**1. Introduction**

Renal cell carcinoma (RCC) affects more than 200.000 people annually worldwide resulting in 102.000 deaths each year. Men are twice as frequently affected as women; population aged between 50 and 70 years is most frequently affected. Obesity, hypertension, tobacco smoking and certain occupational exposures have been shown to increase one's risk for developing RCC. Rarely RCC develops as a part of the familiar syndrome (e.g. von Hippel-Lindau) [1,2].

Treatment of renal cell carcinoma has changed dramatically over the past few years. Until 2005 cytokine therapy (interferon (IFN-α) or interleukin (IL-2)) was the only (IFN-α) or interleukin (IL-2) was the only available treatment for mRCC patients. Treatment with cytokines was associated with little clinical benefit together with substantial side effects; even treatment related deaths were not infrequent. Treatment options for second line therapy were very limited; patients could be treated only with another cytokine or best supportive care. Re‐ sponses to second line cytokine therapy were modest. Fewer than 4% of patients had partial response and < 12% had stable disease [2,3].

Lack of effective therapy together with better knowledge about the cancer biology led to the development of new targeted agents. Since the start of the "targeted era" development of new therapies evolved swiftly. Better treatment results in the first line therapy are allied to the better outcome of the patients on subsequent lines of treatment. Prognosis of patients improved and mRCC is becoming more a chronic type of disease, rather than a rapidly progressing and fatal one [3].

Despite rapid progress in development of new treatments, many questions still remain unanswered. Patients on targeted therapies progress some time during their treatment and

© 2013 Rajer; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Rajer; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

mRCC is considered an incurable disease [4]. In trying to overcome this, the mechanism of action and especially mechanisms of resistance to targeted therapies, need to be studied and explained even more in detail [3-7].

involved in glucose uptake and metabolism. Up-regulation of targeted genes involved in neovascularization by HIF1α offers the explanation of high vascularity of RCC [2,8]. Beside this, pVHL has numerous other functions in the processes of regulation of extracellular matrix, senescence, phosphorylation enhancers and other. The importance of many physiologically

Changing Mechanisms of Action as a Strategy for Sequential Targeted Therapy of Metastatic Renal-Cell Carcinoma

http://dx.doi.org/10.5772/55694

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Besides VHL, six other genes have been found to predispose to RCC (MET, FLCN, FH, SDH, TSC 1 and TSC 2). These genes interact trough common nutrient and energy sensing pathways. Understanding of the molecular mechanisms by which these genes interact in these pathways

Loss of both alleles of VHL gene leads to up-regulated transcription of growth factors such as VEGF, PDGF and TGF-α. These factors bind to their tyrosine kinase receptors. This leads to downstream signalling and ultimately to effects such as increased angiogenesis, increased cell proliferation and decreased apoptosis. As described previously pVHL mutations are inevita‐ bly connected to flawed HIF inactivation which results in production of VEGF. VEGF is the most prominent angiogenesis regulator. Its function is mediated through two tyrosine kinase receptors VEGF-R1 and VEGF-R2 in vascular endothelial cells. VEGF in the beginning binds to VEGF-R2, which promotes endothelial cell proliferation, migration and vascular permea‐ bility. In the next step VEGF binds to VEGF-R1 to assist the organization of new capillaries [9].

mTOR is another regulator of HIF 1α, its signalling activity increases the cellular levels of HIF 1α, which worsens the already high levels of it because of absence of pVHL function. mTOR is a serine/threonine kinase that has a key function in apoptosis, cell growth and tumor proliferation. mTOR forms complexes with regulatory associated proteins named mTORC1 and mTORC2. mTORC 1 can be activated by growth factors including VEGFR, PDGFR, EGFR and IGFR and nutrients trough phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway. Activated mTORC1 stimulate protein synthesis, entrance into G 1 phase, and proteins that

The successes on other solid tumors led researches to the assumption chemotherapy would be effective also in mRCC. Chemotherapeutic trials were conducted between 1983 and 1993. Different agents; bleomycin, cisplatin, 5-FU, gemcitabine and vinblastine have been tested. Results were disappointing; less than 10% of patients had clinical benefit in all of these trials. Response rates in the range of 10 to 15% have been achieved with combination of two agents.

relevant functions of pVHL is at present difficult to interpret [8].

has enabled the development of targeted therapies [2].

**3. Development of systemic therapy in mRCC**

**2.2. VEGF-R pathway**

**2.3. mTOR pathway**

regulate apoptosis [9].

**3.1. Chemotherapy**

In this chapter evidence on sequential therapy after progression to the first line will be presented with the emphasis on changing mechanism of action. Additionally, mechanisms of resistance to targeted therapies and therapeutic options to overcome resistance will be discussed.
