BACKGROUND & AIMS:: Pancreatic cancers contain exclusively tumorigenic cancer stem cells (CSC), which are highly resistant to chemotherapy, resulting in a relative increase in CSC numbers during gemcitabine treatment. Signaling through sonic hedgehog and 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 a 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 CSC 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 CSC. 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.[Thanks to Alexey Bersenev].
Wednesday, June 10, 2009
Combined treatment to eliminate CSC in pancreatic cancer
Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer by Maria-Theresa Mueller and 13 co-authors, including Christopher Heeschen, Gastroenterology 2009(Jun 4). PubMed Abstract: