Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 4538
© 2007 American Society of Clinical Oncology

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Abstract

FOXO3a predicts for survival and its phosphorylated form is downregulated following mTOR or MEK inhibitor therapy in Hepatocellular Carcinoma

National Cancer Centre Singapore, Singapore

4538

Background: Hepatocellular carcinoma (HCC) is an aggressive cancer endemic in Asia with few effective treatments. We hypothesize that FOXO3a may be a potential prognostic marker in HCC and analyze the effects of targeted therapy acting on the PI3K/AKT pathway, of which FOXO3a is downstream. PI3K activates serine/threonine protein kinase AKT, causing FOXO3a phosphorylation and its nuclear translocation, promoting apoptosis. Tumor suppressor, promyelocytic leukemia (PML), inactivates nuclear phosphorylated AKT (pAKT). mTOR, also of the P13K/AKT pathway, is dysregulated in many cancers. PI3K is an effector of RAS, which controls downstream mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) pathway. AZD6244 is a selective inhibitor of MEK1/2. RAD001 (Everolimus) specifically inhibits mTOR. Avastin (bevacizumab) is an anti-angiogenic agent. These therapies have shown clinical efficacy in various cancers, including preliminary results with either RAD001 or avastin treatment in HCC. Method: We analyzed FOXO3a status in 91 stage I and II HCC patients using relative real-time PCR and immunoblotting analysis. Using a primary human HCC xenograft SCID mouse model, we examined tumor efficacy and molecular effects of AZD6244, RAD001 and Avastin treatment. Results: The median survival of the high FOXO3a-expressing group (2-fold increased expression vs normal, >2.0, n=16) was 27 months versus 95 months for the low expressing group (2-fold decreased expression vs normal, <0.5, n=58) (p=0.037). Pearson correlation analysis indicated a positive correlation between FOXO3a and PML (n=46, correlation=0.533, p<0.001). Immunoblotting results for 8 random HCC samples reveal increased levels of pFOXO3a (Ser253) in all tumor tissue compared to adjacent normal. Treatment of HCC xenograft mice with AZD6244 or RAD001 caused significant tumor shrinkage and reduced levels of pAKT (Ser308) and pFOXO3a (Ser318). Avastin had cytostatic effects and unchanged levels of pFOXO3a (Ser318). Conclusion: FOXO3a predicts for overall survival in HCC. A positive correlation is established between FOXO3a and PML. AZD6244 and RAD001 can induce tumor regression via the AKT-FOXO3a pathway in HCC xenografts.

No significant financial relationships to disclose.

Abstract presentation from the 2007 ASCO Annual Meeting