Antitumor Activity of Ridaforolimus and Potential Cell-Cycle Determinants of Sensitivity in Sarcoma and Endometrial Cancer Models

Abstract

Ridaforolimus is a nonprodrug rapamycin analogue that potently inhibits mTOR and has shown significant activity in patients with metastatic sarcoma and endometrial cancer, two diseases where high unmet need remains. Here, we evaluated the activity of ridaforolimus in preclinical models of these tumor types and used these models to explore molecular correlates of sensitivity. The in vitro sensitivity of a panel of sarcoma and endometrial cancer cell lines was established by measuring the effect of ridaforolimus on cell proliferation rate, revealing broad inhibition at low nanomolar concentrations. Additional benefit was found when ridaforolimus was combined with agents used to treat sarcoma and endometrial cancer patients. In vivo, potent antitumor activity of ridaforolimus associated with inhibition of mTOR signaling was observed in sarcoma and endometrial xenograft models. Immunoblot analysis was conducted to assess the expression and activation state of multiple signaling proteins in the phosphoinositide-3-kinase/AKT/mTOR and cell-cycle pathways. In endometrial but not sarcoma cell lines, the absence of PTEN or elevated levels of phosphorylated or total AKT was associated with greater sensitivity. However, in both tumor types, the proportion of cells in the G 0 -G 1 phase before treatment correlated significantly with ridaforolimus sensitivity. Consistent with this, expression of several G 1 phase cell-cycle proteins, notably p21 and p27, was higher in more sensitive lines. These results underscore the promise of ridaforolimus as a single agent or combination treatment of these tumor types and suggest novel potential predictive biomarkers of sensitivity to an mTOR inhibitor based on cell-cycle status. Mol Cancer Ther; 10(10); 1959-68. Ó2011 AACR.

The PI3K/AKT/mTOR Pathway as a Therapeutic Target in Endometrial Cancer

“…Furthermore, everolimus reduced progression of endometrial hyperplasia in a PTEN heterozygous mouse model (31), and repressed tumor growth in mouse xenograft models harboring endometrial cancer cells with loss of PTEN and/or PIK3CA mutations (32). Consistent with these findings, ridaforolimus also showed antitumor activity in endometrial cancer cells and a mouse xenograft model, with greatest sensitivity observed in cells with loss of PTEN or increased phosphorylated or total AKT (33). In patients with recurrent and/or metastatic endometrial cancer, single-agent treatment with everolimus, temsirolimus, and ridaforolimus has led to clinical benefit rates of 21% (34), 52% to 83% (35), and 33% to 66% (36,37), respectively.…”

Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors

“…A deeply situated tumor is often difficult to resect completely and is one of the factors in poor prognosis for MPNSTs. This finding implies that a deeply situated MPNST should be a good candidate for an AKT/mTOR inhibitor, because elevated p-AKT was associated with greater sensitivity for mTOR inhibitor in an endometrial cancer model (47). 4E-BP1 and ERK1/2 activation was associated with both high-mitotic counts and high-histologic grade.…”

A Phase I Trial of Combined Ridaforolimus and MK-2206 in Patients with Advanced Malignancies

“…Ridaforolimus, a non-prodrug analogue of rapamycin that inhibits mTOR, has demonstrated antiproliferative activity in a broad range of human tumor cell lines in vitro and in murine tumor xenograft models (10)(11)(12)(13). Ridaforolimus has been evaluated as single-agent or combination therapy for pediatric and adult patients with advanced malignancies by both the intravenous and oral routes of administration (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”