Evaluation of the mTOR inhibitor, everolimus, in combination with cytotoxic antitumor agents using human tumor models in vitro and in vivo

Abstract

The aim was to determine the potential of the allosteric mammalian target of rapamycin inhibitor, everolimus, to act in combination with cytotoxic anticancer compounds in vitro and in vivo. A concomitant combination in vitro showed no evidence of antagonism, but enhanced the antiproliferative effects (additive to synergistic) with cisplatin, doxorubicin, 5-fluorouracil, gemcitabine, paclitaxel, and patupilone. Everolimus (1-5 mg/kg/d orally) was evaluated for antitumor activity in vivo alone or in combination with suboptimal cytotoxic doses using athymic nude mice bearing subcutaneous human H-596 lung, KB-31 cervical, or HCT-116 colon tumor xenografts. Everolimus monotherapy was very well tolerated and caused inhibition of tumor growth, rather than regression, and this was associated with a dose-dependent decline in tumor pS6 levels, a key downstream protein of mammalian target of rapamycin. At the doses used, the cytotoxics inhibited tumor growth and caused tolerable body-weight loss. Concomitant combinations of cisplatin, doxorubicin, paclitaxel, or patupilone with everolimus produced cooperative antitumor effects, in some cases producing regressions without clinically significant increases in toxicity. In contrast, combinations with gemcitabine and 5-fluorouracil were less well tolerated. Alternative administration schedules were tested for cisplatin, gemcitabine, or paclitaxel combined with everolimus: these did not dramatically affect cisplatin or gemcitabine activity or tolerability but were antagonistic for paclitaxel. Everolimus showed promising maintenance activity after treatment with doxorubicin or paclitaxel ceased. Overall, the results confirm that everolimus is an effective, well-tolerated suppressor of experimental human tumor growth, and although it did not show strong potentiation of efficacy, antitumor activity in vivo was increased without marked increases in toxicity, supporting clinical use of everolimus as a partner for conventional cytotoxics.

Second-Line Treatment of Advanced Urothelial Cancer with Paclitaxel and Everolimus in a German Phase II Trial (AUO Trial AB 35/09)

“…Despite only marginal ORR, relevant disease control rates (27-51%) were likewise observed. Nevertheless, in spite of encouraging preclinical data showing synergistic effects by combining everolimus with paclitaxel, the results of our trial were below our expectations [8]. …”

“…In preclinical models, the efficacy of paclitaxel could be increased by the addition of everolimus [8]. Everolimus is an inhibitor of the PI3K/pAkt pathway targeting the serine/threonine kinase mTOR [9].…”

Autophagy as a mediator of chemotherapy-induced cell death in cancer

“…Everolimus indeed induces massive autophagy in vivo, with reduced tumoral mass, for example in leukemia [76], in advanced pancreatic tumors [77] and in many other tumors [78]. Concomitant combinations of etoposide, cisplatin or doxorubicin with everolimus produced cooperative antitumor effects, in some cases producing regressions without clinically significant increases in toxicity [79]. One mechanism responsible for this synergy is the activation of p53 by the DNA damaging agent.…”

Colorectal Cancers

“…While rapalogs display favorable characteristics in cell culture, such as induction of apoptosis and inhibition of proliferation, migration and invasion of CRC cells (Fujishita et al 2008;Gulhati et al 2011;O'Reilly et al 2011), their effectiveness as a stand-alone treatment in CRC patients has proved limited (Altomare and Hurwitz 2013;Ng et al 2013). However, preclinical studies have demonstrated cooperative antitumor effects using rapalogs in combination with cisplatin, doxorubicin or paclitaxel (O'Reilly et al 2011). There are currently several clinical trials assessing the efficacy of rapalogs in combinations with other chemotherapeutic drugs, especially in advanced CRCs or as a second-line treatment (see clinicaltrials.gov).…”

“…These compounds have received much attention in CRC, as various components of the mTOR pathway, including mTORC1, mTORC2, AKT1, AKT2 and others are elevated and/or activated in these cancers (Fujishita et al 2008;Gulhati et al 2011;Johnson et al 2010). While rapalogs display favorable characteristics in cell culture, such as induction of apoptosis and inhibition of proliferation, migration and invasion of CRC cells (Fujishita et al 2008;Gulhati et al 2011;O'Reilly et al 2011), their effectiveness as a stand-alone treatment in CRC patients has proved limited (Altomare and Hurwitz 2013;Ng et al 2013). However, preclinical studies have demonstrated cooperative antitumor effects using rapalogs in combination with cisplatin, doxorubicin or paclitaxel (O'Reilly et al 2011).…”