PMID- 21835932 OWN - NLM STAT- MEDLINE DCOM- 20120116 LR - 20211203 IS - 1521-0103 (Electronic) IS - 0022-3565 (Linking) VI - 339 IP - 2 DP - 2011 Nov TI - 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. PG - 421-9 LID - 10.1124/jpet.111.185249 [doi] AB - 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. FAU - Wang, Xinkang AU - Wang X AD - Imaging Biomarker Laboratory, Translational Medicine, Pfizer, Collegeville, Pennsylvania, USA. wangxk2000@yahoo.com FAU - Zhan, Yutian AU - Zhan Y FAU - Zhao, Lei AU - Zhao L FAU - Alvarez, John AU - Alvarez J FAU - Chaudhary, Inder AU - Chaudhary I FAU - Zhou, Bin-Bing AU - Zhou BB FAU - Abraham, Robert T AU - Abraham RT FAU - Feuerstein, Giora Z AU - Feuerstein GZ LA - eng PT - Journal Article DEP - 20110811 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Biomarkers, Pharmacological) RN - 0 (Protein Kinase Inhibitors) RN - 624KN6GM2T (temsirolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Biomarkers, Pharmacological/*analysis MH - Cell Line, Tumor MH - Disease Progression MH - Dose-Response Relationship, Drug MH - Drug Screening Assays, Antitumor MH - Female MH - Infusions, Intravenous MH - Mammary Neoplasms, Experimental/*drug therapy MH - Mice MH - Mice, Transgenic MH - Protein Kinase Inhibitors/administration & dosage/pharmacokinetics/*pharmacology MH - Signal Transduction/drug effects MH - Sirolimus/administration & dosage/*analogs & derivatives/pharmacokinetics/pharmacology MH - TOR Serine-Threonine Kinases/analysis/*antagonists & inhibitors MH - Translational Research, Biomedical/methods MH - Tumor Burden/*drug effects MH - Xenograft Model Antitumor Assays EDAT- 2011/08/13 06:00 MHDA- 2012/01/17 06:00 CRDT- 2011/08/13 06:00 PHST- 2011/08/13 06:00 [entrez] PHST- 2011/08/13 06:00 [pubmed] PHST- 2012/01/17 06:00 [medline] AID - jpet.111.185249 [pii] AID - 10.1124/jpet.111.185249 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2011 Nov;339(2):421-9. doi: 10.1124/jpet.111.185249. Epub 2011 Aug 11.