Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer.
OBJECTIVE
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.
Mueller
Maria-Theresa
MT
Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Hermann
Patrick C
PC
Witthauer
Juliane
J
Rubio-Viqueira
Belen
B
Leicht
Simon F
SF
Huber
Stephan
S
Ellwart
Joachim W
JW
Mustafa
Mona
M
Bartenstein
Peter
P
D'Haese
Jan G
JG
Schoenberg
Michael H
MH
Berger
Frank
F
Jauch
Karl-Walter
KW
Hidalgo
Manuel
M
Heeschen
Christopher
C
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000093542:Gemcitabine
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D053823:Hedgehog Proteins; D010455:Peptides; D014704:Veratrum Alkaloids; D003841:Deoxycytidine; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; C000541:cyclopamine; D000093542:Gemcitabine