title: 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.affiliation: Oncology Research Unit, Pfizer Global Research & Development, San Diego, California, United States of America.
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Fang
authors.forename: Cathy C
authors.initials: CC
authors.lastname: Zhang
authors.forename: Yin
authors.initials: Y
authors.lastname: Gu
authors.forename: Jitesh P
authors.initials: JP
authors.lastname: Jani
authors.forename: Joan
authors.initials: J
authors.lastname: Cao
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tsaparikos
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: Melissa
authors.initials: M
authors.lastname: Thiel
authors.forename: Amy
authors.initials: A
authors.lastname: Jackson-Fisher
authors.forename: Qing
authors.initials: Q
authors.lastname: Zong
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Lappin
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hayashi
authors.forename: Richard B
authors.initials: RB
authors.lastname: Schwab
authors.forename: Anthony
authors.initials: A
authors.lastname: Wong
authors.forename: Annette
authors.initials: A
authors.lastname: John-Baptiste
authors.forename: Shubha
authors.initials: S
authors.lastname: Bagrodia
authors.forename: Geritt
authors.initials: G
authors.lastname: Los
authors.forename: Steve
authors.initials: S
authors.lastname: Bender
authors.forename: James
authors.initials: J
authors.lastname: Christensen
authors.forename: Todd
authors.initials: T
authors.lastname: Vanarsdale
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D016513:Mice, SCID; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; C546842:MTOR protein, human; C484760:PIK3CA protein, human