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IDH1 and IDH2 mutations as friends and foes in human cancer
Published on 2018-05-071669 Views
The enzyme isocytrate dehydrogenase IDH is very important in carbohydrate metabolism, and when mutated in cancer cells, the metabolic pathway is drastically altered. Somatic mutations in IDH1/2 occur
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Presentation
IDH1 and IDH2 mutations as friends and foes in human cancer00:00
Isocitrate dehydrogenase (IDH) mutations in cancer00:35
110,000 cnacer cases01:10
5,000 IDH-mutated cancers01:18
IDH mutations associate with longer overall survival - 101:35
Wild-type IDH05:58
Mutated IDH06:11
IDH1/2 mutations are early genetic events in glio(blasto)ma06:43
IDH mutations associate with longer overall survival - 208:28
Increased DNA damage - 110:13
Increased DNA damage - 210:38
Increased DNA damage - 310:47
Increased DNA damage - 410:58
HCT116 IDH1R132H knock-in as a mechanistic model11:03
IDH1R132H radiosensitizes HCT116 cells12:32
D-2HG radiosentisizes HCT116 cells13:14
Measuring enzyme kinetics in situ14:03
IDH1R132H decreases NADPH production capacity15:22
D-2HG decreases NADPH production capacity - 116:03
D-2HG decreases NADPH production capacity - 216:57
IDH1 mutations increase ROS17:35
N-acetyl cysteine equalizes radiosensitivity of HCT116 cells18:51
Pharma’s incentive…22:05
IDH-mutant inhibitors - 123:41
IDH-mutant inhibitors - 224:05
An IDH1-mutant inhibitor restores NADPH production - 124:35
An IDH1-mutant inhibitor restores NADPH production - 225:33
IDH1 mutant inhibitors decrease ROS25:44
IDH-mutant inhibitors - 326:29
IDH mutations and survival - 126:33
Increased DNA damage26:47
IDH mutations and survival - 226:56
IDH-mutated cells, radiation and an IDH-mutant inhibitor27:13
No effect in IDH wild-type28:41
IDH1 therapy sensitivity cascade28:58
An IDH1-mutant inhibitor cannot protect in the presence of D-2HG29:28
IDH1 mutations increase DNA damage levels31:34
Conclusions - 132:02
The association between our research and Agios stock prices - 133:00
The association between our research and Agios stock prices - 233:33
An IDH1-mutant inhibitor protects against daunorubicin35:28
An IDH2-mutant inhibitor protects against daunorubicin35:38
An IDH1/2-mutant inhibitor protects against daunorubicin35:48
IDH1/2 therapy sensitivity cascade - 136:05
NADPH production is reduced in IDH1/2-mutated AML36:18
IDH1/2-mutant inhibitors restore NADPH production37:43
Redox states are unchanged in IDH1/2-mutated AML37:56
IDH1/2 therapy sensitivity cascade - 238:37
IDH1/2 mutations reduce ATM expression39:07
IDH1/2 mutations increase DNA damage in AML39:45
ATM is responsible for the sensitization to daunorubicin - 141:16
IDH1/2 mutations sensitize AML cells to daunorubicin43:19
ATM is responsible for the sensitization to daunorubicin - 243:52
ATM is responsible for the sensitization to daunorubicin - 344:16
IDH1/2 therapy sensitivity cascade - 345:17
Conclusions - 245:51
IDH1/2 mutations sensitize AML cells to PARP inhibition46:15
IDH1/2-mutant inhibitors protect against PARP inhibition - 147:20
IDH1/2-mutant inhibitors protect against PARP inhibition - 247:36
IDH1/2-mutant inhibitors protect against PARP inhibition - 347:45
IDH1/2-mutant inhibitors protect against PARP inhibition - 447:56
Conclusions - 349:21
IDH in cellular metabolism49:42
Metformin and chloroquine for IDH1/2-mutated tumors - 151:20
Metformin and chloroquine for IDH1/2-mutated tumors - 252:26
Conclusions - 453:20
Collaborators54:49
Thank you!54:55