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Safety and clinical efficacy of everolimus in the treatment of advanced renal cell carcinoma (RCC).

Shahani R, Kwan KG, Kapoor A - Drug Healthc Patient Saf (2010)

Bottom Line: Recently, there has been a paradigm shift in the management of advanced RCC.The first mTOR inhibitor, temsirolimus, an intravenous prodrug, has shown improved overall survival in poor prognosis patients.More recently, an oral mTOR inhibitor, everolimus (RAD 001), has been developed which has been shown to delay disease progression in patients with metastatic RCC who have progressed on other targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Division of Urology, Department of Surgery, St. Joseph's Healthcare Hamilton and McMaster University, Hamilton, Ontario, Canada.

ABSTRACT
Renal cell carcinoma (RCC) is one of the most lethal genitourinary malignancies. Recently, there has been a paradigm shift in the management of advanced RCC. New targeted therapies including vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors have been developed which have shown promising results in a patient population who otherwise had very few options for treatment. The first mTOR inhibitor, temsirolimus, an intravenous prodrug, has shown improved overall survival in poor prognosis patients. More recently, an oral mTOR inhibitor, everolimus (RAD 001), has been developed which has been shown to delay disease progression in patients with metastatic RCC who have progressed on other targeted therapies. Although a survival advantage in phase III trials is seen with everolimus, associated systemic toxicities, while generally well tolerated, are not insignificant. These include mucositis, hyperglycemia, hyperlipidemia, and pneumonitis. Despite the side effects, emerging evidence points to everolimus as the optimal second-line treatment for patients with advanced renal cell carcinoma.

No MeSH data available.


Related in: MedlinePlus

The mammalian target of rapamycin (mTOR) network. mTOR is a central component of the phosphoinositide 3′ kinase/protein kinase B (PI3K)/Akt signaling pathway that mediates eukaryotic cell growth and proliferation. The mTOR kinase is the catalytic component of two distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. mTORC1 also contains raptor, MLST8, and praline-rich Akt substrate 40 (PRAS40) (a repressor). In tumor cells, mTORC1 activity is aberrantly elevated. Diverse positive and negative growth signals influence the activity level of mTORC1, many of which converge upon the tuberous sclerosis complex 1 (TSC1)/TSC2 complex and Ras homolog enriched in brain (Rheb). PI3K receives activating signals from growth factor receptors or it may be activated constitutively in some tumors. Phosphatase and tensin homolog (PTEN) reverses the action of PI3K and functions as a tumor suppressor. Akt also promotes mTORC1 activity by phosphorylating TSC1/TSC2 and PRAS40, resulting in guanosine-5’-triphosphate (GTP) loading of Rheb and suppression of the PRAS40 repressor. Downstream, mTORC1 phosphorylates the 70-kDa ribosomal protein S6 kinase (p70S6K) (activation) and eukaryotic translation initiation factor 4E binding protein (4EBP-1) (inhibition of negative regulator) to increase messenger RNA translation of specific proteins. mTOR-regulated proteins include D-type cyclins and c-Myc (which increase cell proliferation), hypoxia-inducible factor-1α (HIF-1α) (which increases synthesis of the proangiogenic factor vascular endothelial growth factor [VEGF]), various glycolytic enzymes, and growth factors (which can promote cell survival). Activation and inhibition induced by direct phosphorylation at one or more sites is indicated by a phosphate (P). The mTOR inhibitors (rapamycin, temsirolimus, everolimus, deforolimus) inhibit mTORC1 by first binding to the intracellular protein FK506 binding protein 1A, 12 kDa (FKBP12); the resultant mTOR inhibitor-FKBP12 complex then binds mTOR, blocking mTORC1 to inhibit its kinase activity. Through the specific inhibition of mTORC1 activity, the mTOR inhibitors display a multifunctional biologic activity profile, blocking cell proliferation, cell growth, cell survival, and angiogenesis in preclinical tumor models.13 Figure reprinted with permission from Wyeth Pharmaceuticals, Collegeville, PA, USA.Abbreviations: MAPK, mitogen-activated protein kinase; S6RP, S6 ribosomal protein.
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f1-dhps-2-085: The mammalian target of rapamycin (mTOR) network. mTOR is a central component of the phosphoinositide 3′ kinase/protein kinase B (PI3K)/Akt signaling pathway that mediates eukaryotic cell growth and proliferation. The mTOR kinase is the catalytic component of two distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. mTORC1 also contains raptor, MLST8, and praline-rich Akt substrate 40 (PRAS40) (a repressor). In tumor cells, mTORC1 activity is aberrantly elevated. Diverse positive and negative growth signals influence the activity level of mTORC1, many of which converge upon the tuberous sclerosis complex 1 (TSC1)/TSC2 complex and Ras homolog enriched in brain (Rheb). PI3K receives activating signals from growth factor receptors or it may be activated constitutively in some tumors. Phosphatase and tensin homolog (PTEN) reverses the action of PI3K and functions as a tumor suppressor. Akt also promotes mTORC1 activity by phosphorylating TSC1/TSC2 and PRAS40, resulting in guanosine-5’-triphosphate (GTP) loading of Rheb and suppression of the PRAS40 repressor. Downstream, mTORC1 phosphorylates the 70-kDa ribosomal protein S6 kinase (p70S6K) (activation) and eukaryotic translation initiation factor 4E binding protein (4EBP-1) (inhibition of negative regulator) to increase messenger RNA translation of specific proteins. mTOR-regulated proteins include D-type cyclins and c-Myc (which increase cell proliferation), hypoxia-inducible factor-1α (HIF-1α) (which increases synthesis of the proangiogenic factor vascular endothelial growth factor [VEGF]), various glycolytic enzymes, and growth factors (which can promote cell survival). Activation and inhibition induced by direct phosphorylation at one or more sites is indicated by a phosphate (P). The mTOR inhibitors (rapamycin, temsirolimus, everolimus, deforolimus) inhibit mTORC1 by first binding to the intracellular protein FK506 binding protein 1A, 12 kDa (FKBP12); the resultant mTOR inhibitor-FKBP12 complex then binds mTOR, blocking mTORC1 to inhibit its kinase activity. Through the specific inhibition of mTORC1 activity, the mTOR inhibitors display a multifunctional biologic activity profile, blocking cell proliferation, cell growth, cell survival, and angiogenesis in preclinical tumor models.13 Figure reprinted with permission from Wyeth Pharmaceuticals, Collegeville, PA, USA.Abbreviations: MAPK, mitogen-activated protein kinase; S6RP, S6 ribosomal protein.

Mentions: The primary function of the VHL protein complex is to target the hypoxia-inducible factor 1 (HIF-1) for ubiquitin-mediated degradation, keeping the levels of HIF-1 low under normal conditions. HIF-1 is an intracellular protein that plays an important role in regulating cellular responses to hypoxia, starvation, and other stresses. Inactivation or mutation of the VHL gene leads to dysregulated expression of HIF-1, and this protein begins accumulating within the cell.9 This leads to upregulation of the expression of vascular endothelial growth factor (VEGF), the primary proangiogenic growth factor in clear cell RCC, in addition to platelet derived growth factor (PDGF) and glucose transporter (Glut-1), which are also involved in tumorogenesis (Figure 1).10


Safety and clinical efficacy of everolimus in the treatment of advanced renal cell carcinoma (RCC).

Shahani R, Kwan KG, Kapoor A - Drug Healthc Patient Saf (2010)

The mammalian target of rapamycin (mTOR) network. mTOR is a central component of the phosphoinositide 3′ kinase/protein kinase B (PI3K)/Akt signaling pathway that mediates eukaryotic cell growth and proliferation. The mTOR kinase is the catalytic component of two distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. mTORC1 also contains raptor, MLST8, and praline-rich Akt substrate 40 (PRAS40) (a repressor). In tumor cells, mTORC1 activity is aberrantly elevated. Diverse positive and negative growth signals influence the activity level of mTORC1, many of which converge upon the tuberous sclerosis complex 1 (TSC1)/TSC2 complex and Ras homolog enriched in brain (Rheb). PI3K receives activating signals from growth factor receptors or it may be activated constitutively in some tumors. Phosphatase and tensin homolog (PTEN) reverses the action of PI3K and functions as a tumor suppressor. Akt also promotes mTORC1 activity by phosphorylating TSC1/TSC2 and PRAS40, resulting in guanosine-5’-triphosphate (GTP) loading of Rheb and suppression of the PRAS40 repressor. Downstream, mTORC1 phosphorylates the 70-kDa ribosomal protein S6 kinase (p70S6K) (activation) and eukaryotic translation initiation factor 4E binding protein (4EBP-1) (inhibition of negative regulator) to increase messenger RNA translation of specific proteins. mTOR-regulated proteins include D-type cyclins and c-Myc (which increase cell proliferation), hypoxia-inducible factor-1α (HIF-1α) (which increases synthesis of the proangiogenic factor vascular endothelial growth factor [VEGF]), various glycolytic enzymes, and growth factors (which can promote cell survival). Activation and inhibition induced by direct phosphorylation at one or more sites is indicated by a phosphate (P). The mTOR inhibitors (rapamycin, temsirolimus, everolimus, deforolimus) inhibit mTORC1 by first binding to the intracellular protein FK506 binding protein 1A, 12 kDa (FKBP12); the resultant mTOR inhibitor-FKBP12 complex then binds mTOR, blocking mTORC1 to inhibit its kinase activity. Through the specific inhibition of mTORC1 activity, the mTOR inhibitors display a multifunctional biologic activity profile, blocking cell proliferation, cell growth, cell survival, and angiogenesis in preclinical tumor models.13 Figure reprinted with permission from Wyeth Pharmaceuticals, Collegeville, PA, USA.Abbreviations: MAPK, mitogen-activated protein kinase; S6RP, S6 ribosomal protein.
© Copyright Policy
Related In: Results  -  Collection

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f1-dhps-2-085: The mammalian target of rapamycin (mTOR) network. mTOR is a central component of the phosphoinositide 3′ kinase/protein kinase B (PI3K)/Akt signaling pathway that mediates eukaryotic cell growth and proliferation. The mTOR kinase is the catalytic component of two distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. mTORC1 also contains raptor, MLST8, and praline-rich Akt substrate 40 (PRAS40) (a repressor). In tumor cells, mTORC1 activity is aberrantly elevated. Diverse positive and negative growth signals influence the activity level of mTORC1, many of which converge upon the tuberous sclerosis complex 1 (TSC1)/TSC2 complex and Ras homolog enriched in brain (Rheb). PI3K receives activating signals from growth factor receptors or it may be activated constitutively in some tumors. Phosphatase and tensin homolog (PTEN) reverses the action of PI3K and functions as a tumor suppressor. Akt also promotes mTORC1 activity by phosphorylating TSC1/TSC2 and PRAS40, resulting in guanosine-5’-triphosphate (GTP) loading of Rheb and suppression of the PRAS40 repressor. Downstream, mTORC1 phosphorylates the 70-kDa ribosomal protein S6 kinase (p70S6K) (activation) and eukaryotic translation initiation factor 4E binding protein (4EBP-1) (inhibition of negative regulator) to increase messenger RNA translation of specific proteins. mTOR-regulated proteins include D-type cyclins and c-Myc (which increase cell proliferation), hypoxia-inducible factor-1α (HIF-1α) (which increases synthesis of the proangiogenic factor vascular endothelial growth factor [VEGF]), various glycolytic enzymes, and growth factors (which can promote cell survival). Activation and inhibition induced by direct phosphorylation at one or more sites is indicated by a phosphate (P). The mTOR inhibitors (rapamycin, temsirolimus, everolimus, deforolimus) inhibit mTORC1 by first binding to the intracellular protein FK506 binding protein 1A, 12 kDa (FKBP12); the resultant mTOR inhibitor-FKBP12 complex then binds mTOR, blocking mTORC1 to inhibit its kinase activity. Through the specific inhibition of mTORC1 activity, the mTOR inhibitors display a multifunctional biologic activity profile, blocking cell proliferation, cell growth, cell survival, and angiogenesis in preclinical tumor models.13 Figure reprinted with permission from Wyeth Pharmaceuticals, Collegeville, PA, USA.Abbreviations: MAPK, mitogen-activated protein kinase; S6RP, S6 ribosomal protein.
Mentions: The primary function of the VHL protein complex is to target the hypoxia-inducible factor 1 (HIF-1) for ubiquitin-mediated degradation, keeping the levels of HIF-1 low under normal conditions. HIF-1 is an intracellular protein that plays an important role in regulating cellular responses to hypoxia, starvation, and other stresses. Inactivation or mutation of the VHL gene leads to dysregulated expression of HIF-1, and this protein begins accumulating within the cell.9 This leads to upregulation of the expression of vascular endothelial growth factor (VEGF), the primary proangiogenic growth factor in clear cell RCC, in addition to platelet derived growth factor (PDGF) and glucose transporter (Glut-1), which are also involved in tumorogenesis (Figure 1).10

Bottom Line: Recently, there has been a paradigm shift in the management of advanced RCC.The first mTOR inhibitor, temsirolimus, an intravenous prodrug, has shown improved overall survival in poor prognosis patients.More recently, an oral mTOR inhibitor, everolimus (RAD 001), has been developed which has been shown to delay disease progression in patients with metastatic RCC who have progressed on other targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Division of Urology, Department of Surgery, St. Joseph's Healthcare Hamilton and McMaster University, Hamilton, Ontario, Canada.

ABSTRACT
Renal cell carcinoma (RCC) is one of the most lethal genitourinary malignancies. Recently, there has been a paradigm shift in the management of advanced RCC. New targeted therapies including vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors have been developed which have shown promising results in a patient population who otherwise had very few options for treatment. The first mTOR inhibitor, temsirolimus, an intravenous prodrug, has shown improved overall survival in poor prognosis patients. More recently, an oral mTOR inhibitor, everolimus (RAD 001), has been developed which has been shown to delay disease progression in patients with metastatic RCC who have progressed on other targeted therapies. Although a survival advantage in phase III trials is seen with everolimus, associated systemic toxicities, while generally well tolerated, are not insignificant. These include mucositis, hyperglycemia, hyperlipidemia, and pneumonitis. Despite the side effects, emerging evidence points to everolimus as the optimal second-line treatment for patients with advanced renal cell carcinoma.

No MeSH data available.


Related in: MedlinePlus