title: Multimodal Treatment Eliminates Cancer Stem Cells and Leads to Long-Term Survival in Primary Human Pancreatic Cancer Tissue Xenografts.
abstract: In spite of intense research efforts, pancreatic ductal adenocarcinoma remains one of the most deadly malignancies in the world. We and others have previously identified a subpopulation of pancreatic cancer stem cells within the tumor as a critical therapeutic target and additionally shown that the tumor stroma represents not only a restrictive barrier for successful drug delivery, but also serves as a paracrine niche for cancer stem cells. Therefore, we embarked on a large-scale investigation on the effects of combining chemotherapy, hedgehog pathway inhibition, and mTOR inhibition in a preclinical mouse model of pancreatic cancer.
  
  
  
  Prospective and randomized testing in a set of almost 200 subcutaneous and orthotopic implanted whole-tissue primary human tumor xenografts.
  
  
  
  The combined targeting of highly chemoresistant cancer stem cells as well as their more differentiated progenies, together with abrogation of the tumor microenvironment by targeting the stroma and enhancing tissue penetration of the chemotherapeutic agent translated into significantly prolonged survival in preclinical models of human pancreatic cancer. Most pronounced therapeutic effects were observed in gemcitabine-resistant patient-derived tumors. Intriguingly, the proposed triple therapy approach could be further enhanced by using a PEGylated formulation of gemcitabine, which significantly increased its bioavailability and tissue penetration, resulting in a further improved overall outcome.
  
  
  
  This multimodal therapeutic strategy should be further explored in the clinical setting as its success may eventually improve the poor prognosis of patients with pancreatic ductal adenocarcinoma.
authors.affiliation: Stem Cells and Cancer Group, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Hermann
authors.forename: Sara M
authors.initials: SM
authors.lastname: Trabulo
authors.forename: Bruno
authors.initials: B
authors.lastname: Sainz
authors.forename: Anamaria
authors.initials: A
authors.lastname: Balic
authors.forename: Elena
authors.initials: E
authors.lastname: Garcia
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Hahn
authors.forename: Mallaredy
authors.initials: M
authors.lastname: Vandana
authors.forename: Sanjeeb K
authors.initials: SK
authors.lastname: Sahoo
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tunici
authors.forename: Annette
authors.initials: A
authors.lastname: Bakker
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D000093542:Gemcitabine