title: Stromal disrupting effects of nab-paclitaxel in pancreatic cancer.
abstract: BACKGROUND
  Nab-paclitaxel and gemcitabine have demonstrated a survival benefit over gemcitabine alone in advanced pancreatic cancer (PDA). This study aimed to investigate the clinical, biological, and imaging effects of the regimen in patients with operable PDA.
  
  
  METHODS
  Patients with operable PDA received two cycles of nab-paclitaxel and gemcitabine before surgical resection. FDG-PET and CA19.9 tumour marker levels were used to measure clinical activity. Effects on tumour stroma were determined by endoscopic ultrasound (EUS) elastography. The collagen content and architecture as well as density of cancer-associated fibroblasts (CAFs) were determined in the resected surgical specimen and compared with a group of untreated and treated with conventional chemoradiation therapy controls. A co-clinical study in a mouse model of PDA was conducted to differentiate between the effects of nab-paclitaxel and gemcitabine.
  
  
  RESULTS
  A total of 16 patients were enrolled. Treatment resulted in significant antitumour effects with 50% of patients achieving a >75% decrease in circulating CA19.9 tumour marker and a response by FDG-PET. There was also a significant decrement in tumour stiffness as measured by EUS elastography. Seven of 12 patients who completed treatment and were operated had major pathological regressions. Analysis of residual tumours showed a marked disorganised collagen with a very low density of CAF, which was not observed in the untreated or conventionally treated control groups. The preclinical co-clinical study showed that these effects were specific of nab-paclitaxel and not gemcitabine.
  
  
  CONCLUSIONS
  These data suggest that nab-paclitaxel and gemcitabine decreases CAF content inducing a marked alteration in cancer stroma that results in tumour softening. This regimen should be studied in patients with operable PDA.
authors.affiliation: Centro Integral Oncológico Clara Campal, Oña 10, 28050 Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Alvarez
authors.forename: M
authors.initials: M
authors.lastname: Musteanu
authors.forename: E
authors.initials: E
authors.lastname: Garcia-Garcia
authors.forename: P P
authors.initials: PP
authors.lastname: Lopez-Casas
authors.forename: D
authors.initials: D
authors.lastname: Megias
authors.forename: C
authors.initials: C
authors.lastname: Guerra
authors.forename: M
authors.initials: M
authors.lastname: Muñoz
authors.forename: Y
authors.initials: Y
authors.lastname: Quijano
authors.forename: A
authors.initials: A
authors.lastname: Cubillo
authors.forename: J
authors.initials: J
authors.lastname: Rodriguez-Pascual
authors.forename: C
authors.initials: C
authors.lastname: Plaza
authors.forename: E
authors.initials: E
authors.lastname: de Vicente
authors.forename: S
authors.initials: S
authors.lastname: Prados
authors.forename: S
authors.initials: S
authors.lastname: Tabernero
authors.forename: M
authors.initials: M
authors.lastname: Barbacid
authors.forename: F
authors.initials: F
authors.lastname: Lopez-Rios
authors.forename: M
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018395:CA-19-9 Antigen / Q000097:blood; D003094:Collagen / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D054459:Elasticity Imaging Techniques; D019160:Endosonography; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D000093542:Gemcitabine
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D018395:CA-19-9 Antigen; D003841:Deoxycytidine; D003094:Collagen; D017239:Paclitaxel; D000093542:Gemcitabine
references.citation: Eur J Cancer. 2009 Jan;45(2):228-47
references.pmid: 19097774
references.citation: J Clin Oncol. 2011 Dec 1;29(34):4548-54
references.pmid: 21969517
references.citation: Ann Surg Oncol. 2012 May;19(5):1644-62
references.pmid: 22012027
references.citation: J Clin Oncol. 2007 Jan 20;25(3):319-25
references.pmid: 17235047
references.citation: Ann Surg Oncol. 2011 Dec;18(13):3601-7
references.pmid: 21947697
references.citation: Gastrointest Endosc. 2007 Jun;65(7):971-8
references.pmid: 17531630
references.citation: Cancer Discov. 2012 Mar;2(3):260-269
references.pmid: 22585996
references.citation: Clin Gastroenterol Hepatol. 2008 Oct;6(10):1155-61
references.pmid: 18639493
references.citation: Cancer Cell. 2012 Mar 20;21(3):418-29
references.pmid: 22439937
references.citation: Cancer Cell. 2011 Jun 14;19(6):728-39
references.pmid: 21665147
references.citation: Dis Model Mech. 2010 Jan-Feb;3(1-2):57-72
references.pmid: 20007485
references.citation: Mol Cancer Ther. 2007 Apr;6(4):1186-97
references.pmid: 17406031
references.citation: N Engl J Med. 2010 Apr 29;362(17):1605-17
references.pmid: 20427809
references.citation: Gastrointest Endosc. 2012 Nov;76(5):953-61
references.pmid: 22854060
references.citation: Histopathology. 2005 Aug;47(2):141-6
references.pmid: 16045774
references.citation: Science. 2009 Jun 12;324(5933):1457-61
references.pmid: 19460966
references.citation: Cancer Cell. 2009 Jul 7;16(1):7-8
references.pmid: 19573807
references.citation: Gut. 2013 Jan;62(1):112-20
references.pmid: 22466618
references.citation: Gastroenterology. 2010 Oct;139(4):1172-80
references.pmid: 20600020