Program for the Evaluation of Targeted Therapy (PETT)
The Program for the Evaluation of Targeted Therapy (PETT) is a multi-disciplinary team comprised of scientists, medical oncologists and bioinformaticians under the directorship of Dr. Gail Eckhardt. The focus of PETT is colorectal cancer (CRC) and melanoma, diseases for which there are few therapeutic alternatives. Our primary goal is to bring promising new therapies from the laboratory to the clinic (bench to bedside) through the utilization of novel cancer model systems including cell lines, orthotopic and metastatic models, as well as direct patient xenograft models of GI cancers and melanoma. In addition to conducting correlative biological assays for some of our Phase I clinical trials, a major focus of our lab is the development of predictive and pharmacodynamic biomarkers for novel, molecularly-targeted anticancer agents. Our current focus is on inhibitors of mitogen-activated kinase kinase (MEK), insulin-like growth factor-1 receptor (IGF-1R), p21-activated kinase-4 (PAK-4), Aurora kinase, NEDD8, TWEAK and the hedgehog signaling pathway, all of which are de-regulated in cancer. To accomplish this, we have developed a unique platform that integrates data from our preclinical models with differential gene expression and synthetic lethal approaches to generate molecular signatures of therapeutic response that can be used for patient-selective clinical trials. Additionally, we use preclinical imaging techniques such as micro-CT/PET, DCE-MRI, as well as metabolomics to gain mechanistic insights into cancer drug action with a view towards improving their efficacy. Our funding sources include the National Cancer Institute, the pharmaceutical industry, the American Association for Cancer Research and other private foundations
Tentler JJ, Bradshaw-Pierce EL, Serkova NJ, Hasebroock KM, Pitts TM, Diamond JR, Fletcher GC, Bray MR, Eckhardt SG.
Clin Cancer Res. 2010;16(11):2989-98. Assessment of the in vivo antitumor effects of ENMD-2076, a novel multitargeted kinase inhibitor, against primary and cell line-derived human colorectal cancer xenograft models.
Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, Leong S, O'Bryant C, Chow LQ, Serkova NJ, Meropol NJ, Lewis NL, Chiorean EG, Fox F, Youssoufian H, Rowinsky EK, Eckhardt SG. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 2010 Feb 10;28(5):780-7
Leong S, Cohen RB, Gustafson DL, Langer CJ, Camidge DR, Padavic K, Gore L, Smith M, Chow LQ, von Mehren M, O'Bryant C, Hariharan S, Diab S, Fox NL, Miceli R, Eckhardt SG. Mapatumumab, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase I and pharmacokinetic study. J Clin Oncol. 2009 Sep 10;27(26):4413-21
Jimeno A, Messersmith WA, Hirsch FR, Franklin WA, Eckhardt SG. KRAS mutations and susceptibility to cetuximab and panitumumab in colorectal cancer. Cancer J. 2009 Mar-Apr;15(2):110-3
Pitts TM, Morrow M, Kaufman SA, Tentler JJ and Eckhardt SG. Vorinostat and Bortezomib Exert Synergistic Anti-proliferative and Pro-apoptotic Effects in Colon Cancer Cell Models. Mol Cancer Ther. 2009 Feb;8(2):342-9 (PMID 19174560)
Morelli MP, Meyer AM, Pitts TM, Tentler JJ, Ciardiello F, Ryan A,. Jurgensmeier JM and Eckhardt SG Targeting Vascular Endothelial Growth Factor Receptor-1 and -3 With Cediranib (AZD2171): Effects on Migration and Invasion of GI Cancer Cell Lines. Mol Cancer Ther. 2009;8 2546-2558 (PMID 19755510)
Pitts TM, Tan AC, Kulikowski GN, Tentler JJ, Brown AM Flanigan SA, Leong S, Coldren C, Hirsch FR Varella-Garcia M, Korch C, Eckhardt SG. Development of an Integrated Genomic Classifier for a Novel Agent in Colorectal Cancer: Approach to Individualized Therapy in Early Development Clin Cancer Res 2010 Accepted