mTOR Inhibition & Renal Cell Carcinoma Biology

Because mTOR regulates the production of HIF-a, an essential subunit of HIF-1, mTOR inhibition may play an important role in the management of renal cell carcinoma. In preclinical studies, increased HIF expression resulting from VHL loss has been shown to sensitize renal cell carcinoma cells to mTOR inhibition.22 A potential benefit of mTOR inhibition is that it works downstream from other agents available to treat renal cell carcinoma, at the point where a number of important signaling pathways that are activated in renal cell carcinoma converge (Figure). In a tumor model, combining mTOR inhibition with a VEGF receptor tyrosine kinase (RTK) inhibitor reduced angiogenesis synergistically.23

Clinical studies of mTOR inhibition in renal cell carcinoma are ongoing.

mTOR Inhibition Works Downstream from Other Agents Available For Treating Renal Cell Carcinoma 2,3

mTOR inhibition works on other agents where a number of important signaling pathways are activated.

IGF-1 = insulin-like growth factor 1; PDGF = platelet-derived growth factor; RTK = receptor tyrosine kinase; TGF-α = transforming growth factor α; VEGF = vascular endothelial growth factor


References:

  1. Gnarra JR, Tory K, Weng Y, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nature Genet. 1994;7(1):85-90.
  2. Kim WY. Kaelin WG. Molecular pathways in renal cell carcinoma—rationale for targeted therapy. Semin Oncol. 2006;33(5):588-595.
  3. Patel PH, Chadalavada RSV, Chaganti RSK, Motzer RJ. Targeting the von Hippel-Lindau pathway in renal cell carcinoma. Clin Cancer Res. 2006;12(24):7215-7220.
  4. Pan J, Mestas J, Burdick MD, et al. Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. Mol Cancer. 2006;5(1):56.
  5. Pouysségur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006;441(7092):437-443.
  6. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721-732.
  7. Höpfl G, Ogunshola O, Gassman M. HIFs and tumors—causes and consequences. Am J Physiol Regul Integr Comp Physiol. 2004;286(4):R608-R623.
  8. Raval RR, Lau KW, Tran MGB, et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Bio. 2005;25(13):5675-5686.
  9. Wiesener MS, Münchenhagen PM, Berger I, et al. Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor 1-α in clear cell renal carcinomas. Cancer Res. 2001;61(13):5215-5222.
  10. Levitzki A. PDGF receptor kinase inhibitors for the treatment of PDGF driven diseases. Cytokine Growth Factor Rev. 2004;15(4):229-235.
  11. Landis DM, Zimmer M, Borgesi R, Iliopoulis O, Balk S, Bubley G. The effect of mTOR inhibition and HIF-2a expression on radiation sensitivity. Presented at: 2005 Prostate Cancer Symposium; February 17-19, 2005; Orlando, FL.
  12. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nature Rev Drug Discov. 2006;5(8):671-688.
  13. Robb VA, Karbowniczek M, Klein-Szanto AJ, Henske EP. Activation of the mTOR signaling pathway in renal clear cell carcinoma. J Urol. 2007;177(1):346-352.
  14. Schips L, Ziguener R, Ratschek M, Rehak P, Rüschoff J, Langner C. Analysis of insulin-like growth factors and insulin-like growth factor I receptor expression in renal cell carcinoma. Am J Clin Pathol. 2004;122(6):931-937.
  15. Gomella LG, Sargent ER, Wade TP, Anglard P, Marston Linehan W, Kasid A. Expression of transforming growth factor a in normal human adult kidney and enhanced expression of transforming growth factors a and ß1 in renal cell carcinoma. Cancer Res. 1989;49(24):6972-6975.
  16. Mackler NJ, Bhandari M, Redman B, Rhodes D, Chinnaiyan A. The PI3K/AKT pathway in renal (clear cell) carcinoma via meta-analysis of expression microarrays. J Clin Oncol. 2005;23(16s)(suppl):4537.
  17. Lam JS, Pantuck AJ, Belldegrun AS, Figlin RA. Protein expression profiles in renal cell carcinoma: staging, prognosis, and patient selection for clinical trials. Clin Cancer Res. 2007;13(suppl 2):703S-708S.
  18. Rathmell WK, Wright TM, Rini BI. Molecularly targeted therapy in renal cell carcinoma. Expert Rev Anticancer Ther. 2005;5(6):1031-1040.
  19. Bjornsson J, Short MP, Kwiatkowski DJ, Petri Henske E. Tuberous sclerosis-associated renal cell carcinoma. Am J Pathol. 1996;149(4):1201-1208.
  20. Merseburger AS, Hennenlotter J, Kuehs U, et al. Activation of PI3K is associated with reduced survival in renal cell carcinoma. Urol Int. 2008;80(4):372-377.
  21. Chan DA, Sutphin PD, Denko NC, Giaccia AJ. Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1α. J Biol Chem. 2002;277(42):40112-40117.
  22. Thomas GV, Tran C, Mellinghoff IK, et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med. 2006;12(1):122-127.
  23. O’Reilly TM, Wood, JM, Littlewood-Evans A, et al. Differential anti-vascular effects of mTOR or VEGFR pathway inhibition: A rational basis for combining RAD001 and PTK787/ZK222584. Proc Am Assoc Cancer Res. 2005;46:Abstract 3038.
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