Colorectal cancer is the second leading cause of cancer deaths in the United States. When localized to the mucosa and submucosa of the bowel wall (Stage I), the five year survival approaches 100%;however, metastasis to lymph nodes (Stage 111) results in a precipitous decrease in five year survival and systemic metastasis to the liver (ie, Stage IV) is associated with a five year survival that is less than 5%. Activation of phosphatidylinositol 3-kinase (PI3K), a ubiquitous lipid kinase composed of an 85 kDa regulatory subunit (p85) and a 110 kDa catalytic subunit (p110), and its downstream effector protein, Akt, is associated with the growth and progression of a number of cancers, including colorectal cancer. We have shown that inhibition of PISK/Akt decreases viability and growth, increases differentiation and apoptosis of human colorectal cancer cells. Furthermore, PISK/Akt inhibition decreases colon cancer xenograft growth in athymic nude mice and sensitizes these cancers to the apoptotic effects of chemotherapeutic agents (eg, 5- FU). Moreover, we have shown altered PISK/Akt expression in colorectal cancers and surrounding stroma with increased expression of the p8Sa subunit and Akt2 in colorectal cancers of increasing stage. Targeted inhibition of either p8Sa or p110a by RNA interference (RNAi) increased sensitivity of resistant colorectal cancers to the effects of chemotherapy and significantly suppressed colorectal cancer metastasis to the liver in preclinical animal models. The central hypothesis of this project is that colorectal cancer growth and progression are augmented by increased p85a and Akt2 expression;the selective inhibition of PISK/Akt components can suppress colorectal cancer growth and metastasis and can sensitize resistant colorectal cancers to chemotherapeutic agents. The long-term qoai is to develop more selected therapies for colorectal cancer progression and metastasis based on a systematic analysis of colorectal cancers, tumor stroma and surrounding mucosa for expression of piSK/Akt pathway components. To examine our hypothesis and address the long-term goal, we have designed experiments with the following Specific Aims: 1) To provide clinical validation of the pattern and significance of PISK/Akt/PTEN pathway component expression in polyps and colorectal cancers of different stages. 2) To assess novel strategies of selective PISK component inhibition on in vivo tumor growth and liver metastasis using preclinical animal models. 3) To evaluate the therapeutic efficacy of RNAi to the PISK pathway in combination with conventional chemotherapy. The cumulative information derived from ttiese studies will lead to better targeted therapeutics and treatment paradigms for colorectal cancer.