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Faculty Kevin Claffey
Associate Professor of Cell Biology
Associate Director, Graduate Program in Cell Biology
claffey@nso2.uchc.edu
Areas of Interest:
The projects in Dr. Claffey's laboratory are focused on the molecular
regulation of VEGF in human tumor cells which is responsible for
promoting new blood vessel growth during tumor progression and
metastasis. Preventing tumor cell expression of VEGF has been a major
focus in many clinical and pharmaceutical research labs. The response of
tumor cells to hypoxic stress and activation of signal transduction
cascades upstream of the regulation of transcriptional and mRNA
stabilization mechanisms which control VEGF gene expression are being
defined. In vivo models of tumor growth and metastases are used to
evaluate angiogenic and growth inhibitors as well as determine the
function of angiogenic cytokines on metastatic events.
Lab Rotation Projects:
- Regulation of hypoxia-induced gene expression by mRNA binding
proteins that promote vascular endothelial growth factor (VEGF) mRNA
stability and facilitated translation. Project examines the
mechanisms of mRNA transcription and intracellular shuttling of the
major angiogenic factor, VEGF under hypoxic stress. Hypoxic-induced
genes such as VEGF are essential to tumor cell expansion and survival
and the mechanism required for expression are potential targets of
therapeutic intervention. Our current focus is on mRNA-binding
proteins that promote nuclear-cytoplasmic shuttling of the mRNA mRNA
association with endoplasmic reticulum to allow translation even under
metabolic stress.
- Metabolic tumor cell signaling that promotes survival and
expansion. We have recently investigated the response of human
glioblastoma to hypoxic stress. A key response pathway was found to
promote survival and expression of hypoxia-induced survival genes,
including glucose transporter-1 and VEGF. We defined a critical
pathway downstream of the PTEN tumor suppressor, which is
deleted/mutated in 30-50% of advance human gliomas. The pathway is
activated by the expression of a specific isoform of the AMP-dependent
kinases (AMPK) that are activated when cells are under metabolic
stress and the AMP:ATP ratios increase. We are currently evaluating
whether targeting this pathway promotes glioma tumor sensitivity to
hypoxia as a potential therapeutic application for radio- and
chemo-resistant human glioblastoma multiforme. A similar pathway
appears to be operating in human breast cancer as well and we are
using both in vitro and animal models of breast cancer and metastasis
to determine its specific function, contribution to breast
tumorigenesis and metastasis.
- Translational research on breast cancer antigen-dependent
immune activation events. A novel methodology has been developed
in the lab to investigate whether patients have an activated mechanism
for identifying cancer antigens within tumor-draining lymph nodes. We
have taken tumor draining lymph nodes from patients and identified
B-cell activation within the tissues, isolated complete cDNA libraries
for the antibodies being synthesized there and used recombinant
monobodies to trap tumor antigens from the same patient tumor extracts
using advanced and sensitive proteomic methods. One antigen is present
in 50% of primary breast cancers that result in distal metastatic
lesions, even with current therapy. These antibodies will be developed
for primary biomarker diagnostics as well as therapeutic options for
late stage secondary breast cancer metastasis.
Selected Publications:
Sanchez T, Estrada-Hernandez T, Paik JH, Wu MT, Venkataraman K,
Brinkmann V, Claffey K, Hla T. Phosphorylation and action of the
immunomodulator FTY720 inhibits VEGF-induced vascular permeability.J
Biol Chem. 2003 Sep 3.
Claffey KP. Molecular profiling of angiogenic markers: a step towards
interpretive analysis of a complex biological function. No abstract
available. Am J Pathol. 2002 Jul;161(1):7-11.
Shih SC, Claffey KP. Role of AP-1 and HIF-1 transcription factors in
TGF-beta activation of VEGF expression. Growth Factors.
2001;19(1):19-34.
Claffey KP, Abrams K, Shih SC, Brown LF, Mullen A, Keough M.
Fibroblast growth factor 2 activation of stromal cell vascular
endothelial growth factor expression and angiogenesis. Lab Invest. 2001
Jan;81(1):61-75.
Shih SC, Mullen A, Abrams K, Mukhopadhyay D, Claffey KP. Role of
protein kinase C isoforms in phorbol ester-induced vascular endothelial
growth factor expression in human glioblastoma cells. J Biol. Chem. 2000
Sep 15;275(37):29178. |
