SPORE
Research Programs
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SPORE
Gastrointestinal Cancers SPORE
Projects
Project 1
Project Leader: LEMON, Stanley (University of Texas Medical Branch)
This project seeks to determine the clinical relevance and potential role in
hepatic carcinogenesis of interactions between host cell and hepatitis C virus
(HCV) proteins that have been identified in previous cell culture-based
experiments. The retinoblastoma susceptibility protein (pRb) and the cellular
DEAD-box RNA helicase DDX3 play critical roles in regulating the cell cycle. Our
previous work indicates that the HCV RNA polymerase, NS5B, forms a complex with
pRb, targeting it for ubiquitination and proteasome-dependentdegradation,
activating E2F-responsive promoters, and stimulating cell proliferation.
Similarly, HCV core protein expression alters the cellular abundance and
localization of DDX3. Our hypothesis is that these and other interactions with
host proteins (p53 and DDX5) promote proliferation of hepatocytes and impair DNA
damage responses, thereby contributing to HCV carcinogenesis. In Aim 1, we will
develop and validate fluorescent quantum dot probes capable of sensitive
detection of HCV proteins expressed in virus-infected cells. We will also
determine whether HCV protein expression correlates with altered tumor
suppressor expression in transgenic mice. Aim 2 will utilize these novel probes
in laser scanning confocal and multi-photon microscopy studies of liver tissue
from patients with chronic hepatitis C, and ask whether the abundance and
cellular localization of pRb, p53, DDX3, or DDX5 is altered in infected
hepatocytes. In Aim 3, we will determine whether HCV infection is associated on
a single-cell basis with increased expression of the proliferation markers Ki-67
and PCNA. We will also determine whether the proportion of cells displaying
proliferation markers is reduced after standard-of-care peg-IFN/ribavirin
therapy. These results will be correlated with oligonucleotide microarray and
quantitative RT-PCR assays to determine whether liver specimens with a high
proportion of HCV-infected cells display transcriptional patterns indicative of
hepatocellular proliferation and/or E2F transcription factor activation.
RELEVANCE TO PUBLIC HEATH: Liver cancer is one of the most rapidly increasing
types of cancers in the United States, reflecting an increased prevalence and
risk of liver cancer in persons with chronic hepatitis C. This project seeks a
better understanding of the interaction of HCV proteins with important
regulators of cell proliferation (pRb, p53, DDX3, and DDX5) and the role of such
interactions in liver cancer caused by HCV infection.
Project 2
Principal Investigator: EVERS, B. Mark
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 III) results in a
precipitous decrease in five year survival and systemic metastasis to the liver
(ie, Stage IV) is assocProject Leader: EVERS, B. Mark
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 III) 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 PI3K/Akt decreases viability
and growth, increases differentiation and apoptosis of human colorectal cancer
cells. Furthermore, PI3K/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 PI3K/Akt
expression in colorectal cancers and surrounding stroma with increased
expression of the p85α subunit and Akt2 in colorectal cancers of increasing
stage. Targeted inhibition of either p85α or p110α 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 p85α
and Akt2 expression; the selective inhibition of PI3K/Akt components can
suppress colorectal cancer growth and metastasis and can sensitize resistant
colorectal cancers to chemotherapeutic agents. The long-term goal 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 PI3K/Akt pathway components. To examine our hypothesis
and address the long-term goal, we have designed experiments with the following
Specific Aims:
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To provide clinical validation of the pattern and significance of PI3K/Akt/PTEN
pathway component expression in polyps and colorectal cancers of different
stages.
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To assess novel strategies of selective PI3K component inhibition on in vivo tumor growth
and liver metastasis using preclinical animal models.
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To evaluate the therapeutic efficacy of RNAi to the PI3K pathway in combination
with conventional chemotherapy. The cumulative information derived from these
studies will lead to better targeted therapeutics and treatment paradigms for
colorectal cancer.
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