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Clinical candidate and genistein analogue AXP107-11 has chemoenhancing functions in pancreatic adenocarcinoma through G protein-coupled estrogen receptor signaling
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- Mesmar, Fahmi (författare)
- KTH,Proteinvetenskap,Science for Life Laboratory, SciLifeLab,Univ Houston, Dept Biol & Biochem, Ctr Nucl Receptors & Cell Signaling, Houston, TX USA;KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, S-17121 Solna, Sweden;Indiana Univ, Sch Informat Comp & Engn, Dept Intelligent Syst Engn, Bloomington, IN USA
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- Dai, Bingbing (författare)
- Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA.
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- Ibrahim, Ahmed (författare)
- KTH,Science for Life Laboratory, SciLifeLab,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, S-17121 Solna, Sweden
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- (creator_code:org_t)
- 2019-09-30
- 2019
- Engelska.
- Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 8:18, s. 7705-7719
- Tidskriftsartikel (refereegranskat)
Abstract
Ämnesord
Stäng
- Despite advances in cancer therapeutics, pancreatic cancer remains difficult to treat and often develops resistance to chemotherapies. We have evaluated a bioavailable genistein analogue, AXP107-11 which has completed phase Ib clinical trial, as an approach to sensitize tumor cells to chemotherapy. Using organotypic cultures of 14 patient-derived xenografts (PDX) of pancreatic ductal adenocarcinoma, we found that addition of AXP107-11 indeed sensitized 57% of cases to gemcitabine treatment. Results were validated using PDX models in vivo. Further, RNA-Seq from responsive and unresponsive tumors proposed a 41-gene treatment-predictive signature. Functional and molecular assays were performed in cell lines and demonstrated that the effect was synergistic. Transcriptome analysis indicated activation of G-protein-coupled estrogen receptor (GPER1) as the main underlying mechanism of action, which was corroborated using GPER1-selective agonists and antagonists. GPER1 expression in pancreatic tumors was indicative of survival, and our study proposes that activation of GPER1 may constitute a new avenue for pancreatic cancer therapeutics.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- AXP107-11
- chemoresistance
- genistein
- GPER1
- pancreatic ductal adenocarcinoma
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