BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is up-regulated in many human cancers, and agents targeting the mTOR pathway are in various stages of clinical development. The goal of the study was to evaluate the potential and limitations of targeting the mTOR pathway in renal cell carcinoma (RCC). METHODS: Immunohistochemical analysis using antibodies against pAkt, PTEN, p27, and pS6 was performed on a tissue microarray constructed from paraffin-embedded specimens from 375 patients treated by nephrectomy for RCC. The expression was associated with pathological parameters and survival. RESULTS: The mTOR pathway was more significantly altered in clear-cell RCC, high-grade tumors, and tumors with poor prognostic features. PS6 and PTEN showed the strongest associations with pathological parameters. Survival tree analysis regarding expression of cytoplasmic pAkt, nuclear pAkt, PTEN, cytoplasmic p27, and pS6 identified staining percentages of 40%, 10%, 75%, 7%, and 70%, respectively, as ideal cutoff values for stratification, with corresponding P-values of .03, .001, .02, .005, and <.0001, respectively. Interestingly, high nuclear pAkt expression was associated with a favorable prognosis, whereas high cytoplasmic pAkt expression was associated with a poor prognosis. In multivariate Cox regression analysis, ECOG PS, T classification, N classification, M classification, cytoplasmic Akt, nuclear pAkt, PTEN, and pS6 were independent prognostic factors of DSS. CONCLUSIONS: Components of the mTOR pathway are significantly associated with pathological features and survival. Not all RCC tumor types seem to be equally amenable to mTOR targeted therapy. PTEN, pAkt, p27, and pS6 may serve as surrogate parameters for patient selection and predicting prognosis. Patients with a highly activated mTOR pathway should benefit most from this therapy. External validation of our results is recommended. (c) 2007 American Cancer Society.
BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is up-regulated in many humancancers, and agents targeting the mTOR pathway are in various stages of clinical development. The goal of the study was to evaluate the potential and limitations of targeting the mTOR pathway in renal cell carcinoma (RCC). METHODS: Immunohistochemical analysis using antibodies against pAkt, PTEN, p27, and pS6 was performed on a tissue microarray constructed from paraffin-embedded specimens from 375 patients treated by nephrectomy for RCC. The expression was associated with pathological parameters and survival. RESULTS: The mTOR pathway was more significantly altered in clear-cell RCC, high-grade tumors, and tumors with poor prognostic features. PS6 and PTEN showed the strongest associations with pathological parameters. Survival tree analysis regarding expression of cytoplasmic pAkt, nuclear pAkt, PTEN, cytoplasmic p27, and pS6 identified staining percentages of 40%, 10%, 75%, 7%, and 70%, respectively, as ideal cutoff values for stratification, with corresponding P-values of .03, .001, .02, .005, and <.0001, respectively. Interestingly, high nuclear pAkt expression was associated with a favorable prognosis, whereas high cytoplasmic pAkt expression was associated with a poor prognosis. In multivariate Cox regression analysis, ECOG PS, T classification, N classification, M classification, cytoplasmic Akt, nuclear pAkt, PTEN, and pS6 were independent prognostic factors of DSS. CONCLUSIONS: Components of the mTOR pathway are significantly associated with pathological features and survival. Not all RCC tumor types seem to be equally amenable to mTOR targeted therapy. PTEN, pAkt, p27, and pS6 may serve as surrogate parameters for patient selection and predicting prognosis. Patients with a highly activated mTOR pathway should benefit most from this therapy. External validation of our results is recommended. (c) 2007 American Cancer Society.
Authors: Ana M Molina; Satish K Tickoo; Nicole Ishill; Michael J Trinos; Lawrence H Schwartz; Sujata Patil; Darren R Feldman; Victor E Reuter; Paul Russo; Robert J Motzer Journal: Am J Clin Oncol Date: 2011-10 Impact factor: 2.339
Authors: Boyi Gan; Carol Lim; Gerald Chu; Sujun Hua; Zhihu Ding; Michael Collins; Jian Hu; Shan Jiang; Eliot Fletcher-Sananikone; Li Zhuang; Michelle Chang; Hongwu Zheng; Y Alan Wang; David J Kwiatkowski; William G Kaelin; Sabina Signoretti; Ronald A DePinho Journal: Cancer Cell Date: 2010-11-16 Impact factor: 31.743
Authors: Luciana Schultz; Alcides Chaux; Roula Albadine; Jessica Hicks; Jenny J Kim; Angelo M De Marzo; Mohamad E Allaf; Michael A Carducci; Ronald Rodriguez; Hans-Joerg Hammers; Pedram Argani; Victor E Reuter; George J Netto Journal: Am J Surg Pathol Date: 2011-10 Impact factor: 6.394
Authors: Venkateshwar Madka; Altaf Mohammed; Qian Li; Yuting Zhang; Laura Biddick; Jagan M R Patlolla; Stan Lightfoot; Rheal A Towner; Xue-Ru Wu; Vernon E Steele; Levy Kopelovich; Chinthalapally V Rao Journal: Cancer Prev Res (Phila) Date: 2015-11-17
Authors: Huiqing Liu; Angela R Brannon; Anupama R Reddy; Gabriela Alexe; Michael W Seiler; Alexandra Arreola; Jay H Oza; Ming Yao; David Juan; Louis S Liou; Shridar Ganesan; Arnold J Levine; W K Rathmell; Gyan V Bhanot Journal: BMC Syst Biol Date: 2010-04-27