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Mueller, M.T.* ; Hermann, P.C.* ; Witthauer, J.* ; Rubio-Viqueira, B.* ; Leicht, S.F.* ; Huber, S.* ; Ellwart, J.W. ; Mustafa, M.* ; Bartenstein, P.* ; D'Haese, J.G.* ; Schoenberg, M.H.* ; Berger, F.* ; Jauch, K.W.* ; Hidalgo, M.* ; Heeschen, C.*

Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer.

Gastroenterology 137, 1102-1113 (2009)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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 effectivety 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter endothelial growth-factor; tumor-growth; phase-ii; in-vivo; hedgehog; pathway; identification; gemcitabine; inhibition; expression
ISSN (print) / ISBN 0016-5085
e-ISSN 1528-0012
Zeitschrift Gastroenterology
Quellenangaben Band: 137, Heft: 3, Seiten: 1102-1113 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort Philadelphia
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Immunology (IMI)