Activity of irinotecan and the tyrosine kinase inhibitor CEP-751 in medullary thyroid cancer

Christopher J. Strock, Jong In Park, D. Marc Rosen, Bruce Ruggeri, Samuel R Denmeade, Douglas W Ball, Barry D Nelkin

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)79-84
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume91
Issue number1
DOIs
StatePublished - Jan 2006

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irinotecan
Protein-Tyrosine Kinases
Heterografts
S Phase Cell Cycle Checkpoints
CEP 751
Medullary Thyroid cancer
Cell culture

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Activity of irinotecan and the tyrosine kinase inhibitor CEP-751 in medullary thyroid cancer. / Strock, Christopher J.; Park, Jong In; Rosen, D. Marc; Ruggeri, Bruce; Denmeade, Samuel R; Ball, Douglas W; Nelkin, Barry D.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 91, No. 1, 01.2006, p. 79-84.

Research output: Contribution to journalArticle

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abstract = "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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