title: Patient-derived xenografts faithfully replicated clinical outcome in a phase II co-clinical trial of arsenic trioxide in relapsed small cell lung cancer.
abstract: SCLC has limited treatment options and inadequate preclinical models. Promising activity of arsenic trioxide (ASO) recorded in conventional preclinical models of SCLC supported the clinical evaluation of ASO in patients. We assessed the efficacy of ASO in relapsed SCLC patients and in corresponding patient-derived xenografts (PDX).
  
  
  
  Single arm, Simon 2-stage, phase II trial to enroll patients with relapsed SCLC who have failed at least one line of therapy. ASO was administered as an intravenous infusion over 1-2 h daily for 4 days in week 1 and for 2 days in weeks 2-6 of an 8-week cycle. Treatment continued until disease progression. Pretreatment tumor biopsy was employed for PDX generation through direct implantation into subcutaneous pockets of SCID mice without in vitro manipulation and serially propagated for five generations. Ex vivo efficacy of cisplatin (3 mg/kg i.p. weekly) and ASO (3.75 mg/kg i.p. every other day) was tested in PDX representative of platinum sensitive and platinum refractory SCLC.
  
  
  
  The best response in 17 evaluable patients was stable disease in 2 (12 %), progressive disease in 15 (88 %) patients and median time-to-progression of seven (range 1-7) weeks. PDX was successfully grown in 5 of 9 (56 %) transplanted biopsy samples. Serially-propagated PDXs preserved characteristic small cell histology and genomic stability confirmed by immunohistochemistry, short tandem repeat (STR) profiling and targeted sequencing. ASO showed in vitro cytotoxicity but lacked in vivo efficacy against SCLC PDX tumor growth.
  
  
  
  Cisplatin inhibited growth of PDX derived from platinum-sensitive SCLC but was ineffective against PDX from platinum-refractory SCLC. Strong concordance between clinical and ex vivo effects of ASO and cisplatin in SCLC supports the use of PDX models to prescreen promising anticancer agents prior to clinical testing in SCLC patients. Trial Registration The study was registered at http://www.clinicaltrials.gov (NCT01470248).
authors.affiliation: Department of Hematology & Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365C Clifton Road, NE, Suite C3080, Atlanta, GA, 30322, USA. towonik@emory.edu.
authors.forename: Taofeek K
authors.identifier: 0000-0002-7724-7728
authors.initials: TK
authors.lastname: Owonikoko
authors.affiliation: Department of Hematology & Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365C Clifton Road, NE, Suite C3080, Atlanta, GA, 30322, USA.
authors.forename: Guojing
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Radiology, Division of Interventional Radiology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, 30322, USA.
authors.forename: Hyun S
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Winship Cancer Institute, Atlanta, GA, 30322, USA.
authors.forename: Renea M
authors.initials: RM
authors.lastname: Stinson
authors.affiliation: Department of Medicine, Division of Interventional Pulmonology, Winship Cancer Institute, Atlanta, GA, 30322, USA.
authors.forename: Rabih
authors.initials: R
authors.lastname: Bechara
authors.affiliation: Department of Biostatistics, Rollins School of Public Health and Biostatistics Shared Resource, Winship Cancer Institute, Atlanta, GA, 30322, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics, Rollins School of Public Health and Biostatistics Shared Resource, Winship Cancer Institute, Atlanta, GA, 30322, USA.
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Hematology & Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365C Clifton Road, NE, Suite C3080, Atlanta, GA, 30322, USA.
authors.forename: Nabil F
authors.initials: NF
authors.lastname: Saba
authors.affiliation: Department of Hematology & Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365C Clifton Road, NE, Suite C3080, Atlanta, GA, 30322, USA.
authors.forename: Suchita
authors.initials: S
authors.lastname: Pakkala
authors.affiliation: Department of Hematology & Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365C Clifton Road, NE, Suite C3080, Atlanta, GA, 30322, USA.
authors.forename: Rathi
authors.initials: R
authors.lastname: Pillai
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Atlanta, GA, 30322, USA.
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Hematology & Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365C Clifton Road, NE, Suite C3080, Atlanta, GA, 30322, USA.
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
authors.affiliation: Department of Radiation Oncology, Winship Cancer Institute, Atlanta, GA, 30322, USA.|Department of Pathology, Winship Cancer Institute, Atlanta, GA, 30322, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rossi
authors.affiliation: Department of Pathology, Winship Cancer Institute, Atlanta, GA, 30322, USA.
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Sica
authors.affiliation: Department of Hematology & Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365C Clifton Road, NE, Suite C3080, Atlanta, GA, 30322, USA.
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.affiliation: Department of Hematology & Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, 1365C Clifton Road, NE, Suite C3080, Atlanta, GA, 30322, USA.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D004586:Electrophoresis; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D016513:Mice, SCID; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010087:Oxides / Q000009:adverse effects / Q000627:therapeutic use*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy*; D040521:Subcutaneous Tissue / Q000473:pathology; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D001152:Arsenicals; D010087:Oxides; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin; D000077237:Arsenic Trioxide
keywords: Arsenic trioxide; Clinical trial; Efficacy; Ex vivo; Patient-derived xenograft; Small cell lung cancer; Survival