|
| Status |
Public on May 03, 2012 |
| Title |
The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Pancreatic ductal adenocarcinoma (PDAC) is a nearly uniformly lethal malignancy, with most patients facing an adverse clinical outcome. Given the pivotal role of aberrant Notch signaling in the initiation and progression of PDAC, we investigated the effect of MRK-003, a potent and selective γ-secretase inhibitor, in preclinical PDAC models. We used a panel of human PDAC cell lines, as well as patient-derived PDAC xenografts, to determine whether pharmacological targeting of the Notch pathway could inhibit pancreatic tumor growth and potentiate gemcitabine sensitivity. In vitro, MRK-003 treatment downregulated the canonical Notch target gene Hes-1, significantly inhibited anchorage independent growth, and reduced the subset of CD44+CD24+ and aldehyde dehydrogenase (ALDH)+ cells that have been attributed with tumor initiating capacity. Ex vivo pretreatment of PDAC cells with MRK-003 in culture significantly inhibited the subsequent engraftment in immunocompromised mice. In vivo, MRK-003 monotherapy significantly blocked tumor growth in 5 of 9 (56%) patient-derived PDAC xenografts. Moreover, a combination of MRK-003 and gemcitabine showed enhanced antitumor effects compared to gemcitabine alone in 4 of 9 (44%) PDAC xenografts. Baseline gene expression analysis of the treated xenografts indicated that upregulation of nuclear factor kappa B (NFκB) pathway components was associated with the sensitivity to single MRK-003, while upregulation in B-cell receptor (BCR) signaling and nuclear factor erythroid-derived 2-like 2 (NRF2) pathway correlated with response to the combination of MRK-003 with gemcitabine. The preclinical findings presented here provide further rationale for small molecule inhibition of Notch signaling as a therapeutic strategy in PDAC.
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| Overall design |
Pancreatic ductal adenocarcinoma xenografts were grown in Athymic Nude-Foxn1nu mice. RNA was extracted and profiled in Affymetrix platform to identify genes correlating with sensitivity to MRK-003
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| |
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| Contributor(s) |
Puig O, Maitra A, Kumar R |
| Citation(s) |
22752426 |
| |
| Submission date |
Apr 29, 2012 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Oscar Puig |
| E-mail(s) |
oscar_puig@merck.com
|
| Organization name |
Merck Research Laboratories
|
| Department |
Molecular Profiling Research Informatics
|
| Street address |
126 East Lincoln Ave
|
| City |
Rahway |
| State/province |
NJ |
| ZIP/Postal code |
07065 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
|
| Samples (18)
|
| GSM924978 |
Panc265 xenograft GSI_265B Sensitive to MRK-003 |
| GSM924979 |
Panc253 xenograft GSI_253B Non-sensitive to MRK-003 |
| GSM924980 |
Panc291 xenograft GSI_291B Non-sensitive to MRK-003 |
| GSM924981 |
Panc374 xenograft GSI_374B Sensitive to MRK-003 |
| GSM924982 |
Panc253 xenograft GSI_253A Non-sensitive to MRK-003 |
| GSM924983 |
Panc291 xenograft GSI_291A Non-sensitive to MRK-003 |
| GSM924984 |
Panc374 xenograft GSI_374A Sensitive to MRK-003 |
| GSM924985 |
Panc215 xenograft GSI_215A Non-sensitive to MRK-003 |
| GSM924986 |
JH033 xenograft GSI_JH033A Sensitive to MRK-003 |
| GSM924987 |
Panc198 xenograft GSI_198A Non-sensitive to MRK-003 |
| GSM924988 |
Panc420 xenograft GSI_420A Sensitive to MRK-003 |
| GSM924989 |
Panc219 xenograft GSI_219B Sensitive to MRK-003 |
| GSM924990 |
Panc219 xenograft GSI_219A Sensitive to MRK-003 |
| GSM924991 |
Panc215 xenograft GSI_215B Non-sensitive to MRK-003 |
| GSM924992 |
JH033 xenograft GSI_JH033B Sensitive to MRK-003 |
| GSM924993 |
Panc420 xenograft GSI_420B Sensitive to MRK-003 |
| GSM924994 |
Panc265 xenograft GSI_265A Sensitive to MRK-003 |
| GSM924995 |
Panc198 xenograft GSI_198B Non-sensitive to MRK-003 |
|
| Relations |
| BioProject |
PRJNA163081 |
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