sirolimus and von-Hippel-Lindau-Disease

The recent contributions to renal cell carcinoma in the fields of molecular biology and the expanded use of molecularly targeted agents will be reviewed. This study is intended to update prognostic and therapeutic decision-making data and provide perspective on advances in understanding the molecular biology of this disease.. Updates to the currently used prognostic algorithms for renal cell carcinoma are needed, and recently verified prognostic nomograms will be discussed. This comes in the wake of numerous advances in the use of molecularly targeted drugs, which will be reviewed. Finally, advancements in understanding the biology of renal cell carcinoma include the discovery of von Hippel-Lindau associated mechanisms involved in renal cyst formation and renewed appreciation for the influence of this pathway on the tumor cell glucose utilization profile.. Renal cell carcinoma continues to evolve swiftly with the approval of new agents and the maturation of clinical trials to provide relevant structure to treatment decisions. This study will give an overview of the latest concepts in the epidemiology and biology of renal cell carcinoma and provide current surgical and systemic updates for managing renal cell carcinoma.

Topics: Algorithms; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Mutation; Niacinamide; Nomograms; Phenylurea Compounds; Prognosis; Pyridines; Sirolimus; Sorafenib; Vascular Endothelial Growth Factor A; von Hippel-Lindau Disease

Recent developments in molecular biology have lead to an increased understanding of the events involved in renal cell carcinoma (RCC) carcinogenesis. In this field, basic molecular pathways important to oncogenic transformation secondary to Von Hippel-Lindau (VHL) tumor suppression gene inactivation, associated to clear-cell RCC, have been elucidated. Loss of function of VHL results in the high-expression of pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). New therapies against specific targets in RCC have demonstrated significant clinical activity in patients. These therapeutic approaches are based on the VEGF inhibition by using anti-VEGF monoclonal antibodies (bevacizumab) or multi-kinase inhibitors, that also target PDGF and c-kit tyrosine kinases (sorafenib, sunitinib); or by the inhibition of the mammalian target of rapamycin (mTOR) pathway (temsirolimus). This article reviews current knowledge of molecular pathogenesis of inherited and sporadic RCC.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Exons; Humans; Indoles; Kidney Neoplasms; Molecular Biology; Mutation; Niacinamide; Phenylurea Compounds; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Pyridines; Pyrroles; raf Kinases; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sirolimus; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A; von Hippel-Lindau Disease

Animal models are instrumental in understanding disease pathophysiology and mechanisms of therapy action and resistance in vivo.. To establish and characterize a panel of mouse models of renal cell carcinoma (RCC) derived from patients undergoing radical nephrectomy.. In vivo and in vitro animal experiments.. Tumor tissues obtained during surgery were implanted into the subcutaneous space of female BALB/c nude mice and serially passaged into new mice. Tumors were characterized by histology, short tandem repeat (STR) fingerprinting, von Hippel-Lindau (VHL) gene sequencing, and single nucleotide polymorphism (SNP) analysis. Tumor-bearing mice were treated with sunitinib or everolimus. Primary cell cultures were derived from patient tumors and transfected with a lentivirus carrying the luciferase gene. Four subcutaneous xenograft mouse models were developed, representing papillary type 1, papillary type 2, clear cell, and clear cell with sarcomatoid features RCC.. RCC mouse models were established from four patients with distinct histologies of RCC. Tumor growth was dependent on histologic type, the size of the implanted tumor chip, and the passage number. Mouse tumors accurately represented their respective original patient tumors, as STR fingerprints were matching, histology was comparable, and SNP profiles and VHL mutation status were conserved with multiple passages. Bioluminescence imaging results were commensurate with subcutaneous xenograft growth patterns. Mice treated with sunitinib and everolimus exhibited an initial response, followed by a later stage of resistance to these agents, which mimics the clinical observations in patients with RCC.. We developed four mouse xenograft models of RCC with clear-cell and papillary histologies, with stable histologic and molecular characteristics. These models can be used to understand the basic biology of RCC as well as response and resistance to therapy.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Disease Models, Animal; DNA Fingerprinting; Everolimus; Female; Humans; Immunosuppressive Agents; Indoles; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Polymorphism, Single Nucleotide; Pyrroles; Sirolimus; Sunitinib; Transfection; Tumor Cells, Cultured; von Hippel-Lindau Disease; Xenograft Model Antitumor Assays

von Hippel-Lindau (VHL) disease is a genetic syndrome based on an abnormality of the VHL gene located on the short arm of chromosome 3. Clinically, it presents as multiple tumors at several levels. The VHL gene product (pVHL) acts as a tumor-suppressing protein. In conditions of hypoxia it leads to an increase in several growth factor levels. mTOR inhibitors have proved to have dual properties: immunosuppressive and antitumor effects. Herein we have presented a case in which conversion to sirolimus improved graft function and also caused regression of retinal angioblastomas.

Topics: Adenocarcinoma; Humans; Immunosuppressive Agents; Kidney Neoplasms; Kidney Transplantation; Male; Middle Aged; Renal Dialysis; Sirolimus; Treatment Outcome; von Hippel-Lindau Disease