Sirolimus plus gemcitabine: a new therapeutic combination for resistant sarcomas?

Abstract

Sarcomas are a rare family of heterogeneous tumors of mesenchymal origin characterized by their bad prognosis. In addition, limited active therapeutic options are available. The cytotoxic drug gemcitabine and the inhibition of the mTOR pathway have demonstrated modest activity in sarcomas as monotherapy. However, preclinical data suggest that the combination of both treatments results in enhanced antitumor activity. In vitro and in vivo experiments with the mTOR inhibitor sirolimus plus gemcitabine showed dramatic results in preclinical models of sarcoma. Moreover, a Phase I study demonstrated the favorable toxicity profile of the combination in patients with advanced solid tumors. Therefore, treatment with sirolimus plus gemcitabine deserves further investigation in sarcomas.

Keywords:

• gemcitabine
• rapamycin
• sirolimus
• soft tissue sarcoma

The term sarcoma comprises >50 different malignancies that share a mesenchymal origin. In the majority of cases, the prognosis of patients affected by these conditions is poor. Thus, the average median survival of advanced sarcoma patients is around 1 year [1]. A number of efforts have been made in the past decades to improve these poor outcomes, but no major successes have been achieved. Therefore, the finding of active novel therapeutic strategies in sarcomas is still an outstanding challenge in oncology. However, the encouraging signal of activity recently observed with the combination of the mTOR inhibitor sirolimus plus gemcitabine in preclinical models of sarcoma might represent an advance in the treatment of these malignancies [2].

Gemcitabine is a classic chemotherapeutic agent widely used in cancer [3]. Specifically in sarcomas, it has also demonstrated to be active although its efficacy as single agent is modest [4]. Nevertheless, it is generally a well-tolerated drug, which allows its combination with other agents. In recent years, some of those gemcitabine-containing treatments have achieved favorable results in sarcomas. For instance, Maki et al. reported a Phase II clinical trial in 2007 that assessed the combination of gemcitabine with docetaxel. Results showed that the doublet regimen was superior to gemcitabine alone in terms of progression-free survival (PFS) and overall survival (OS), with especially encouraging results in the leiomyosarcoma subgroup [5]. In addition, a study conducted by the French Sarcoma Group demonstrated that gemcitabine and docetaxel was an active second-line treatment for both uterine and nonuterine leiomyosarcomas [6]. More recently, García del Muro et al. compared treatment with gemcitabine plus dacarbazine versus dacarbazine alone in a randomized Phase II trial. The combination proved to be well tolerated and active: both PFS and OS were found to be clearly superior in the experimental arm [7]. These encouraging data suggest that the combination of gemcitabine with another cytotoxic agent may enhance its activity against sarcomas. But, is the combination of gemcitabine with targeted therapies safe and effective?

The mTOR pathway is a well-known signaling network frequently altered in cancer. Nearly 50% of all human tumors harbor abnormalities in some of its key effectors [8,9]. A large number or drugs able to inhibit mTOR have been developed and clinically assessed in different malignancies. In sarcomas, a randomized, placebo-controlled Phase III trial has demonstrated that the mTOR inhibitor ridaforolimus is able to delay tumor progression as maintenance therapy [10]. However, the benefit achieved was marginal (only 3 weeks of improvement in PFS), indicating that further strategies are needed. Is the combination of mTOR inhibitors with gemcitabine a rational approach in sarcomas? Preclinical data suggest so. Thus, Merimsky et al. reported that, in leiomyosarcoma cell lines, the combination of the mTOR inhibitor sirolimus with gemcitabine results in a dramatic effect in cell cycle [11]. Furthermore, a response has been seen in a patient affected by leiomyosarcoma treated with this therapeutic strategy [12]. These observations are consistent with several studies in epithelial tumors in which sirolimus plus gemcitabine are able to increase apoptosis in vitro and enhance antitumoral activity in vivo [13,14]. Such encouraging preliminary data led us to conduct a series of experiments in two cell lines representative of two of the most common soft-tissue sarcoma subtypes, leiomyosarcoma and synovial sarcoma. We found that the administration of gemcitabine and sirolimus resulted in higher cell death rate and activation of apoptosis compared with each drug alone. Moreover, we reported the striking finding that the mTOR pathway was activated as a result of the treatment with gemcitabine, which might represent a cellular mechanism of defence to the aggression of the cytotoxic drug. Interestingly, the activation of the mTOR pathway was inhibited when sirolimus was added [2]. To our knowledge, this was a novel observation never reported before.

In view of this strong preclinical rationale, we conducted a Phase I study to assess the tolerability of this combination, its efficacy in an in vivo model of leiomyosarcoma and to characterize its pharmacokinetic and pharmacodynamic properties [15]. The treatment had a favorable toxicity profile in patients affected by advanced solid tumors. Only three dose-limiting toxicities were observed from a total of 19 patients and the final recommended dose of daily oral sirolimus 5 mg continuously plus gemcitabine 800 mg/m² iv. at a fixed-dose rate of 10 mg/m²/min on days 1 and 8 of each 21-day cycle allowed administration of active doses of both agents. Moreover, pharmacokinetic analysis demonstrated no significant interactions between the drugs, and the pharmacodynamics confirmed that the mTOR pathway was successfully inhibited at the recommended dose. In addition, the in vivo experiment was also successful. Xenograft models of leiomyosarcoma were treated with gemcitabine and sirolimus, as well as both drugs alone. Tumor growth was dramatically inhibited with the combination, achieving much better results than with each drug in monotherapy. Therefore, the in vivo results confirmed our promising in vitro observations [2].

Given the good results in terms of toxicity and efficacy of the Phase I study, we conducted a single-arm Phase II trial to evaluate the activity of sirolimus plus gemcitabine in 28 previously treated advanced soft-tissue sarcoma patients. The primary endpoint was progression-free rate at 3 months, an European Organisation for Research and Treatment of Cancer recommended endpoint in these malignancies [16]. Provisional results showed that progression-free rates at 3 and 6 months was 44 and 20%, respectively. In terms of survival, median PFS was 1.85 months (95% CI: 0.7–2.9) and median OS was 9.1 months (95% CI: 6.1–12.2) [17]. Although they may seem modest, these preliminary results are positive as per the trial prespecified criteria and it is worth mentioning that the study was conducted in a heavily pretreated population, which might have negatively affected the outcomes.

Further investigation, both clinical and preclinical, on the combination of gemcitabine and sirolimus is needed. The clinical comparison of this treatment with other gemcitabine-containing regimens and the preclinical identification of predictive biomarkers that help to select those patients that might benefit from treatment are exciting lines of investigation. In a group of malignancies with such scarce treatment options, any therapeutic approach with a solid rationale should be exhaustively explored. In decades, only one new drug – the antiangiogenic compound pazopanib – has been licensed in both Europe and US for the treatment of soft-tissue sarcomas, except GIST [18]. Moreover, pazopanib is also the only targeted therapy available for patients with sarcoma, in spite of the revolution that targeted agents has meant in many other tumor types. Therefore, the alarming lack of active therapeutic alternatives makes the encouraging signal of activity of our combination worth exploring. Combination or sequential treatment with promising novel drugs that are currently under evaluation in sarcomas, such as targeted therapies or immunotherapeutic agents, might represent a therapeutic alternative in forthcoming years.

In summary, the encouraging preclinical rationale behind the combination of sirolimus and gemcitabine in sarcomas and its positive preliminary clinical results deserve further research to confirm its efficacy definitely. The success of this treatment would be an another good example of the close relationship that must be established between preclinical and clinical research to identify therapeutic targets and develop new efficient strategies against cancer.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.