Abstract
BackgroundWell-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) are characterized by a consistent amplification of the MDM2 gene. The PI3K/AKT/mTOR pathway has been suggested to play also an important role in their tumorigenesis. Our goal was to determine whether combined MDM2 and PI3K/AKT/mTOR targeting is associated with higher anti-tumor activity than single agent alone in preclinical models of WDLPS/DDLPS.MethodsWDLPS/DDLPS cells were exposed to RG7388 (MDM2 antagonist) and BEZ235 (PI3K/mTOR dual inhibitor) after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis. Xenograft mouse models were used to assess tumor growth and animal survival. Western blotting, histopathology, and tumor volume evolution were used for the assessment of treatment efficacy.ResultsThe PI3K/AKT/mTOR was upregulated in up to 81% of the human WDLPS/DDLPS samples analysed. Treatment with RG7388 and BEZ235 resulted in a greater tumor activity than either drug alone with a significant difference in terms of cell viability after 72h of treatment with RG-73888 alone, BEZ235 alone and a combination of both agents. Consistent with these observations, we found a significant increase in apoptosis with the combination versus the single agent treatment alone. We then analysed the in vivo antitumor activity of RG7388 and BEZ235 in a xenograft model of DDLPS. The combination regimen significantly reduced tumor growth rate in comparison with single agent alone.ConclusionsOur results represent the first in vivo evidence of synergy between MDM2 and PI3K/AKT/mTOR antagonists and represent a strong rationale to evaluate the therapeutic potential of such a combination in WDLPS/DDLPS.
Highlights
Accounting for up to 25% of all sarcomas in adults [1], liposarcoma (LPS) is the most common soft tissue sarcoma (STS)
We report here a study which aims at determining whether targeting both MDM2-TP53 interaction and PI3K/AKT/mTOR pathways is associated with synergistic activity in WDLPS/DDLPS
To test whether the PI3K/AKT/mTOR pathway is altered in human WDLPS/DDLPS, we performed immunohistochemical analysis to evaluate the expression of PTEN, a negative regulator of AKT, and of protein S6 kinase (p-S6K), one crucial downstream target of mTORC1 on clinical specimens from 37 patients with well-differentiated (n=10) and dedifferentiated liposarcomas (n=27)
Summary
Accounting for up to 25% of all sarcomas in adults [1], liposarcoma (LPS) is the most common soft tissue sarcoma (STS). The three main locations are the limbs (50%), the retroperitoneum (30%) and the paratesticular area (20%) These tumors do not metastasize, retroperitoneal and paratesticular ones are associated with a high risk of local recurrence (up to 90%) and a high a risk of dedifferentiation (up to 20%) [2, 3] whereas these risks are lower for tumors located in the limbs [4]. About 90% of DDLPS arise de novo, while 10% occur in recurrence This histological subtype is found mostly in the retroperitoneum [3, 5] and has a more aggressive behavior than WDLPS with an estimated 5-year disease-specific-survival of 44% versus 93% [6]. Our goal was to determine whether combined MDM2 and PI3K/AKT/ mTOR targeting is associated with higher anti-tumor activity than single agent alone in preclinical models of WDLPS/DDLPS
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