[783] mTOR Pathway Activation in pT1 Urothelial Cell Carcinomas of the Bladder: A Potential Target of Therapy.

Roni Cox, Alcides Chaux, Jason Solus, Luciana Schultz, Angelo Demarzo, Eva Comperat, George J Netto. Johns Hopkins University, Baltimore, MD; Hopital Pitié, Paris, France

Background: The mammalian target of rapamycin (mTOR) pathway has been implicated in a variety of urological malignancies, including urothelial carcinoma of the bladder. Currently, several ongoing clinical trials are evaluating the usefulness of pharmacological agents targeting this pathway. However, there is scant information on mTOR pathway activation in bladder carcinomas with invasion limited to lamina propria. Herein we assess the expression of mTOR pathway protein members and their prognostic role in predicting recurrence and progression in pT1 urothelial carcinomas of the bladder.
Design: Tissue microarrays (TMA) were constructed from 195 consecutive cases of pT1 papillary urothelial carcinomas of the bladder. Each tumor was represented by up to three 1-mm spots. Standard immunohistochemistry analysis for mTOR pathway members (PTEN, phos AKT, mTOR, phos S6, and phos 4EBP1) was performed. H-score was generated for each marker as a product of intensity (0 to 3+) by percent of positive cells. PTEN H-score <10 was considered as PTEN loss; any H-score >0 was considered positive for the remaining four mTOR pathway-related proteins.
Results: Loss of PTEN was found in 18.5% of tumors; phos AKT, mTOR, phos S6, and phos 4EBP1 were expressed in the majority of cases (expression rates of 83.1%, 75.4%, 80.5%, and 74.4%, respectively).

Table 1: Expression rates of mTOR pathway members in pT1 urothelial carcinoma (%)

	phos AKT+	mTOR+	phos S6+	phos 4EBP1+
PTEN loss	58.3	55.6	75.0	52.8
No PTEN loss	88.7	79.9	81.8	79.2
P-value	<0.0001	0.005	0.357	0.002

PTEN loss and immunoexpression levels of the four studied mTOR pathway proteins failed to predict recurrence or progression in the current cohort (P>0.05).
Conclusions: We found high expression rates of mTOR pathway members in pT1 stage urothelial carcinomas of bladder indicating activation of the mTOR pathway in the superficially invasive phase of disease. The current findings support a potential role for mTOR-targeted pharmacological therapies in superficially invasive bladder cancer. Our data suggests that PTEN loss may be responsible for only a minor fraction of such activation. Alternate molecular mechanisms may be implicated in our observed mTOR pathway activation.
Category: Genitourinary (including renal tumors)

Tuesday, March 1, 2011 9:30 AM

Poster Session III # 170, Tuesday Morning