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Activity of Irinotecan and the Tyrosine Kinase Inhibitor CEP-751 in Medullary Thyroid Cancer

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (C.J.S., J.-I.P., D.M.R., S.R.D., D.W.B., B.D.N.) and Department of Medicine, Johns Hopkins University School of Medicine (D.W.B.), Baltimore, Maryland 21231; and Cephalon, Inc. (B.R.), West Chester, Pennsylvania 19380

Address all correspondence and requests for reprints to: Dr. Barry Nelkin, CRB, Room 552, 1650 Orleans Street, Baltimore, Maryland 21231. E-mail: bnelkin{at}jhmi.edu.

Context: Medullary thyroid cancer (MTC) is a cancer of the parafollicular C cells that commonly presents with an inherited or acquired RET gene mutation. There is currently no effective systemic treatment for MTC.

Objective: The objective of this study was to investigate a systemic therapeutic approach to treat MTC. We studied the sensitivity of an MTC cell line and xenograft to irinotecan, alone and in combination with the tyrosine kinase inhibitor, CEP-751.

Results: In TT cell culture and xenografts, irinotecan treatment was highly effective. This effect was augmented by treatment with CEP-751. Treatment of TT cell xenografts resulted in durable complete remission in 100% of the mice, with median time to recurrence of 70 d for irinotecan alone and more than 130 d for irinotecan plus CEP-751. Although irinotecan induced an S phase checkpoint arrest in TT cells, CEP-751 in combination with irinotecan resulted in a loss of this arrest. CEP-751 induced a loss in the induction of the DNA repair program marked by phospho-H2AX and the checkpoint pathway marked by the activated Chk1 pathway.

Conclusions: Irinotecan treatment was highly effective in a preclinical model of human MTC, resulting in complete remission in 100% of the xenografts treated. The duration of remission was further enhanced by combination with the kinase inhibitor, CEP-751. These results suggest that irinotecan, alone or in combination, may be useful for the treatment of MTC.

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