Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewing's family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression

• Published in: Clinical cancer research Vol. 21; no. 5; pp. 1139 - 1150
• Main Authors: Kang, Min H, Wang, Jing, Makena, Monish R, Lee, Joo-Sang, Paz, Nancy, Hall, Connor P, Song, Michael M, Calderon, Ruben I, Cruz, Riza E, Hindle, Ashly, Ko, Winford, Fitzgerald, Jonathan B, Drummond, Daryl C, Triche, Timothy J, Reynolds, C Patrick
• Format: Journal Article
• Language: English
• Published: United States 01.03.2015
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Cell Line, Tumor; Disease Models, Animal; Drug Combinations; Female; Gene Expression; Humans; Irinotecan; Liposomes; Macrophages - immunology; Macrophages - pathology; Mice; Nuclear Proteins - genetics; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - genetics; Sarcoma, Ewing - mortality; Sarcoma, Ewing - pathology; Sucrose - administration & dosage; Sucrose - analogs & derivatives; Sucrose - pharmacokinetics; Tissue Distribution; Tumor Burden - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-1882

To determine the pharmacokinetics and the antitumor activity in pediatric cancer models of MM-398, a nanoliposomal irinotecan (nal-IRI). Mouse plasma and tissue pharmacokinetics of nal-IRI and the current clinical formulation of irinotecan were characterized. In vivo activity of irinotecan and nal-IRI was compared in xenograft models (3 each in nu/nu mice) of Ewing's sarcoma family of tumors (EFT), neuroblastoma (NB), and rhabdomyosarcoma (RMS). SLFN11 expression was assessed by Affymetrix HuEx arrays, Taqman RT-PCR, and immunoblotting. Plasma and tumor concentrations of irinotecan and SN-38 (active metabolite) were approximately 10-fold higher for nal-IRI than for irinotecan. Two doses of NAL-IRI (10 mg/kg/dose) achieved complete responses maintained for >100 days in 24 of 27 EFT-xenografted mice. Event-free survival for mice with RMS and NB was significantly shorter than for EFT. High SLFN11 expression has been reported to correlate with sensitivity to DNA damaging agents; median SLFN11 mRNA expression was >100-fold greater in both EFT cell lines and primary tumors compared with NB or RMS cell lines or primary tumors. Cytotoxicity of SN-38 inversely correlated with SLFN11 mRNA expression in 20 EFT cell lines. In pediatric solid tumor xenografts, nal-IRI demonstrated higher systemic and tumor exposures to SN-38 and improved antitumor activity compared with the current clinical formulation of irinotecan. Clinical studies of nal-IRI in pediatric solid tumors (especially EFT) and correlative studies to determine if SLFN11 expression can serve as a biomarker to predict nal-IRI clinical activity are warranted.