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

• Authors: Taofeek Owonikoko, Emory University; Guojing Zhang, Emory University; Hyun S. Kim, Emory University; Renea M. Stinson, Emory University; Rabih Bechara, Emory University; Chao Zhang, Emory University; Georgia Chen, Emory University; Nabil Saba, Emory University; Suchita Pakkala, Emory University; Rathi Pillai, Emory University; Xingming Deng, Emory University; Shi-Yong Sun, Emory University; Michael Rossi, Emory University; Gabriel Sica, Emory University; Suresh Ramalingam, Emory University; Fadlo Khuri, Emory University
• Journal Title: Journal of Translational Medicine
• Volume: Volume 14, Number 1
• Publisher: BioMed Central | 2016-05-03, Pages 111-111
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/s12967-016-0861-5
• Subjects: Health Sciences, Oncology; Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery
• 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

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.