title: ALDH+ tumor-initiating cells exhibiting gain in NOTCH1 gene copy number have enhanced regrowth sensitivity to a γ-secretase inhibitor and irinotecan in colorectal cancer.
abstract: The Notch signaling pathway has been shown to be upregulated in colorectal cancer (CRC) and important for the self-renewal of cancer stem cells. In this study, we evaluated the efficacy of PF-03084014, a γ-secretase inhibitor, in combination with irinotecan to identify the effects of treatment on tumor recurrence and the tumor-initiating population in our CRC preclinical explant model. The combination of PF-03084014 and irinotecan had the greatest effect at reducing tumor growth on four CRC tumors when compared with treatment with PF-03084014 or irinotecan alone. The combination significantly reduced tumor recurrence in two CRC explants (CRC001 and CRC036) after treatment was discontinued. Both of these tumors exhibited elevated baseline levels of Notch pathway activation as well as an increase in NOTCH1 gene copy number when compared with the two CRC explants (CRC026 and CRC027) where tumors reappeared quickly after termination of treatment. Isolation and injection of aldehyde dehydrogenase (ALDH(+) and ALDH(-)) cells in an in vivo explant model demonstrated that the ALDH(+) cell population were tumorigenic. Evaluation of the ALDH(+) cells after 28 days of treatment showed that the combination reduced the ALDH(+) population in the tumors that did not regrow. Furthermore, ALDH(+) cells from CRC001 and CRC027 were injected in vivo and treated immediately for 28 days. Two months after treatment, tumors were evident in the combination treatment group for CRC027 but not for CRC036. These results indicate the combination of PF-03084014 and irinotecan may be effective in reducing tumor recurrence in CRC patients whose tumors exhibit elevated levels of the Notch pathway.
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Aurora, CO 80045, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Arcaroli
authors.forename: Rebecca W
authors.initials: RW
authors.lastname: Powell
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Martine
authors.initials: M
authors.lastname: McManus
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Quackenbush
authors.forename: Todd M
authors.initials: TM
authors.lastname: Pitts
authors.forename: Dexiang
authors.initials: D
authors.lastname: Gao
authors.forename: Anna
authors.initials: A
authors.lastname: Spreafico
authors.forename: Arvind
authors.initials: A
authors.lastname: Dasari
authors.forename: Basel M
authors.initials: BM
authors.lastname: Touban
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D051881:Receptor, Notch1; D000077146:Irinotecan; D000444:Aldehyde Dehydrogenase; D053829:Amyloid Precursor Protein Secretases; D002166:Camptothecin