Biomarkers Of Sensitivity To Pf-03084014, A Gamma-Secretase Inhibitor, In A Preclinical Model Of Colorectal Cancer

Purpose: To evaluate the efficacy of PF-03084014, a γ-secretase inhibitor, in a preclinical model of colorectal cancer (CRC) and to identify biomarkers that predicts sensitivity to the compound. Experimental Design: Fourteen patient-derived CRC explants were treated with PF-03084014 (150mg/kg/day- BID) for 28 days. Gene expression of the Notch pathway was evaluated at baseline and day 28 using RT-PCR. Additionally, baseline gene expression profiles were determined using gene array. An Aldefluor assay (stem cell technologies) was used to determine the effect of treatment on tumor initiating cells. Fluorescence in situ hybridization (FISH) was used to determine Notch 1 gene copy number. Results: Three out of the fourteen explants showed sensitivity (cytostatic effects) to PF-03084014. Treatment reduced Notch pathway gene expression (Hes-1, Notch 1, Notch 3, and Jag1) in the sensitive tumors when evaluated by RT-PCR. Baseline gene array data showed an increase in IL-8 gene expression in resistant tumors and pathway analysis demonstrated an increase in focal adhesion, Jack-STAT, and MAPK signaling pathways in resistant explants. Evaluation of the ALDH+ cell population after 28 days of treatment showed that PF-03084014 reduced the ALDH+ cell population in the most sensitive explant (CRC001) when compared to the vehicle group. Evaluation of Notch 1 gene copy number in four CRC explants by FISH showed increased gene copy number in two sensitive explants (CRC027 and CRC001) and one intermediate explant (CRC036) and no gain in gene copy number in one resistant explant (CRC042). Conclusion: Treatment with PF-03084014 significantly reduced tumor growth in three CRC explants. In addition, treatment inhibited expression of the Notch pathway and reduced the tumorigenic ALDH+ population. These results indicate that a subset of patients may derive benefit from treatment with PF-03084014 and biomarkers could be identified that predict sensitivity to the compound. Acknowledgements: This work was supported by a Pfizer IIR grant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5190. doi:10.1158/1538-7445.AM2011-5190