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.
OBJECTIVE
To determine the pharmacokinetics and the antitumor activity in pediatric cancer models of MM-398, a nanoliposomal irinotecan (nal-IRI).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Departments of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
Min H
MH
Kang
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Departments of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
Jing
J
Wang
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Departments of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
Monish R
MR
Makena
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Departments of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
Joo-Sang
JS
Lee
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Nancy
N
Paz
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Departments of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
Connor P
CP
Hall
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Departments of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
Michael M
MM
Song
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Departments of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
Ruben I
RI
Calderon
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Departments of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
Riza E
RE
Cruz
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Departments of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
Ashly
A
Hindle
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Departments of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
Winford
W
Ko
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Jonathan B
JB
Fitzgerald
Merrimack Pharmaceuticals, Cambridge, Massachusetts.
Daryl C
DC
Drummond
Department of Pathology Keck School of Medicine, University of Southern California, Los Angeles, California.
Timothy J
TJ
Triche
Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Departments of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas. Patrick.reynolds@ttuhsc.edu.
C Patrick
CP
Reynolds
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D015870:Gene Expression; D006801:Humans; D000077146:Irinotecan; D008081:Liposomes; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D013395:Sucrose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004338:Drug Combinations; D008081:Liposomes; D009687:Nuclear Proteins; C576668:SLFN11 protein, human; D013395:Sucrose; D000077146:Irinotecan; C584112:irinotecan sucrosofate; D002166:Camptothecin