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Renal Cell Carcinoma Diagnosis And Management
- 1. Renal Cell Carcinoma Diagnosis & Management Raúl H. Morales - Borges, MD, FICPS, FIACATH Chairman of the Board of Trustees and Lecturer of Pathology, Immunology & Genetics San Juan Bautista School of Medicine Medical Director of The Ashford Institute of Hematology & Oncology Attending Physician and Consultant Ashford Presbyterian Community Hospital
- 5. Overview of RCC Epidemiology Pathology Pathogenesis
- 8. Pathology Clear cell (non-papillary) carcinoma is the most common.
- 12. Pathogenesis A number of environmental, hormonal, cellular, and genetic factors have been studied as possible causes of RCC.
- 22. Clinical Manifestations Evaluation and Staging Of RCC
- 33. Prognosis and Treatment of RCC
- 44. Targeted Therapies for RCC
- 50. Adjuvant Therapy
- 57. Metastatic RCC: Frontline/Monotherapy
- 63. CA IX and Response to Interleukin-2 (IL-2) Therapy in RCC * Including all CRs. Bui MH, et al. Clin Cancer Res. 2003;9:802-811. Atkins M, et al. Clin Cancer Res. 2005;11:3714-3721. 51 80 Nonresponders with high CA IX 78 91 Responders with high CA IX 24 14 Response in low CA IX 51 27* Response in high CA IX 62 77 No of metastatic pts with > 85% CA IX Boston, % (N = 66) UCLA, % (N = 83) Outcome
- 65. Metastatic RCC: Determining Clinical Cross-Resistance to VEGF-Targeted Agents
- 68. 6-Arm Randomized Phase II Trial (E9805): Sunitinib Failures Patients failing sunitinib Sunitinib daily Arm A Arm B Sunitinib + Bevacizumab Arm C Change to Sorafenib
- 69. 6-Arm Randomized Phase II Trial (E9805): Sorafenib Failures Patients failing sorafenib Increase Sorafenib dose Sorafenib + Bevacizumab Arm D Arm E Arm F Change to Sunitinib Arm D Arm D Arm E
- 75. Thank You THANK YOU !!!
Hinweis der Redaktion
- Clues to the pathogenesis of RCC have been identified through study of von Hippel Lindau (VHL) syndrome, an autosomal dominant disorder with inherited susceptibility to clear-cell RCC and other tumors. VHL syndrome is associated with overexpression of various growth factors that have been linked with tumorigenesis, including VEGF and PDGF. In VHL syndrome, VHL gene inactivation due to gene mutation or methylation leads to defective VHL protein function. VHL protein normally earmarks another protein called hypoxia inducible factor-1 (HIF-1 ) for metabolic degradation, so loss of VHL protein function leads to an accumulation of HIF-1 HIF- forms a complex with HIF- that regulates gene transcription, including the genes encoding VEGF, PDGF, and TGF- . Hence, accumulation of HIF- in VHL syndrome leads to overexpression of VEGF, PDGF, and TGF- Patients with VHL syndrome have a lifetime risk of RCC that approaches 50% Reference Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol . 2005;23:1028-1043.
- Multiple receptor tyrosine kinases (RTKs) have been implicated in different cancers. Activation of RTKs triggers signaling cascades within the cells that are associated with processes important for cancer development or progression. 1-3 RTKs are transmembrane receptors. The intracellular domains are associated with tyrosine kinase activity (i.e., ability to transfer a phosphate group from ATP to tyrosine residues of various proteins). RTKs are commonly involved in cellular growth and other processes associated with cancer development or progression 4 Normally, ligand binding is required to activate the receptor. Ligand binding causes the RTK to dimerize with a similar RTK (see the various RTK pairs in the figure), which leads to kinase activation 4 The receptor or receptor pair is usually the first site of phosphorylation (autophosphorylation, as shown in the figure, the little circles linked with the intracellular domain). The resulting signal cascades within the cell modify gene expression and promote processes involved in tumor development: cell differentiation and proliferation, cell survival by inhibiting apoptosis, cell adhesion and invasion (processes involved in tumor metastasis), and (for certain cells) angiogenesis (development of new blood vessels) 4 Some tumors are associated with mutated RTKs that are activated independently of ligand binding. These receptors are said to be constitutively active. Gastrointestinal stromal tumor(GIST) is an example of a tumor associated with mutated and constitutively active RTKs (KIT and PDGFR) linked with tumor development 5 Angiogenesis is involved in the progression of most solid tumors. Two types of vascular cells, associated with two distinct RTKs, work together to promote tumor-related angiogenesis: VEGFRs on vascular endothelial cells and PDGFRs on pericytes (upper right of figure). Overexpression of ligands for these RTKs may promote tumor progression, as appears to be the case with RCC 1,6 References Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor–targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23:1028-1043. Duensing A, Heinrich MC, Fletcher CDM, Fletcher JA. Biology of gastrointestinal stromal tumors: KIT mutations and beyond. Cancer Invest . 2004;22:106-116. Marmor MD, Skaria KB, Yarden Y. Signal transduction and oncogenesis by ErbB/HER receptors. Int J Radiat Oncol Biol Phys. 2004;58:903-913. Tibes R, Trent J, Kurzrock R. Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu Rev Pharmacol Toxicol . 2005;45:357-384. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol . 2004;22:3813-3825. Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncology . 2005;7:452-464.
- Sunitinib inhibits the kinase activity of multiple RTKs associated with cancer, including isoforms of VEGFR, isoforms of PDGFR, KIT, wild-type and mutated FLT, and RET 1-4 Angiogenesis is a key process involved in the progression of most solid tumors. VEGFRs (particularly VEGFR-2) and PDGFRs (particularly PDGFR- ) are important for tumor-related angiogenesis 5 RCC is a highly vascular tumor where inhibition of angiogenesis is thought to be an important therapeutic strategy 6 Mutated forms of KIT and PDGFR- , resulting in receptors with constitutive or ligand-independent kinase activity, have been implicated in GIST 7 References Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res . 2003;9:327-337. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor in preclinical models of human small cell lung cancer. Mol Cancer Ther . 2003;2:471-478. O’Farrell A-M, Abrams TJ, Yeun HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood . 2003;101:3597-3605. Data on file. Pfizer Inc, New York, NY. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth an angiogenesis. J Clin Oncol . 2005;23(5):1011-1027. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor–targeted therapy in renal cell carcinoma. J Clin Oncol . 2005;23:1028-1043. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol . 2004;22:3813-3825.
- In preclinical studies, treatment with sunitinib demonstrated both direct antitumor and antiangiogenic effects through inhibition of RTKs on tumors and vascular cells, respectively. RTKs on two types of vascular cells work together to promote tumor-related angiogenesis, namely VEGFRs on vascular endothelial cells and PDGFR- on supportive pericytes (bottom right) 1,2 Sunitinib demonstrated antiangiogenic activity by inhibiting PDGF receptors on pericytes and VEGF receptors on endothelial cells in preclinical studies 3,4 Sunitinib demonstrated direct antiproliferative activity by inhibiting PDGF and KIT receptors on tumor cells in preclinical studies 4,5 References Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncology . 2005;7:452-464. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol . 2005;23:1011-1027. Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J . 2004;18:338-340. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest . 2003;111:1287-1295. Abrams TJ. Lee LB, Murray LJ Pryer, NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor ß in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2:471-478.
- BCG, Bacillus Calmette-Guérin; VEGF, vascular endothelial growth factor.
- UISS, UCLA integrated staging system.
- CWG, Cytokine Working Group
- DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging .
- KPS, Karnofsky Performance Status