cell-based screens of drug combinations at nci - holbeck.pdf · cell-based screens of drug...
TRANSCRIPT
![Page 1: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/1.jpg)
CELL-BASED SCREENS OF DRUG COMBINATIONS AT NCI SUSAN HOLBECK DEVELOPMENTAL THERAPEUTICS PROGRAM DIVISION OF CANCER TREATMENT AND DIAGNOSIS NATIONAL CANCER INSTITUTE
![Page 2: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/2.jpg)
NEED FOR DRUG COMBINATIONS Single agents are rarely curative Even responding patients will relapse
Strategies "Rational" combinations hit multiple nodes in a pathway, or hit parallel pathways Comprehensive approaches to combination discovery
• siRNA • empiric screens
![Page 3: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/3.jpg)
TWO PARALLEL COMBINATION DRUG SCREENS AT NCI • Comprehensive screen of approved cancer drugs • Combination screening of investigational agents
![Page 4: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/4.jpg)
THE NCI ALMANAC TESTING ~ ALL PAIRWISE COMBINATIONS OF APPROVED CANCER DRUGS The NCI ALMANAC (A Large Matrix of AntiNeoplastic Agent Combinations) Currently just over 100 small molecule oncology drugs are FDA-approved. Test all possible pairwise combinations of these • ~5000 drug pairs
Test each drug pair in each of the cell lines in the NCI-60 panel. • ~300,000 experiments
• ~4.3 million wells
Screen run at 2 contract locations • ~$4 million over 2 years
![Page 5: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/5.jpg)
Approved drug pairs in clinicaltrials.gov
Search for “cancer” Parse out drug names Only about one quarter of approved drug pairs are found. Approx. 3700 approved drug pairs have no clinical trials. Can we discover beneficial pairs that can be put into clinical trials?
Drug A Drug Z
Drug A
Drug Z
![Page 6: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/6.jpg)
WHY THE NCI-60? Large database of drug action Large catalog of molecular characterization Most of the cell lines will grow as xenografts Molecular characterization of the xenografts derived from the NCI-60, at passages 1, 4 and 10 Possibility for predictive biomarker discovery
![Page 7: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/7.jpg)
MOLECULAR CHARACTERIZATION OF THE NCI-60
Larger scale projects • Exome sequencing • mRNA microarrays
• multiple platforms
• SNP arrays • CNV • Proteins by MS • Proteins by RPPA • miRNA • CpG methylation • Metabolomics
Smaller focused projects
• SNPs in cancer relevant genes
• Protein and phospho-proteins
• Activity measurements
• Karyotype
![Page 8: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/8.jpg)
COMBO DATA: EXAMPLE 3X3 CONCENTRATION MATRIX COMBO SCORE
microM agent 1
Agent 1 alone Agent 1 + low dose Agent 2 Agent 1 + med dose Agent 2 Agent 1 + high dose Agent 2 low dose Agent 2 alone med dose Agent 2 alone high dose Agent 2 alone
![Page 9: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/9.jpg)
COMBO DATA: EXAMPLE 3X3 CONCENTRATION MATRIX COMBO SCORE
microM agent 1
Agent 1 alone Agent 1 + med dose Agent 2 med dose Agent 2 alone
Expected if additive Increased over additive
![Page 10: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/10.jpg)
COMBO DATA: EXAMPLE 3X3 CONCENTRATION MATRIX COMBO SCORE
microM agent 1
Agent 1 alone Agent 1 + low dose Agent 2 Agent 1 + med dose Agent 2 Agent 1 + high dose Agent 2 low dose Agent 2 alone med dose Agent 2 alone high dose Agent 2 alone
![Page 11: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/11.jpg)
COMBO SCREEN RESULTS COMBOSCORE BASED ON BLISS INDEPENDENCE
Cell lines D
rug
Pai
rs
Red = Better than additive Blue = Worse than additive
![Page 12: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/12.jpg)
EXAMPLE 1: BORTEZOMIB + CLOFARABINE
Red arrows: Combo active in xenografts Blue arrows: no xenograft benefit over single agents
B
C
combo
![Page 13: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/13.jpg)
![Page 14: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/14.jpg)
R P M I - 8 2 2 6O V C A R - 3H S 5 7 8 TM D A - M B - 4 6M O L T - 4C C R F - C E MR X F 3 9 3K - 5 6 2S F - 5 3 9U A C C - 6 2K M 1 2B T - 5 4 9O V C A R - 8H L - 6 0 ( T B )H T 2 9S N B - 7 5H C C - 2 9 9 8M D A - M B - 2 3D U - 1 4 5M D A - M B - 4 3N C I - H 5 2 2S RS K - M E L - 5N C I - H 2 3N C I - H 2 2 6S W - 6 2 0I G R O V 1A 4 9 8C O L O 2 0 5L O X I M V IU 2 5 1H C T - 1 1 6S N 1 2 CU A C C - 2 5 7S F - 2 9 5N C I / A D R - R EC A K I - 17 8 6 - 0A 5 4 9 / A T C CS K - O V - 3M C F 7H C T - 1 5N C I - H 4 6 0A C H NE K V XU O - 3 1O V C A R - 4P C - 3S K - M E L - 2 8O V C A R - 5S N B - 1 9M A L M E - 3 MM 1 4S F - 2 6 8T - 4 7 DT K - 1 0N C I - H 3 2 2 MH O P - 6 2H O P - 9 2S K - M E L - 2
R P M I - 8 2 2 6O V C A R - 3H S 5 7 8 TM D A - M B - 4 6M O L T - 4C C R F - C E MR X F 3 9 3K - 5 6 2S F - 5 3 9U A C C - 6 2K M 1 2B T - 5 4 9O V C A R - 8H L - 6 0 ( T B )H T 2 9S N B - 7 5H C C - 2 9 9 8M D A - M B - 2 3D U - 1 4 5M D A - M B - 4 3N C I - H 5 2 2S RS K - M E L - 5N C I - H 2 3N C I - H 2 2 6S W - 6 2 0I G R O V 1A 4 9 8C O L O 2 0 5L O X I M V IU 2 5 1H C T - 1 1 6S N 1 2 CU A C C - 2 5 7S F - 2 9 5N C I / A D R - R EC A K I - 17 8 6 - 0A 5 4 9 / A T C CS K - O V - 3M C F 7H C T - 1 5N C I - H 4 6 0A C H NE K V XU O - 3 1O V C A R - 4P C - 3S K - M E L - 2 8O V C A R - 5S N B - 1 9M A L M E - 3 MM 1 4S F - 2 6 8T - 4 7 DT K - 1 0N C I - H 3 2 2 MH O P - 6 2H O P - 9 2S K - M E L - 2
TNB
C
EXAMPLE 2: A DRUG PAIR THAT IS BENEFICIAL IN TRIPLE-NEGATIVE BREAST CANCER MODELS
combo
no drug
drug A
drug B
Tumor-free animals months after treatment completed
Period of drug treatment
![Page 15: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/15.jpg)
NCI ALMANAC DATA TO BE PUBLIC Manuscript in final stages Web site developed to • Browse the data • Display the data • Download the data
![Page 16: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/16.jpg)
![Page 17: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/17.jpg)
![Page 18: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/18.jpg)
![Page 19: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/19.jpg)
TWO PARALLEL COMBINATION DRUG SCREENS AT NCI • Comprehensive screen of approved cancer drugs • Combination screening of investigational agents
![Page 20: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/20.jpg)
Com
bo S
et d
rugs
(~7
0)
Test agents (~130 tested)
cell line 1 2 3
cell line 1 2 3
cell line 1 2 3
cell line 1 2 3
cell line 1 2 3
cell line 1 2 3
cell line 1 2 3
~9000 drug pairs tested each in 3-5 cell lines ~27,000 total combination assays
COMBO TESTING OF INVESTIGATIONAL AGENTS
![Page 21: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/21.jpg)
INVESTIGATIONAL COMBO DATA
Com
bo S
et d
rugs
(~7
0)
Test agents (~130 tested) and cell lines (3-5)
![Page 22: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/22.jpg)
EXAMPLES FROM THE INVESTIGATIONAL COMBO SCREEN • Test agents with the same molecular target have
similar activity patterns • Patterns of combination benefit reveal a
potential new mechanism for an investigational agent
![Page 23: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/23.jpg)
AGENTS WITH SAME TARGET SIMILARITIES AND DIFFERENCES
Select 4 "hits" Test each of these drugs in the NCI-60 with Agent 1 with Agent 2
Drug 1
Drug 2 Drug 3
Drug 4
![Page 24: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/24.jpg)
DRUGS 1 & 2 COMBINED WELL WITH BOTH AGENTS
MDA-MB-468T-47D
BT-549HS 578T
MDA-MB-231/ATCCMCF7
DU-145PC-3
UO-31TK-10
SN12CRXF-393
CAKI-1ACHNA498786-0
SK-OV-3NCI/ADR-RES
OVCAR-8OVCAR-5OVCAR-4OVCAR-3
IGROV1UACC-62
UACC-257SK-MEL-5
SK-MEL-28SK-MEL-2
MDA-MB-435M14
LOX IMVIU251
SNB-19SNB-75SF-539SF-295SF-268
SW-620KM12HT29
HCT-15HCT-116
HCC-2998COLO 205NCI-H522NCI-H460
NCI-H322MNCI-H23
NCI-H226HOP-92HOP-62
EKVXA549/ATCC
SRRPMI-8226
MOLT-4K-562
HL-60(TB)CCRF-CEM
Agent 1 Agent 2
Drug 1
Drug 1
Drug 2 Drug 3
Drug 4
MDA-MB-468T-47D
BT-549HS 578T
MDA-MB-231/ATCCMCF7
DU-145PC-3
UO-31TK-10
SN12CRXF-393
CAKI-1ACHNA498786-0
SK-OV-3NCI/ADR-RES
OVCAR-8OVCAR-5OVCAR-4OVCAR-3
IGROV1UACC-62
UACC-257SK-MEL-5
SK-MEL-28SK-MEL-2
MDA-MB-435M14
LOX IMVIU251
SNB-19SNB-75SF-539SF-295SF-268
SW-620KM12HT29
HCT-15HCT-116
HCC-2998COLO 205NCI-H522NCI-H460
NCI-H322MNCI-H23
NCI-H226HOP-92HOP-62
EKVXA549/ATCC
SRRPMI-8226
MOLT-4K-562
HL-60(TB)CCRF-CEM
Agent 1 Agent 2
Drug 2
![Page 25: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/25.jpg)
DRUGS 3 & 4 COMBINED WELL WITH ONLY AGENT 2
Drug 1
Drug 2 Drug 3
Drug 4
MDA-MB-468T-47D
BT-549HS 578T
MDA-MB-231/ATCCMCF7
DU-145PC-3
UO-31TK-10
SN12CRXF-393
CAKI-1ACHNA498786-0
SK-OV-3NCI/ADR-RES
OVCAR-8OVCAR-5OVCAR-4OVCAR-3
IGROV1UACC-62
UACC-257SK-MEL-5
SK-MEL-28SK-MEL-2
MDA-MB-435M14
LOX IMVIU251
SNB-19SNB-75SF-539SF-295SF-268
SW-620KM12HT29
HCT-15HCT-116
HCC-2998COLO 205NCI-H522NCI-H460
NCI-H322MNCI-H23
NCI-H226HOP-92HOP-62
EKVXA549/ATCC
SRRPMI-8226
MOLT-4K-562
HL-60(TB)CCRF-CEM
MDA-MB-468T-47D
BT-549HS 578T
MDA-MB-231/ATCCMCF7
DU-145PC-3
UO-31TK-10
SN12CRXF-393
CAKI-1ACHNA498786-0
SK-OV-3NCI/ADR-RES
OVCAR-8OVCAR-5OVCAR-4OVCAR-3
IGROV1UACC-62
UACC-257SK-MEL-5
SK-MEL-28SK-MEL-2
MDA-MB-435M14
LOX IMVIU251
SNB-19SNB-75SF-539SF-295SF-268
SW-620KM12HT29
HCT-15HCT-116
HCC-2998COLO 205NCI-H522NCI-H460
NCI-H322MNCI-H23
NCI-H226HOP-92HOP-62
EKVXA549/ATCC
SRRPMI-8226
MOLT-4K-562
HL-60(TB)CCRF-CEM
Agent 1 Agent 1 Agent 2 Agent 2
Drug 3 Drug 4
![Page 26: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/26.jpg)
2 AGENTS WITH SAME TARGET ADDITIONAL TESTING WITH 4 HITS FROM THE SCREEN
MDA-MB-468T-47D
BT-549HS 578T
MDA-MB-231/ATCCMCF7
DU-145PC-3
UO-31TK-10
SN12CRXF-393
CAKI-1ACHNA498786-0
SK-OV-3NCI/ADR-RES
OVCAR-8OVCAR-5OVCAR-4OVCAR-3
IGROV1UACC-62
UACC-257SK-MEL-5
SK-MEL-28SK-MEL-2
MDA-MB-435M14
LOX IMVIU251
SNB-19SNB-75SF-539SF-295SF-268
SW-620KM12HT29
HCT-15HCT-116
HCC-2998COLO 205NCI-H522NCI-H460
NCI-H322MNCI-H23
NCI-H226HOP-92HOP-62
EKVXA549/ATCC
SRRPMI-8226
MOLT-4K-562
HL-60(TB)CCRF-CEM
MDA-MB-468T-47D
BT-549HS 578T
MDA-MB-231/ATCCMCF7
DU-145PC-3
UO-31TK-10
SN12CRXF-393
CAKI-1ACHNA498786-0
SK-OV-3NCI/ADR-RES
OVCAR-8OVCAR-5OVCAR-4OVCAR-3
IGROV1UACC-62
UACC-257SK-MEL-5
SK-MEL-28SK-MEL-2
MDA-MB-435M14
LOX IMVIU251
SNB-19SNB-75SF-539SF-295SF-268
SW-620KM12HT29
HCT-15HCT-116
HCC-2998COLO 205NCI-H522NCI-H460
NCI-H322MNCI-H23
NCI-H226HOP-92HOP-62
EKVXA549/ATCC
SRRPMI-8226
MOLT-4K-562
HL-60(TB)CCRF-CEM
MDA-MB-468T-47D
BT-549HS 578T
MDA-MB-231/ATCCMCF7
DU-145PC-3
UO-31TK-10
SN12CRXF-393
CAKI-1ACHNA498786-0
SK-OV-3NCI/ADR-RES
OVCAR-8OVCAR-5OVCAR-4OVCAR-3
IGROV1UACC-62
UACC-257SK-MEL-5
SK-MEL-28SK-MEL-2
MDA-MB-435M14
LOX IMVIU251
SNB-19SNB-75SF-539SF-295SF-268
SW-620KM12HT29
HCT-15HCT-116
HCC-2998COLO 205NCI-H522NCI-H460
NCI-H322MNCI-H23
NCI-H226HOP-92HOP-62
EKVXA549/ATCC
SRRPMI-8226
MOLT-4K-562
HL-60(TB)CCRF-CEM
MDA-MB-468T-47D
BT-549HS 578T
MDA-MB-231/ATCCMCF7
DU-145PC-3
UO-31TK-10
SN12CRXF-393
CAKI-1ACHNA498786-0
SK-OV-3NCI/ADR-RES
OVCAR-8OVCAR-5OVCAR-4OVCAR-3
IGROV1UACC-62
UACC-257SK-MEL-5
SK-MEL-28SK-MEL-2
MDA-MB-435M14
LOX IMVIU251
SNB-19SNB-75SF-539SF-295SF-268
SW-620KM12HT29
HCT-15HCT-116
HCC-2998COLO 205NCI-H522NCI-H460
NCI-H322MNCI-H23
NCI-H226HOP-92HOP-62
EKVXA549/ATCC
SRRPMI-8226
MOLT-4K-562
HL-60(TB)CCRF-CEM
Agent 1 Agent 1 Agent 1 Agent 1 Agent 2 Agent 2 Agent 2 Agent 2
Drug 1 Drug 2 Drug 3 Drug 4
Cell line profiles are similar between Agent 1 & Agent 2 Patterns of cell lines benefiting differ between the 4 drugs Possibility to think about "MATCH" style combo trials
![Page 27: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/27.jpg)
COMBO SCREEN: CLUES AS TO MECHANISM
Com
bo S
et d
rugs
(~7
0)
2 agents expected to sensitize cells to DNA damage 1 agent with completely different target -- or maybe not
Similar patterns of Combo Set drugs that give greater than additive activity with these 3 Test Agents
![Page 28: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/28.jpg)
COMBO SCREEN: CLUES AS TO MECHANISM
Com
bo S
et d
rugs
(~7
0)
2 agents expected to sensitize cells to DNA damage 1 agent with completely different target -- or maybe not
Similar patterns of cell lines with combo benefit
![Page 29: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/29.jpg)
TEST COMBINATION WITH 2 ADDITIONAL AGENTS
Agent 1: expected to synergize with Alkylating agents
Agent 2: Unexpected results
2 additional agents with similar mechanism to that reported for Agent 2
![Page 30: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/30.jpg)
SUMMARY NCI ALMANAC - tested ~ 5000 drug pairs of FDA-approved oncology drugs in 60 cell lines
• One novel combination has entered clinical trials • Trial design in progress for a second novel combination
NCI Investigational Combination Screen - tested ~ 9000 drug pairs in 3-5 cell lines
• Similarities and differences for agents with the same or overlapping mechanisms
• Surprising result suggests different mechanism for an investigational agent
![Page 31: Cell-based screens of drug combinations at NCI - Holbeck.pdf · Cell-based screens of drug combinations at NCI Author: Holbeck, Susan (NIH/NCI) [E] Subject: CTAC Meeting Presentation,](https://reader033.vdocuments.net/reader033/viewer/2022042320/5f0a427a7e708231d42ac933/html5/thumbnails/31.jpg)
PEOPLE Jim Doroshow Jerry Collins Dick Camalier Myrtle Davis Millin Melinda Hollingshead Marie Hose Shivaani Kummar Dianne Newton
Eric Polley Larry Rubinstein Karen Schweikart Penny Svetlik SRI International Univ of Pittsburgh