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Author Notes:

Correspondence: towonik@emory.edu.

Study design: TKO, ZC, SSR, FRK.

Patient enrolment on study: TKO, RMS, NFS, SP, RNP, SSR, FRK.

Tumor biopsy collection: GZ, TKO, HSK, RMS, RB.

Ex vivo experiments: TKO, GZ, GLS, XD, SS.

Genomic studies: MRR, GLS.

Data analysis and interpretation and manuscript writing: all authors.

The corresponding author had full access to the entire data and vouch for the integrity of the data presented in the manuscript.

We thank Anthea Hammond, Ph.D. for editorial assistance with proof reading the manuscript and helpful suggestion on data presentation.

ASO was generously provided free to all patients enrolled on study by Teva Pharmaceuticals. Teva Pharmaceuticals reviewed the draft manuscript.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

This study was supported in part by NIH/NCI 5K23CA164015 Grant award (PI: TK Owonikoko) and the Winship-Kennedy pilot Grant award from the Winship Cancer Institute of Emory University (PI: TK Owonikoko).

Research reported in this publication was also supported in part by the Biostatistics and Bioinformatics Shared resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292.

Keywords:

  • Life Sciences & Biomedicine
  • Research & Experimental Medicine
  • Small cell lung cancer
  • Arsenic trioxide
  • Clinical trial
  • Ex vivo
  • Patient-derived xenograft
  • Efficacy
  • Survival
  • ACUTE PROMYELOCYTIC LEUKEMIA
  • CISPLATIN TREATMENT
  • CARCINOMA-CELLS
  • CHEMOTHERAPY
  • EFFICACY
  • PHARMACOKINETICS
  • CYTOTOXICITY
  • RESISTANCE
  • RELEVANCE

Patient-derived xenografts faithfully replicated clinical outcome in a phase II co-clinical trial of arsenic trioxide in relapsed small cell lung cancer

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Journal Title:

Journal of Translational Medicine

Volume:

Volume 14, Number 1

Publisher:

, Pages 111-111

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: 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). Methods: 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 1-2h daily for 4days in week 1 and for 2days 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 (3mg/kg i.p. weekly) and ASO (3.75mg/kg i.p. every other day) was tested in PDX representative of platinum sensitive and platinum refractory SCLC. Results: 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. Conclusions: 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.

Copyright information:

© 2016 Owonikoko et al. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

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