The identification and targeting of dysregulated signal transduction pathways underlying oncogenic states has heralded a new and exciting approach to cancer therapy. The overall objective of our work is to determine whether simultaneous targeting of multiple oncogenic signaling pathways in cancer is safe and effective in humans. We will use chronic myelogenous leukemia (CML) as a disease model, and employ a combination of highly-specific, small molecular inhibitors directed against the Bcr-Abl and mammalian target of rapamycin (mTOR) kinases. The rationale for this approach is based on our recent work demonstrating that combined treatment with imatinib and the mTOR inhibitor, rapamycin, acts synergistically against CML progenitors, as well as overcomes various forms of imatinib resistance. The objectives of this proposal are: 1. To conduct a phase I study using the combination of the rapamycin analog, CCI-779, and imatinib mesylate in patients with high-risk CML; and 2. To validate laboratory correlates for target evaluation and response prediction. These objectives will be accomplished using an adaptive phase I design, employing a fixed dose of imatinib in combination with a dose-escalation schedule for CCI-779 in patients with high-risk CML. An integral part of this study will be the validation of translational correlates, including target identification, evaluation of biomarkers for effective targeting, and response prediction. The specific laboratory correlative studies included in this trial are derived from preliminary data using patient samples in the Principle Investigator's laboratory. This study has been approved and is sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute, and will enroll patients from the Irvine, San Diego, and Davis Campuses of the University of California. The clinical data and laboratory studies outlined in our proposal will form the basis for a future phase II trial in patients with high-risk CML. Since deregulated kinase activity is known to contribute to a wide range of malignancies, these studies will have applicability to cancer therapy in general. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA112936-01A1
Application #
6936956
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Wu, Roy S
Project Start
2005-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$270,502
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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Zhang, Min; Fu, Wuxia; Prabhu, Sharmila et al. (2008) Inhibition of polysome assembly enhances imatinib activity against chronic myelogenous leukemia and overcomes imatinib resistance. Mol Cell Biol 28:6496-509
Prabhu, S; Saadat, D; Zhang, M et al. (2007) A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation. Oncogene 26:1188-200
Moore, James C; Dennehey, Carolyn F; Anavim, Arash et al. (2006) Multiple joint effusions associated with high-dose imatinib therapy in a patient with chronic myelogenous leukaemia. Eur J Haematol 76:444-6