Abstract：
BACKGROUND & AIMS:Pancreatic cancers contain exclusively tumorigenic cancer stem cells (CSCs), which are highly resistant to chemotherapy, resulting in a relative increase in CSC numbers during gemcitabine treatment. Signaling through sonic hedgehog and mammalian target of rapamycin (mTOR), respectively, may be essential for CSC self-renewal and could represent putative targets for novel treatment modalities. METHODS:We used in vitro and in vivo models of pancreatic cancer to examine the effects of sonic hedgehog inhibition (cyclopamine/CUR199691) and mTOR blockade (rapamycin) on the tumorigenic CSC population. RESULTS:Surprisingly, neither cyclopamine nor rapamycin alone or as supplements to chemotherapy were capable of effectively diminishing the CSC pool. Only the combined inhibition of both pathways together with chemotherapy reduced the number of CSCs to virtually undetectable levels in vitro and in vivo. Most importantly, in vivo administration of this triple combination in mice with established patient-derived pancreatic tumors was reasonably tolerated and translated into significantly prolonged long-term survival. CONCLUSIONS:The combined blockade of sonic hedgehog and mTOR signaling together with standard chemotherapy is capable of eliminating pancreatic CSCs. Further preclinical investigation of this promising approach may lead to the development of a novel therapeutic strategy to improve the devastating prognosis of patients with pancreatic cancer.
journal_name
Gastroenterologyjournal_title
Gastroenterologyauthors
Mueller MT,Hermann PC,Witthauer J,Rubio-Viqueira B,Leicht SF,Huber S,Ellwart JW,Mustafa M,Bartenstein P,D'Haese JG,Schoenberg MH,Berger F,Jauch KW,Hidalgo M,Heeschen Cdoi
10.1053/j.gastro.2009.05.053subject
Has Abstractpub_date
2009-09-01 00:00:00pages
1102-13issue
3eissn
0016-5085issn
1528-0012pii
S0016-5085(09)00901-9journal_volume
137pub_type
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