title: Multimodal biomarker investigation on efficacy and mechanism of action for the mammalian target of rapamycin inhibitor, temsirolimus, in a preclinical mammary carcinoma OncoMouse model: a translational medicine study in support for early clinical development.
abstract: The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administered in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 ± 14% from 8 to 10 weeks, p < 0.05, and 26 ± 17% from 11 to 13 weeks, p < 0.01), compared with 493 ± 160 and 376 ± 50% increases, respectively, in vehicle-treated groups. Temsirolimus reduced tumor vascular density, 36 to 48 and 58 to 60%, p < 0.05, by the Texas red-dextran method or CD31-positive vessel count, respectively. Temsirolimus reduced tumor macrophage burden by 46% at 13 weeks (p < 0.05). Temsirolimus inhibited (p < 0.05) the phosphoproteins S6 pS235/236 and S6 pS240/244 up to 81 and 87%, respectively. We conclude that the multimodal biomarkers of temsirolimus efficacy and mechanism of action (phosphoproteins) strongly suggest that it might translate to therapeutic efficacy in human tumors that bear congruency to features present in the mammary carcinoma of PyMT tumors.
authors.affiliation: Imaging Biomarker Laboratory, Translational Medicine, Pfizer, Collegeville, Pennsylvania, USA. wangxk2000@yahoo.com
authors.forename: Xinkang
authors.initials: X
authors.lastname: Wang
authors.forename: Yutian
authors.initials: Y
authors.lastname: Zhan
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: John
authors.initials: J
authors.lastname: Alvarez
authors.forename: Inder
authors.initials: I
authors.lastname: Chaudhary
authors.forename: Bin-Bing
authors.initials: BB
authors.lastname: Zhou
authors.forename: Robert T
authors.initials: RT
authors.lastname: Abraham
authors.forename: Giora Z
authors.initials: GZ
authors.lastname: Feuerstein
mesh_terms: D000818:Animals; D054316:Biomarkers, Pharmacological / Q000032:analysis*; D045744:Cell Line, Tumor; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D007262:Infusions, Intravenous; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors*; D057170:Translational Research, Biomedical / Q000379:methods; D047368:Tumor Burden / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D054316:Biomarkers, Pharmacological; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus