Antitumor Efficacy of the Dual PI3K/mTOR Inhibitor PF-04691502 in a Human Xenograft Tumor Model Derived from Colorectal Cancer Stem Cells Harboring a PIK3CA Mutation.

Abstract

PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) mutations can help predict the antitumor activity of phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway inhibitors in both preclinical and clinical settings. In light of the recent discovery of tumor-initiating cancer stem cells (CSCs) in various tumor types, we developed an in vitro CSC model from xenograft tumors established in mice from a colorectal cancer patient tumor in which the CD133+/EpCAM+ population represented tumor-initiating cells. CD133+/EpCAM+ CSCs were enriched under stem cell culture conditions and formed 3-dimensional tumor spheroids. Tumor spheroid cells exhibited CSC properties, including the capability for differentiation and self-renewal, higher tumorigenic potential and chemo-resistance. Genetic analysis using an OncoCarta™ panel revealed a PIK3CA (H1047R) mutation in these cells. Using a dual PI3K/mTOR inhibitor, PF-04691502, we then showed that blockage of the PI3K/mTOR pathway inhibited the in vitro proliferation of CSCs and in vivo xenograft tumor growth with manageable toxicity. Tumor growth inhibition in mice was accompanied by a significant reduction of phosphorylated Akt (pAKT) (S473), a well-established surrogate biomarker of PI3K/mTOR signaling pathway inhibition. Collectively, our data suggest that PF-04691502 exhibits potent anticancer activity in colorectal cancer by targeting both PIK3CA (H1047R) mutant CSCs and their derivatives. These results may assist in the clinical development of PF-04691502 for the treatment of a subpopulation of colorectal cancer patients with poor outcomes.

• Authors: Douglas D Fang, Cathy C Zhang, Yin Gu, Jitesh P Jani, Joan Cao, Konstantinos Tsaparikos, Jing Yuan, Melissa Thiel, Amy Jackson-Fisher, Qing Zong, Patrick B Lappin, Tomoko Hayashi, Richard B Schwab, Anthony Wong, Annette John-Baptiste, Shubha Bagrodia, Geritt Los, Steve Bender, James Christensen, Todd Vanarsdale
• Journal: PloS one (PLoS One) Vol. 8 Issue 6 Pg. e67258 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23826249 (Publication Type: Journal Article)

Chemical References

• 2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one
• Antineoplastic Agents
• Biomarkers, Tumor
• Phosphoinositide-3 Kinase Inhibitors
• Pyridones
• Pyrimidines
• MTOR protein, human
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Administration, Oral
• Adult
• Animals
• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor (genetics, metabolism)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Class I Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Colorectal Neoplasms (drug therapy, enzymology, genetics, pathology)
• Humans
• Male
• Mice, SCID
• Mutation
• Neoplastic Stem Cells (drug effects, enzymology, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridones (pharmacology)
• Pyrimidines (pharmacology)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays