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dc.contributor.authorCioffi, Men_US
dc.contributor.authorTrabulo, Sen_US
dc.contributor.authorHidalgo, Men_US
dc.contributor.authorCostello, Een_US
dc.contributor.authorGreenhalf, Wen_US
dc.contributor.authorErkan, Men_US
dc.contributor.authorKleeff, Jen_US
dc.contributor.authorSainz, Ben_US
dc.contributor.authorHeeschen, Cen_US
dc.description.abstractPURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a cancer of the exocrine pancreas with unmet medical need and is strongly promoted by tumor-associated macrophages (TAM). The presence of TAMs is associated with poor clinical outcome, and their overall role, therefore, appears to be protumorigenic. The "don't eat me" signal CD47 on cancer cells communicates to the signal regulatory protein-α on macrophages and prevents their phagocytosis. Thus, inhibition of CD47 may offer a new opportunity to turn TAMs against PDAC cells, including cancer stem cells (CSC), as the exclusively tumorigenic population. EXPERIMENTAL DESIGN: We studied in vitro and in vivo the effects of CD47 inhibition on CSCs using a large set of primary pancreatic cancer (stem) cells as well as xenografts of primary human PDAC tissue. RESULTS: CD47 was highly expressed on CSCs, but not on other nonmalignant cells in the pancreas. Targeting CD47 efficiently enhanced phagocytosis of a representative set of primary human pancreatic cancer (stem) cells and, even more intriguingly, also directly induced their apoptosis in the absence of macrophages during long-term inhibition of CD47. In patient-derived xenograft models, CD47 targeting alone did not result in relevant slowing of tumor growth, but the addition of gemcitabine or Abraxane resulted in sustained tumor regression and prevention of disease relapse long after discontinuation of treatment. CONCLUSIONS: These data are consistent with efficient in vivo targeting of CSCs, and strongly suggest that CD47 inhibition could be a novel adjuvant treatment strategy for PDAC independent of underlying and highly variable driver mutations.en_US
dc.format.extent2325 - 2337en_US
dc.relation.ispartofClin Cancer Resen_US
dc.subjectAntibodies, Monoclonal, Murine-Deriveden_US
dc.subjectAntineoplastic Agentsen_US
dc.subjectCD47 Antigenen_US
dc.subjectCarcinoma, Pancreatic Ductalen_US
dc.subjectCell Line, Tumoren_US
dc.subjectMice, Nudeen_US
dc.subjectNeoplastic Stem Cellsen_US
dc.subjectPancreatic Neoplasmsen_US
dc.subjectXenograft Model Antitumor Assaysen_US
dc.titleInhibition of CD47 Effectively Targets Pancreatic Cancer Stem Cells via Dual Mechanisms.en_US
pubs.notesNot knownen_US

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