title: Translational impact of nanoparticle-drug conjugate CRLX101 with or without bevacizumab in advanced ovarian cancer.
abstract: OBJECTIVE
  Increased tumor hypoxia and hence elevated hypoxia-inducible factor-1α (HIF1α) is thought to limit the efficacy of vascular endothelial growth factor (VEGF) pathway-targeting drugs by upregulating adaptive resistance genes. One strategy to counteract this is to combine antiangiogenic drugs with agents able to suppress HIF1α. One such possibility is the investigational drug CRLX101, a nanoparticle-drug conjugate (NDC) containing the payload camptothecin, a known topoisomerase-I poison.
  
  
  METHODS
  CRLX101 was evaluated both as a monotherapy and combination with bevacizumab in a preclinical mouse model of advanced metastatic ovarian cancer. These preclinical studies contributed to the rationale for undertaking a phase II clinical study to evaluate CRLX101 monotherapy in patients with advanced platinum-resistant ovarian cancer.
  
  
  RESULTS
  Preclinically, CRLX101 is highly efficacious as a monotherapy when administered at maximum-tolerated doses. Furthermore, chronic low-dose CRLX101 with bevacizumab reduced bevacizumab-induced HIF1α upregulation and resulted in synergistic efficacy, with minimal toxicity in mice. In parallel, initial data reported here from an ongoing phase II clinical study of CRLX101 monotherapy shows measurable tumor reductions in 74% of patients and a 16% RECIST response rate to date.
  
  
  CONCLUSIONS
  Given these preclinical and initial clinical results, further clinical studies are currently evaluating CRLX101 in combination with bevacizumab in ovarian cancer and warrant the evaluation of this therapy combination in other cancer types where HIF1α is implicated in pathogenesis, as it may potentially be able to improve the efficacy of antiangiogenic drugs.
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pham
authors.affiliation: Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.affiliation: Cerulean Pharma Inc., Cambridge, Massachusetts.
authors.forename: Scott
authors.initials: S
authors.lastname: Eliasof
authors.affiliation: Cerulean Pharma Inc., Cambridge, Massachusetts.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Garmey
authors.affiliation: Cerulean Pharma Inc., Cambridge, Massachusetts.
authors.forename: Douglas
authors.initials: D
authors.lastname: Lazarus
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Lee
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Shan
authors.initials: S
authors.lastname: Man
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.affiliation: Cerulean Pharma Inc., Cambridge, Massachusetts.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Peters
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.affiliation: Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, Boston, Massachusetts. robert.kerbel@sri.utoronto.ca cndrasner@partners.org.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Krasner
authors.affiliation: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. robert.kerbel@sri.utoronto.ca cndrasner@partners.org.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects; D003505:Cyclodextrins / Q000008:administration & dosage* / Q000009:adverse effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D053758:Nanoparticles / Q000008:administration & dosage* / Q000009:adverse effects; D010051:Ovarian Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D003505:Cyclodextrins; C542292:IT-101; D000068258:Bevacizumab; D002166:Camptothecin