Cancer Chemother Pharmacol DOI 10.1007/s00280-015-2770-3
REVIEW ARTICLE
Targeted therapies for treatment of renal cell carcinoma: recent advances and future perspectives Joan Minguet1,2 · Katherine H. Smith1 · Carsten P. Bramlage2 · Peter Bramlage1,2
Received: 25 February 2015 / Accepted: 5 May 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose A wide variety of targeted therapies are available for the treatment of renal cancer that has progressed beyond the point at which surgery is a viable option. In addition, there are many more that are in the different stages of clinical trials. Here, we provide a methodical discussion of the efficacy and safety of targeted therapies for the treatment of advanced renal cell carcinoma. Methods We conducted a systematic literature employing the search terms: renal cell carcinoma targets, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and each of the drugs discussed within these papers. Results The identified targeted therapies work by disrupting specific signalling pathways involved in tumour progression, such as those responsible for angiogenesis and cell proliferation. Tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are now established classes of drugs used in the treatment of renal cancer, with a total of six having received regulatory approval to date (sorafenib, sunitinib, pazopanib, axitinib, temsirolimus, and everolimus). Ongoing trials are likely to result in addition
* Joan Minguet [email protected] Katherine H. Smith [email protected] Carsten P. Bramlage [email protected] Peter Bramlage [email protected] 1
European Institute of Cancer Research (EICR), Carrer del Passeig, 2, 08221 Terrassa, Spain
2
Institute of Pharmacology and Preventive Medicine (IPPMED), Bahnhofstr. 20, 49661 Cloppenburg, Germany
to these in the near future, for example, tivozanib, dovitinib, and cediranib. Furthermore, in addition to these small molecule drugs, immunotherapies involving monoclonal antibodies against signalling molecules such as vascular endothelial growth factor (bevacizumab) or programmed death-1 (nivolumab) are receiving increasing attention. Conclusions Targeted therapies have great potential for disrupting tumour progression by inhibiting certain signalling pathways. As our understanding of the biochemical pathways involved in cancer progresses, additional targets are certain to become apparent, expanding treatment options even further. Keywords Targeted therapy · Tyrosine kinase inhibitors · Mammalian target of rapamycin · Angiogenesis · Programmed death · Antibodies Abbreviations CSF Colony-stimulating factor EMA European Medicines Agency FDA US Food and Drug Administration FGF Fibroblast growth factor FGFR Fibroblast growth factor receptor Flt-3 FMS-like tyrosine kinase-3 IFN-α Interferon-α IL-2 Interleukin-2 mTOR Mammalian target of rapamycin PD-1 Programmed death-1 PDGF Platelet-derived growth factor PDGFR Platelet-derived growth factor receptor PI3K Phosphatidylinositol-3-kinase RCC Renal cell carcinoma TKI Tyrosine kinase inhibitor VEGF Vascular endothelial growth factor VEGFR Vascular endothelial growth factor receptor
13
Introduction Kidney cancer is one of the most prevalent cancers in the world, with an estimated 338,000 new cases diagnosed worldwide in 2012 [1]. Renal cell carcinomas (RCCs) make up approximately 85 % of these cases and often present at an advanced stage resulting in poor prognosis [2]. While a nephrectomy is the preferred treatment for isolated tumours, this is not a viable option for advanced or metastatic cancers. RCC is known to be highly resistant to chemotherapeutic agents, further reducing treatment options [3, 4]. Cytokine-based immunotherapies consisting of interleukin-2 (IL-2) or interferon-α (IFN-α) have demonstrated potential benefits; however, the high level of toxicity is a significant drawback [5, 6]. Recently, improved understanding of the biochemical mechanisms involved in tumour progression has prompted the development of novel therapies for the treatment of RCC. Drugs targeting a variety of signalling pathways in a specific manner have been discovered and are at different stages of clinical investigation. Owing to their rapid growth, tumours require a dedicated blood supply to provide them with adequate oxygen and nutrients. Disruption of angiogenesis is therefore a promising mechanism by which tumour growth can be suppressed. There are a number of different signalling molecules that participate in angiogenesis, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). VEGF is the most significant of the known angiogenic factors, particularly in RCC where it is highly overexpressed [2]. It binds to receptors (VEGFRs) on endothelial cells and promotes their proliferation and migration. Disrupting this pathway with small molecule drugs or monoclonal antibodies has been shown to have anti-tumour effects [7, 8]. A second potential target pathway is that involving mammalian target of rapamycin (mTOR). The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR pathway plays a key role in many cancers [9]. Initiation of the cascade (by VEGF binding for example) leads to activation of mTOR, followed by downstream phosphorylations and tumourpromoting signalling [10]. Inhibition of this pathway can therefore disrupt tumour progression. Cancer cells present a wide range of macromolecules on their surface, many of which are potentially recognisable by the patient’s immune system. In theory, this should result in anti-tumour activity; however, there are a number of mechanisms by which cancer cells can suppress this response [11]. Drugs with the capability to reverse such immunosuppression have shown great promise for the treatment of cancer [12]. In this review, we describe the most promising targeted therapies for treating advanced RCC by disruption of the
13
Cancer Chemother Pharmacol
signalling pathways involved in tumour growth or suppression of anti-tumour immune response. We performed a systematic literature search using PubMed (NCBI), employing the search terms: RCC targets, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and each of the drugs identified within these papers. We here present data regarding the efficacy, safety, and potential of the different therapies under investigation, with a focus on the most recently introduced.
Tyrosine kinase inhibitors (TKIs) Tyrosine kinase inhibitors (TKIs) are small molecules that inhibit a variety of different signalling molecule receptors, including VEGFR-1, VEGFR-2, and VEGFR-3; PDGFR-α and PDGFR-β; c-RET; macrophage colony-stimulating factor (CSF-1R); FMS-like tyrosine kinase-3 receptor (Flt-3); and c-KIT [13]. This activity provides them with the potential to disrupt a range of tumour angiogenesis signalling pathways (Fig. 1). After the regulatory approval of sorafenib in 2005, four further TKIs are now available on the market for treatment of RCC, with a number of others currently undergoing clinical trials. First‑generation TKIs Sorafenib (BAY 43-9006/Nexavar, Bayer) is an orally active TKI that been shown to exhibit inhibitory effects against VEGFR-2 and VEGFR-3, PDGFR-β, Flt-3, RAF1, and c-KIT [14]. Initial clinical testing in patients with RCC found that the drug provided good tolerability and anti-tumour activity [15]. Subsequent phase II trials demonstrated significant disease stabilisation and tumour shrinkage, with equivalent progression-free survival to that achieved with IFN-α2A, the gold standard in targeted therapy at that time [16, 17]. These initial promising results led to the phase III TARGET trial, where patients who had experienced disease progression after cytokine therapy were randomly assigned to sorafenib or a placebo [18, 19]. A significantly higher rate of progression-free survival was reported for patients treated with sorafenib compared to placebo (5.5 vs. 2.8 months; HR 0.44; 95 % CI 0.35–0.55; p
REVIEW ARTICLE
Targeted therapies for treatment of renal cell carcinoma: recent advances and future perspectives Joan Minguet1,2 · Katherine H. Smith1 · Carsten P. Bramlage2 · Peter Bramlage1,2
Received: 25 February 2015 / Accepted: 5 May 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose A wide variety of targeted therapies are available for the treatment of renal cancer that has progressed beyond the point at which surgery is a viable option. In addition, there are many more that are in the different stages of clinical trials. Here, we provide a methodical discussion of the efficacy and safety of targeted therapies for the treatment of advanced renal cell carcinoma. Methods We conducted a systematic literature employing the search terms: renal cell carcinoma targets, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and each of the drugs discussed within these papers. Results The identified targeted therapies work by disrupting specific signalling pathways involved in tumour progression, such as those responsible for angiogenesis and cell proliferation. Tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are now established classes of drugs used in the treatment of renal cancer, with a total of six having received regulatory approval to date (sorafenib, sunitinib, pazopanib, axitinib, temsirolimus, and everolimus). Ongoing trials are likely to result in addition
* Joan Minguet [email protected] Katherine H. Smith [email protected] Carsten P. Bramlage [email protected] Peter Bramlage [email protected] 1
European Institute of Cancer Research (EICR), Carrer del Passeig, 2, 08221 Terrassa, Spain
2
Institute of Pharmacology and Preventive Medicine (IPPMED), Bahnhofstr. 20, 49661 Cloppenburg, Germany
to these in the near future, for example, tivozanib, dovitinib, and cediranib. Furthermore, in addition to these small molecule drugs, immunotherapies involving monoclonal antibodies against signalling molecules such as vascular endothelial growth factor (bevacizumab) or programmed death-1 (nivolumab) are receiving increasing attention. Conclusions Targeted therapies have great potential for disrupting tumour progression by inhibiting certain signalling pathways. As our understanding of the biochemical pathways involved in cancer progresses, additional targets are certain to become apparent, expanding treatment options even further. Keywords Targeted therapy · Tyrosine kinase inhibitors · Mammalian target of rapamycin · Angiogenesis · Programmed death · Antibodies Abbreviations CSF Colony-stimulating factor EMA European Medicines Agency FDA US Food and Drug Administration FGF Fibroblast growth factor FGFR Fibroblast growth factor receptor Flt-3 FMS-like tyrosine kinase-3 IFN-α Interferon-α IL-2 Interleukin-2 mTOR Mammalian target of rapamycin PD-1 Programmed death-1 PDGF Platelet-derived growth factor PDGFR Platelet-derived growth factor receptor PI3K Phosphatidylinositol-3-kinase RCC Renal cell carcinoma TKI Tyrosine kinase inhibitor VEGF Vascular endothelial growth factor VEGFR Vascular endothelial growth factor receptor
13
Introduction Kidney cancer is one of the most prevalent cancers in the world, with an estimated 338,000 new cases diagnosed worldwide in 2012 [1]. Renal cell carcinomas (RCCs) make up approximately 85 % of these cases and often present at an advanced stage resulting in poor prognosis [2]. While a nephrectomy is the preferred treatment for isolated tumours, this is not a viable option for advanced or metastatic cancers. RCC is known to be highly resistant to chemotherapeutic agents, further reducing treatment options [3, 4]. Cytokine-based immunotherapies consisting of interleukin-2 (IL-2) or interferon-α (IFN-α) have demonstrated potential benefits; however, the high level of toxicity is a significant drawback [5, 6]. Recently, improved understanding of the biochemical mechanisms involved in tumour progression has prompted the development of novel therapies for the treatment of RCC. Drugs targeting a variety of signalling pathways in a specific manner have been discovered and are at different stages of clinical investigation. Owing to their rapid growth, tumours require a dedicated blood supply to provide them with adequate oxygen and nutrients. Disruption of angiogenesis is therefore a promising mechanism by which tumour growth can be suppressed. There are a number of different signalling molecules that participate in angiogenesis, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). VEGF is the most significant of the known angiogenic factors, particularly in RCC where it is highly overexpressed [2]. It binds to receptors (VEGFRs) on endothelial cells and promotes their proliferation and migration. Disrupting this pathway with small molecule drugs or monoclonal antibodies has been shown to have anti-tumour effects [7, 8]. A second potential target pathway is that involving mammalian target of rapamycin (mTOR). The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR pathway plays a key role in many cancers [9]. Initiation of the cascade (by VEGF binding for example) leads to activation of mTOR, followed by downstream phosphorylations and tumourpromoting signalling [10]. Inhibition of this pathway can therefore disrupt tumour progression. Cancer cells present a wide range of macromolecules on their surface, many of which are potentially recognisable by the patient’s immune system. In theory, this should result in anti-tumour activity; however, there are a number of mechanisms by which cancer cells can suppress this response [11]. Drugs with the capability to reverse such immunosuppression have shown great promise for the treatment of cancer [12]. In this review, we describe the most promising targeted therapies for treating advanced RCC by disruption of the
13
Cancer Chemother Pharmacol
signalling pathways involved in tumour growth or suppression of anti-tumour immune response. We performed a systematic literature search using PubMed (NCBI), employing the search terms: RCC targets, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and each of the drugs identified within these papers. We here present data regarding the efficacy, safety, and potential of the different therapies under investigation, with a focus on the most recently introduced.
Tyrosine kinase inhibitors (TKIs) Tyrosine kinase inhibitors (TKIs) are small molecules that inhibit a variety of different signalling molecule receptors, including VEGFR-1, VEGFR-2, and VEGFR-3; PDGFR-α and PDGFR-β; c-RET; macrophage colony-stimulating factor (CSF-1R); FMS-like tyrosine kinase-3 receptor (Flt-3); and c-KIT [13]. This activity provides them with the potential to disrupt a range of tumour angiogenesis signalling pathways (Fig. 1). After the regulatory approval of sorafenib in 2005, four further TKIs are now available on the market for treatment of RCC, with a number of others currently undergoing clinical trials. First‑generation TKIs Sorafenib (BAY 43-9006/Nexavar, Bayer) is an orally active TKI that been shown to exhibit inhibitory effects against VEGFR-2 and VEGFR-3, PDGFR-β, Flt-3, RAF1, and c-KIT [14]. Initial clinical testing in patients with RCC found that the drug provided good tolerability and anti-tumour activity [15]. Subsequent phase II trials demonstrated significant disease stabilisation and tumour shrinkage, with equivalent progression-free survival to that achieved with IFN-α2A, the gold standard in targeted therapy at that time [16, 17]. These initial promising results led to the phase III TARGET trial, where patients who had experienced disease progression after cytokine therapy were randomly assigned to sorafenib or a placebo [18, 19]. A significantly higher rate of progression-free survival was reported for patients treated with sorafenib compared to placebo (5.5 vs. 2.8 months; HR 0.44; 95 % CI 0.35–0.55; p
