Mechanisms underlying synergy between DNA topoisomerase I-targeted drugs and mTOR kinase inhibitors in NF1-associated malignant peripheral nerve sheath tumors

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas that frequently arise in patients with neurofibromatosis type 1 (NF1). Most of these tumors are unresectable at diagnosis and minimally responsive to conventional treatment, lending urgency to the identification of new pathway dependencies and drugs with potent antitumor activities. We therefore examined a series of candidate agents for their ability to induce apoptosis in MPNST cells arising in nf1/tp53-deficient zebrafish. In this study, we found that DNA topoisomerase I-targeted drugs and mTOR kinase inhibitors were the most effective single agents in eliminating MPNST cells without prohibitive toxicity. In addition, three members of these classes of drugs, either AZD2014 or INK128 in combination with irinotecan, acted synergistically to induce apoptosis both in vitro and in vivo. In mechanistic studies, irinotecan not only induces apoptosis by eliciting a DNA damage response, but also acts synergistically with AZD2014 to potentiate the hypophosphorylation of 4E-BP1, a downstream target of mTORC1. Profound hypophosphorylation of 4E-BP1 induced by this drug combination causes an arrest of protein synthesis, which potently induces tumor cell apoptosis. Our findings provide a compelling rationale for further in vivo evaluation of the combination of DNA topoisomerase I-targeted drugs and mTOR kinase inhibitors against these aggressive nerve sheath tumors.

suz12 inactivation in p53 and nf1 deficient zebrafish accelerates the onset of MPNSTs and expands the spectrum of tumor types to include adenocarcinoma, leukemia, and soft tissue sarcoma

“…In contrast, very little is known about the factors underlying the prognosis of soft tissue sarcomas. Our study suggests that loss of PRC2- Indeed, we observed an increased sensitivity against MEK-inhibition in suz12-mutant MPNSTs in the p53/nf1-deficient background, which adds up to previous observations on the effectivity of MEK-inhibition in MPNSTs (24,47), especially in cooperation with BRD4-inhibitor JQ1 (13). It has previous been described in the murine system that Suz12 acts as a tumor suppressor in Nf1-deficient but not in Nf1wildtype tumors (13), so that in combination with our findings this indicates that In mice, it is known that combined deficiencies in p53 and nf1 synergize in the onset of MPNSTs and high-grade gliomas and that the combined loss of Suz12 and Nf1 cooperate in the initiation of MPNST without loss of p53 (13).…”

“…This indicated a potentially increased vulnerability of p53 m/m , nf1b −/− , nf1a +/ − , suz12- mutant tumors towards pharmacological inhibition of this pathway. To test this hypothesis, we employed a previously described in vivo transplantation assay in living zebrafish embryos ( Ki et al, 2019 ). For this assay, single cells were isolated from two groups of matched MPNST tumors: (1) p53 m/m , nf1b −/− , nf1a +/− , suz12 -mutant MPNSTs and (2) p53 m/m , nf1b −/− , nf1a +/− , suz12 -wild-type MPNSTs.…”

“…In this study, we report the consequences of loss of suz12 in a p53/nf1 -deficient zebrafish tumor model that is suitable for drug testing ( Ki et al, 2019 ; Shin et al, 2012 ; Ki et al, 2017 ). In our model, we have assessed suz12 LOF-mediated carcinogenesis in a dose-dependent manner and translated our results based on current studies of human cancer genetics.…”

SFCE-RAPIRI Phase I Study of Rapamycin Plus Irinotecan: A New Way to Target Intra-Tumor Hypoxia in Pediatric Refractory Cancers

“…In fact, the presence of a low ADC mean value less than 1000 s 2 /m and the presence of p-mTor and HIF-1α hyperexpressions are warranted a tumor response or at least a stabilized disease. Nevertheless, recent publication might also provide new insight on how the irinotecan combined to mTor inhibitors would act independently from HIF-1α [49]. So, this patient profiling will be even more accurate in phase II trial to determine precisely the targets of this combination and understand their role in response.…”

“…Rapamycin intake was at the end of irinotecan infusion and maintained every day at the same scheduled time. Cefpodoxime (8 mg/kg/day BID orally) was administered transiently starting 2 days prior to the intra-venous irinotecan administration and stopped after 5 days [49]. All patients were expected to receive at least one 28-day cycle to be evaluable for the primary endpoint, which was the determination of the MTD.…”