Puca 2 , N Pham 2 , N Rogers 1 , F Alvarez 1 , C Rodriguez 1 , V Nair 1 , N Akkaladevi 1 , R Thapar 1 , S Vaccaro 1 , A Mendiola 1 , Q Xu 1 , M Geck Do 1 , J Cross 1 , M Soth 1 , Y Jiang 1 , G Draetta 2 , and P Jones 1
0.0001
0.01
1
100
Conc. (nM)
IACS-050595-000-2, IC50 = 1000 nM IACS-075710-000-1, IC50 = 55 nM IACS-135587-000-1, IC50 = 8238 nM
1 Institute for Applied Cancer Science 2 Department of Genomic Medicine
Nov. 17-18, 2022
3
MD Anderson Cancer Center
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