[1568] Frequent Activation of the mTOR Pathway in Adenocarcinoma of the Ampulla of Vater

CD Crowder, OH Iwenofu, AM Bellizzi, WL Frankel. The Ohio State University Medical Center, Columbus, OH; Brigham & Women's Hospital, Boston, MA

Background: Mammalian target of rapamycin (mTOR) is a key serine/threonine kinase that exerts a central regulatory effect on metabolism, cell growth, proliferation and cell cycle progression. Constitutive activation of the PI3K/Akt/mTOR pathway has been described in the carcinogenesis of various organs. Previous studies have demonstrated loss of PTEN function (a tumor suppressor interacting with the pathway) and amplification of Akt (a kinase directly upstream of mTOR) and S6rp (a major downstream effector of mTOR and component of the 40S ribosomal subunit) in pancreatic ductal adenocarcinomas. To our knowledge, the activation of this pathway has not yet been demonstrated in ampullary adenocarcinoma (AdCa). We utilized immunohistochemistry for p-S6rp, PTEN and p-Akt to assess the status of the mTOR pathway in ampullary AdCas.
Design: Tissue microarrays were constructed from 40 ampullary AdCas; 1.5 mm duplicate cores were taken from each tumor. Slides were stained with antibodies to p-Akt, p-S6rp and PTEN, and cases were scored as follows: p-S6rp (0, 1+ modest intensity in ≥ 5%, 2+ strong intensity in ≥ 5%); PTEN and p-Akt (positive ≥ 5% staining, negative). Normal pancreatic ducts (13 cases) served as controls. Controls stained appropriately, and slides were reviewed by 2 pathologists.
Results: The majority of ampullary AdCas stained for p-S6rp (77.5%, 1+ in 13 cases, 2+ in 18 cases). Many cases demonstrated loss of PTEN (77.5% of cases), while p-Akt was expressed in 50% of cases. PTEN and p-Akt were both uniformly positive in normal controls. p-S6rp immunoreactivity was only noted in 1 normal control (8.3%). Results are summarized in the table.

mTOR Pathway Protein Expression
Ampullary AdCaNormal Pancreatic Ducts
p-S6rp0: 9 (22.5%)0: 11 (91.7%)
1+: 13 (32.5%)1+: 1 (8.3%)
2+: 18 (45%)2+: 0 (0%)
PTENNegative: 31 (77.5%)Negative: 0 (0%)
Positive: 9 (22.5%)Positive: 10 (100%)
p-AktNegative: 20 (50%)Negative: 0 (0%)
Positive: 20 (50%)Positive: 13 (100%)
Data refers to number (and percentage) of cases


Conclusions: mTOR pathway activation, as evidenced by p-S6rp immunoreactivity and decreased PTEN staining, is frequent in ampullary AdCa. In most cases this appears to be independent of p-Akt status. Given evidence of pathway activation and the existence of specific anti-mTOR therapeutics, mTOR may represent a logical target for directed biologic therapy in ampullary AdCa.
Category: Liver & Pancreas

Tuesday, March 23, 2010 1:00 PM

Poster Session IV # 195, Tuesday Afternoon

 

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