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Clinical Cancer Research Vol. 5, 3977-3982, December 1999
© 1999 American Association for Cancer Research

Clinical Trials

c-raf-1 Depletion and Tumor Responses in Patients Treated with the c-raf-1 Antisense Oligodeoxynucleotide ISIS 5132 (CGP 69846A)1

Peter J. O’Dwyer2, James P. Stevenson, Maryann Gallagher, Amy Cassella, Irina Vasilevskaya, Brett P. Monia, Jon Holmlund, F. Andrew Dorr and Kang-Shen Yao

Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania 19104 [P. J. O., J. P. S., M. G., A. C., I. V., K-S. Y.], and ISIS Pharmaceuticals, Inc., Carlsbad, California [B. P. M., J. H., F. A. D.]

Abnormally regulated signaling through proliferative signal transduction pathways characterizes many of the common solid tumors. The best described of these involves potentially oncogenic proteins of the Ras family, which activate Raf proteins in the early steps of the mitogen-activated protein kinase cascade. ISIS 5132, a phosphorothioate antisense oligodexoynucleotide directed to the 3' untranslated region of the c-raf-1 mRNA, inhibits the growth of human tumor cell lines in vitro and in vivo in association with specific down-regulation of target message expression. Using a semiquantitative reverse transcription-PCR assay, we analyzed changes in c-raf-1 mRNA expression in peripheral blood mononuclear cells collected from patients with advanced cancers treated with ISIS 5132 as part of a clinical trial. Specimens were collected for analysis pretreatment and on days 3, 5, 8, and 15 of the first cycle and on day 1 of each subsequent cycle. We observed significant reductions of c-raf-1 expression from baseline by day 3 in 13 of 14 patients (P = 0.002). The time course and depletion of c-raf-1 message in peripheral blood mononuclear cells paralleled the clinical benefit in two patients. These findings demonstrate that ISIS 5132 specifically reduces target gene expression in treated patients and that peripheral blood mononuclear cells are suitable tissues for biomarker studies in future trials.




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