Activity of irinotecan and the tyrosine kinase inhibitor CEP-751 in medullary thyroid cancer.
BACKGROUND
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.
Strock
Christopher J
CJ
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
Park
Jong-In
JI
Rosen
D Marc
DM
Ruggeri
Bruce
B
Denmeade
Samuel R
SR
Ball
Douglas W
DW
Nelkin
Barry D
BD
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002227:Carbazoles / Q000627:therapeutic use*; D018276:Carcinoma, Medullary / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006657:Histones / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014183:Transplantation, Heterologous; D020687:cdc25 Phosphatases / Q000096:biosynthesis / Q000235:genetics
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; C107558:CEP 751; D002227:Carbazoles; D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D006657:Histones; D000077146:Irinotecan; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases; D002166:Camptothecin