mTOR inhibitors in advanced renal cell carcinomas: From biology to clinical practice
Introduction
In 2008, about 88,400 new cases of renal cell carcinoma (RCC) occurred in Europe, making it the 10th most common cancer [1]. During last decades, this incidence has constantly increased. At the time of diagnosis, more than 10% of RCC are metastatic [1]. For a long time, metastatic RCC (mRCC) has been considered as resistant to the majority of treatments resulting in a poor outcome. Since 2006, the better knowledge of the biological mechanism of RCC led to the development of novel agents targeting hypoxia inducible factor (HIF)/vascular endothelial growth factor (VEGF) pathways, as well as mammalian target of rapamycin (mTOR) pathway that are both involved in renal cell carcinogenesis. These new agents include tyrosine kinase inhibitors (TKI) targeting the VEGF receptors (VEGF-R) (axitinib, pazopanib, sorafenib, sunitinib, tivozanib); monoclonal antibodies directed against the VEGF (bevacizumab); and mTOR inhibitors (everolimus, temsirolimus) [2].
Angiogenesis is the main pathway playing an important role in invasion and dissemination of RCC. Angiogenesis is mediated by numerous pro-angiogenic factors, including the VEGF considered as the cornerstone of this process [3], and the deletion of the von Hippel Lindau (VHL) gene is the most common genomic event in clear-cell carcinomas, which represents 75% of RCCs [4], [5]. mTOR is a highly conserved serine–threonine kinase and a key regulatory protein in cancer that recognizes stress signals via the phosphoinositide 3-kinase (PI3K)–Akt pathway. The activation of the PI3K/Akt/mTOR pathway is crucial for proliferation and survival of numerous malignancies including RCC. Signals from growth factor receptors activate PI3K, resulting in Akt activation and, finally, activation of the centrally located downstream mTOR (Fig. 1). It has been demonstrated that Akt, mTOR, and p70S6K1 are phosphorylated (activated) in most cancer types. These data suggest that mTOR might be a promising target in cancer treatment [6], [7]. Several arguments highlight an important role of mTOR as element participating in the pro-mitogen transduction of the signal: mTOR and PI3K proteins are essential for the activity of VEGF on proliferation, survival and migration of endothelial cells [8]. The blocking of this pathway would prevent the action of VEGF and consequently the cell proliferation. The mTOR protein regulates the expression of the HIF1-α and HIF2-α, thus linking the mTOR pathway to angiogenesis [9]. The mTOR inhibitors, by decreasing the expression of the HIF, act on the tumor angiogenesis. Direct signs of activation increased by the Akt/mTOR/p70S6K1 pathway were observed in RCC [10].
To date, everolimus and temsirolimus are both registered for the treatment of mRCC. According to the REnal Cell Cancer Treatment with Oral Rad001 (RECORD-1) pivotal study, oral everolimus is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF-targeted therapy [11], [12]. As regards temsirolimus, the Global Advanced Renal Cell Carcinoma (ARCC) pivotal study demonstrated the superiority of intravenous (IV) temsirolimus over interferon alpha (IFN-α) for the first-line treatment of patients with poor prognosis mRCC [13].
The purpose of this article is to summarize the main pharmacological and pharmacokinetic characteristics of mTOR inhibitors, to define targeted populations according to prognostic indexes, to refine indications according to the results of the studies as well as patient's profile such as histological characteristics, safety and comorbidities. In terms of future directions, some topics such as mechanisms of resistance, predictive factors of response to mTOR inhibitors and, thereby, clinical trials to conduct require to go further.
Section snippets
Biological action: the mTOR signaling network
The mTOR signaling pathway was first identified during studies exploring the immunosuppressive activity of an agent called rapamycin. Rapamycin, also named sirolimus, was originally identified as a natural antifungal antibiotic isolated from the bacteria Streptomyces hygroscopicus in the 1970s [14], [15]. Due to its ability to potently inhibit T-cell function, rapamycin was initially mainly used as an immunosuppressant in recipients of solid organ transplantation [16], but subsequently was
Who to treat?
Temsirolimus is indicated for the first-line treatment of patients with poor prognosis mRCC whereas oral everolimus is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF-targeted therapy [11], [12], [13]. Today, how can we define a poor prognosis in the era of antiangiogenic therapy, and, thereby, identify patients eligible for temsirolimus as first-line treatment of mRCC?
At the beginning of the 21st century,
Temsirolimus
Promising results in phase I studies led to a dedicated phase II trial in heavily pretreated mRCC, showing an overall response rate (ORR) of 7%, a median progression-free survival (PFS) of 5.8 months, and a median overall survival (OS) of 15 months [41]. Although efficacy results were comparable among the three tested doses (25, 75 or 250 mg weekly), dose reductions and treatment discontinuations were more frequent at higher doses. A subgroup analysis by MSKCC risk group demonstrated greater
The safety as referee
If efficacy data resulting from numerous randomized trials provided arguments for the selection of a first-line treatment, safety and characteristics of patients remain a crucial point for treatment choice. Sequential treatments represent an opportunity to improve the PFS. However, sequential treatments highlight the need for treating and preventing drug-related toxicities in order to maintain compliance and QoL.
Conclusions
Guidelines for the treatment of mRCC are rapidly evolving to incorporate the new targeted therapies that have been approved by US and European regulatory authorities. The National Comprehensive Cancer Network (NCCN) guidelines were revised as of October 2009 (version 2.2010) and the European Association of Urology (EAU) were updated in April 2010 [77]. Interestingly, the NCCN guidelines take into account the histologic subtype as a discretionary factor for the choice of a first-line treatment.
Reviewers
Sylvie Negrier, MD PhD, Leon Berard Center, INSERM U590, Cytokines and Cancer Research Unit, Medical Oncology Dept., Lyon cédex, F-69373, France.
Alain Ravaud, MD PhD, Hôpital Saint André, CHU de Bordeaux, 1 Rue Jean Burguet, F-33075 Bordeaux Cedex, France.
Conflict of interest statement
Philippe Barthélémy received honoraria from Novartis, Pfizer, Roche; Benjamin Hoch was an advisor for Sanofi-Aventis and Pfizer; Christine Chevreau was an advisor for Pfizer, Novartis, and Bayer Healthcare; Florence Joly was an advisor for Pfizer, Novartis, Sanofi-Aventis, Roche and Janssen; Brigitte Laguerre received honoraria from Pfizer and Novartis; François Lokiec received honoraria from OTD, ADIR, Pfizer and Novartis; Brigitte Duclos received honoraria from Novartis, Pfizer, Bayer
Acknowledgments
Isabelle Chapelle-Marcillac provided editorial assistance in the preparation of the manuscript.
Philippe Barthélémy MD, is currently medical oncologist at the University Hospital of Strasbourg, France. He was graduated in Medicine at the University of Strasbourg in 2009. His main research interests are translational research in breast cancer and urologic tumors. He actively participates in clinical trials, translational research and cooperative groups mainly in breast cancer and urologic tumors.
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Cited by (0)
Philippe Barthélémy MD, is currently medical oncologist at the University Hospital of Strasbourg, France. He was graduated in Medicine at the University of Strasbourg in 2009. His main research interests are translational research in breast cancer and urologic tumors. He actively participates in clinical trials, translational research and cooperative groups mainly in breast cancer and urologic tumors.
Benjamin Hoch MD, is medical oncologist, in the Centre Azuréen de Cancérologie (Mougins, France) and in the Anticancer Centre Antoine Lacassagne Nice, France. He actively participates in urological, and breast cancer clinical trials.
Christine Chevreau MD, is medical oncologist in Institut Claudius Régaud in Toulouse, France. She is in charge of the sarcoma committee in her institution. Her clinical areas of interest are urology, sarcoma and the treatment of AYA (adolescent and young adults). She actively participates in multiples clinical trials and cooperative groups. She is a member of ASCO, EORTC, Unicancer (GETUG, GSF-GETO).
Florence Joly MD, PhD is medical oncologist and head of the clinical research department of Centre Francois Baclesse, in Caen. She coordinates research programs in the Cancer and prevention INSERM Unite U 1086, Caen (quality of life and cancer) and in the North West Canceropole (Cognition and Cancer). Part of her training was done at Toronto, Princess Margaret Hospital (Canada). Her clinical areas of interest are urology and gynecology, and she participates in multiple clinical trials and cooperative groups. Florence Joly is a member of ASCO, EORTC, ESMO, Unicancer, GETUG, French GINECO and she is the chair of the symptom benefit group of the GCIG (Gynecological Cancer Intergroup).
Brigitte Laguerre MD, is medical oncologist in the Department of Medical Oncology at Centre Eugene Marquis in Rennes, France. She actively participates in phase II and III clinical trials concerning urologic cancer, head and neck cancer, breast and gynecologic cancers. Brigitte Laguerre is a member of the French Federation of Cancer Centers, and actively participates in cooperative French groups such as French Genito-Urinary Tumor Group (GETUG) and GORTEC.
François Lokiec PhD ScD is the head of the Department of Radio-Pharmacology at the Curie Institute-René Huguenin Hospital. He is mainly involved in the pharmacological approach (conventional and population pharmacokinetics) for early clinical trials in new drug development and drug combinations (Phase 0, Phase I and Phase II). François Lokiec is a member of AACR, ASCO, EORTC and French Federation of Cancer Centers.
Brigitte Duclos MD is medical oncologist in the Department of Oncology and Hematology of the Strasbourg University Hospitals in Strasbourg. Her clinical area of interest is mainly urology, and she participates in multiples trials and cooperative groups. Brigitte Duclos is member of SF, EORTC, Unicancer Group: GETUG and GSF-GETO.