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

Abstract

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

Mcl-1 downregulation leads to the heightened sensitivity exhibited by BCR-ABL positive ALL to induction of energy and ER-stress

“…Recently, the antiapoptotic protein Mcl-1 was shown to be required for cell survival in BCR-ABL+ leukemia [11], and to play a role in the survival of ALL [12, 13], CML [15], hematopoietic stem cells [35], T-lymphocytes [36], and plasma cells [37]. Herein, we demonstrate that Mcl-1 plays a crucial role in the survival of BCR-ABL+ ALL cells undergoing energy/ER-stress.…”

Reactive Oxygen Species–Mediated Synergism of Fenretinide and Romidepsin in Preclinical Models of T-cell Lymphoid Malignancies

“…1,500 mm 3 ; ref. 33). In case of weight loss or dehydration, mice were given 0.5 mL of 5% sterile glucose water.…”

Watching the gorilla and questioning delivery dogma

“…In this respect, it is important to recognize that the two liposomal doxorubicin preparations marketed for the treatment of cancer (Doxil ® , Myocet ® ) differ markedly in their circulation half-life, but exhibit comparable efficacy [36]. Another clinically approved liposomal product, Onivyde ® (liposomal irinotecan) is non-PEGylated and is not designed to exploit the EPR effect [37]. As previously noted, prolonged circulation can also induce other toxicities that are not seen in formulations with short circulation half-lives [18, 19, 27, 38].…”