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IDH1 and IDH2 mutations as friends and foes in human cancer
Published on May 07, 20181660 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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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
IDH in cellular metabolism02:11
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
IDH1 mutations increase DNA damage levels20:19
IDH1 therapy sensitivity cascade21:18
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
IDH1 therapy sensitivity cascade31:59
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