Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy

Pantuck AJ, Seligson DB, Klatte T, Yu H, Leppert JT, Moore L, O'toole
T, Gibbons J, Belldegrun AS, Figlin RA.
Prognostic relevance of the mTOR pathway in renal cell carcinoma:
implications for molecular patient selection for targeted therapy.
Cancer. 2007 Apr 17; [Epub ahead of print]
PMID: 17440983 [PubMed - as supplied by publisher]
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17440983>

"Department of Urology, David Geffen School of Medicine,
University of California, Los Angeles, California.

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. Cancer 2007. (c) 2007 American Cancer
Society."



--
Matti Narkia
.