title: Improved response to nab-paclitaxel compared with cremophor-solubilized paclitaxel is independent of secreted protein acidic and rich in cysteine expression in non-small cell lung cancer.
abstract: BACKGROUND
  The secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that is produced by tumor and/or neighboring stroma. SPARC expression is thought to facilitate the intracellular accumulation of nanoparticle albumin-bound paclitaxel (nab-paclitaxel, abraxane [ABX]). Gene hypermethylation is a common mechanism for loss of SPARC expression in non-small cell lung cancer (NSCLC). We aim to demonstrate the role of SPARC expression as biomarker for treatment selection using ABX in NSCLC and to evaluate the presence of synergistic antitumor effect when a demethylating agent is combined with ABX.
  
  
  METHODS
  We analyzed the SPARC messenger RNA expression and SPARC gene methylation status in 13 NSCLC cell lines and 22 minimally passaged patient-derived (PD) NSCLC tumors using real-time (RT) polymerase chain reaction. The effect of ABX on tumor growth was compared with cremophor-solubilized paclitaxel (taxol) in severe combined immunodeficiency mice bearing SPARC-positive PD xenografts. The effect of pretreatment with a demethylating agent, 5-Aza-2'-deoxycytidine (DEC) in SPARC-negative tumors was assessed.
  
  
  RESULTS
  SPARC expression was weak to absent in 62% of established NSCLC cell lines and 68% of PD NSCLC tumor xenografts. SPARC expression could be up-regulated/restored by DEC treatment in both SPARC-negative cell lines and PD xenografts in vitro and in vivo. ABX demonstrated better antitumor efficacy than equitoxic dose of taxol in SPARC-expressing xenografts and some SPARC-negative xenografts. At equimolar doses in vitro, there was similar increased cytotoxicity on DEC pretreatment with either ABX or taxol in SPARC-negative cell lines. At equitoxic doses, there was similar additive antitumor activity of DEC with either ABX or taxol in SPARC-negative PD xenografts.
  
  
  CONCLUSIONS
  Endogenous SPARC status is somewhat uncorrelated with response to ABX in NSCLC. The greater antitumor effect of ABX compared with equitoxic dose of taxol observed in SPARC-expressing NSCLC tumors can also be seen in some SPARC-negative tumors. DEC pretreatment similarly enhanced antitumor activity with either ABX or taxol in SPARC-negative tumors.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Huanjie
authors.initials: H
authors.lastname: Shao
authors.forename: Haikuo
authors.initials: H
authors.lastname: Tang
authors.forename: Oreste E
authors.initials: OE
authors.lastname: Salavaggione
authors.forename: Chunrong
authors.initials: C
authors.lastname: Yu
authors.forename: Bonnie
authors.initials: B
authors.lastname: Hylander
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Repasky
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Grace K
authors.initials: GK
authors.lastname: Dy
mesh_terms: D000068196:Albumin-Bound Paclitaxel; D000418:Albumins / Q000627:therapeutic use; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism*; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000627:therapeutic use*; D011092:Polyethylene Glycols; D012333:RNA, Messenger / Q000378:metabolism; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D015676:Osteonectin; D012333:RNA, Messenger; C022131:cremophor; D011092:Polyethylene Glycols; D017239:Paclitaxel