Biomarker and pharmacologic evaluation of the γ-secretase inhibitor PF-03084014 in breast cancer models.

Abstract

PURPOSE:

We aimed to assess the biologic activity of PF-03084014 in breast xenograft models. The biomarkers for mechanism and patient stratification were also explored.

EXPERIMENTAL DESIGN:

The in vitro and in vivo properties of PF-03084014 were investigated. The mRNA expressions of 40 key Notch pathway genes at baseline or after treatment were analyzed to link with the antitumor efficacy of PF-03084014 in a panel of breast cancer xenograft models.

RESULTS:

In vitro, PF-03084014 exhibited activity against tumor cell migration, endothelial cell tube formation, and mammosphere formation. In vivo, we observed apoptosis, antiproliferation, reduced tumor cell self-renewal ability, impaired tumor vasculature, and decreased metastasis activity after the treatment of PF-03084014. PF-03084014 treatment displayed significant antitumor activity in 10 of the 18 breast xenograft models. However, the antitumor efficacy in most models did not correlate with the in vitro antiproliferation results in the corresponding cell lines, suggesting the critical involvement of tumor microenvironment during Notch activation. In the tested breast xenograft models, the baseline expressions of the Notch receptors, ligands, and the cleaved Notch1 failed to predict the antitumor response to PF-03084014, whereas several Notch pathway target genes, including HEY2, HES4, and HES3, strongly corresponded with the response with a P value less than 0.01. Many of the best molecular predictors of response were also significantly modulated following PF-03084014 treatment.

CONCLUSIONS:

PF-03084014 showed antitumor and antimetastatic properties via pleiotropic mechanisms. The Notch pathway downstream genes may be used to predict the antitumor activity of PF-03084014 and enrich for responders among breast cancer patients.

• Authors: Cathy C Zhang, Adam Pavlicek, Qin Zhang, Maruja E Lira, Cory L Painter, Zhengming Yan, Xianxian Zheng, Nathan V Lee, Mark Ozeck, Ming Qiu, Qing Zong, Patrick B Lappin, Anthony Wong, Paul A Rejto, Tod Smeal, James G Christensen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 18 Pg. 5008-19 (Sep 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22806875 (Publication Type: Journal Article)
• Copyright: ©2012 AACR.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Receptors, Notch
• Tetrahydronaphthalenes
• Amyloid Precursor Protein Secretases
• Valine
• nirogacestat

Topics

• Amyloid Precursor Protein Secretases (antagonists & inhibitors, metabolism)
• Antineoplastic Agents (administration & dosage, pharmacology)
• Biomarkers, Tumor (genetics, metabolism)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cluster Analysis
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• Neoplasm Metastasis (drug therapy)
• Receptors, Notch (metabolism)
• Signal Transduction (drug effects)
• Tetrahydronaphthalenes (administration & dosage, pharmacology)
• Valine (administration & dosage, analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays