Cancer Research AACR Conference on Molecular Diagnostics - 2008  Tumor Immunology: New Perspectives
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Cancer Research 67, 11463-11469, December 1, 2007. doi: 10.1158/0008-5472.CAN-07-2976
© 2007 American Association for Cancer Research

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Prevention

3'-Deoxy-3'-[18F]Fluorothymidine Positron Emission Tomography Is a Sensitive Method for Imaging the Response of BRAF-Dependent Tumors to MEK Inhibition

David B. Solit1,5, Elmer Santos2, Christine A. Pratilas3,4, Jose Lobo5, Maxim Moroz4, Shangde Cai2, Ronald Blasberg4, Judith Sebolt-Leopold6, Steven Larson2 and Neal Rosen1,4

Departments of 1 Medicine, 2 Radiology, 3 Pediatrics, and 4 Molecular Pharmacology and Chemistry and 5 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York and 6 Pfizer Global Research and Development, Ann Arbor, Michigan

Requests for reprints: Neal Rosen, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 646-888-2075; E-mail: rosenn{at}mskcc.org.

Activating mutations of BRAF occur in ~7% of all human tumors and in the majority of melanomas. These tumors are very sensitive to pharmacologic inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), which causes loss of D-cyclin expression, hypophosphorylation of Rb, and G1 arrest. Growth arrest is followed by differentiation or senescence and, in a subset of BRAF mutant tumors, by apoptosis. The former effects result in so-called "stable disease" and, in patients with cancer, can be difficult to distinguish from indolent tumor growth. The profound G1 arrest induced by MEK inhibition in BRAF mutant tumors is associated with a marked decline in thymidine uptake and is therefore potentially detectable in vivo by noninvasive 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) imaging. In SKMEL-28 tumor xenografts, MEK inhibition completely inhibited tumor growth and induced differentiation with only modest tumor regression. MEK inhibition also resulted in a rapid decline in the [18F]FLT signal in V600E BRAF mutant SKMEL-28 xenografts but not in BRAF wild-type BT-474 xenografts. The data suggest that [18F]FLT PET can effectively image induction of G1 arrest by MEK inhibitors in mutant BRAF tumors and may be a useful noninvasive method for assessing the early biological response to this class of drugs. [Cancer Res 2007;67(23):11463–9]




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J. S. Sebolt-Leopold
Advances in the Development of Cancer Therapeutics Directed against the RAS-Mitogen-Activated Protein Kinase Pathway
Clin. Cancer Res., June 15, 2008; 14(12): 3651 - 3656.
[Abstract] [Full Text] [PDF]




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Copyright © 2007 by the American Association for Cancer Research.