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
1. Therapeutic Targeting of Breast Cancer Dormancy,
Resistance and Stem Cell Mechanisms. A new project in the
lab that targets the cancer stem cell phenotype and dormant
metastatic breast cancer. The current approach blocks the effect
of detoxification pathways which promote cell survival in
metastatic sites during chemotherapy treatment. The “unblocking”
this protection pathway with unique therapeutic compounds will
significantly improve therapeutic targeting of distal metastatic
disease to prevent recurrence. Project involves the testing of
various unique compounds using in vitro breast cancer cell
models as well as translating effective compounds into animal
pre-clinical models of primary and metastatic disease.
2. Breast Cancer Initiation and Progression through the
Epigenetic Suppression of Key Metabolic and Signaling Pathways.
Our long-standing interest in stress responses that are
overridden in cancer have evolved into defining early events
that define breast cancer risk and promote progression. One key
pathway is the activation of the AMP-dependent kinases (AMPK)
under metabolic stress. The catalytic isoform AMPKa2 appears to
be crucial to suppression of proliferation signals and has been
shown to be epigenetically suppressed in early human breast
cancer. We are currently testing models of cancer cells
deficient in AMPKa2 by RNA interference in vitro, long-term
suppression using in vivo models and genetic deletion in
endogenous animal cancers. The suppression of this pathway and
its contribution to breast tumorigenesis and metastasis
indicates the importance of normal growth control. The main
project relates to genetic animal models and in vivo tumor
growth and metastasis of cells with modified levels of AMPKa2
expression.
3. Isolation of Patient-Derived Anti-Cancer Antibodies
from Tumor Draining Sentinel Lymph Nodes in Breast Cancer and
Melanoma. A novel methodology has been developed in the lab
to investigate whether patients have a strong immune response to
cancer antigens within tumor-draining lymph nodes. We have taken
tumor draining lymph nodes from patients and identified B-cell
activation within the node, isolated complete cDNA libraries for
the antibodies being synthesized there, and used recombinant
antibodies to identified novel tumor antigens. A novel
methodology is being tested to identify antibodies from live
cells and produce antibody clones within a week of sentinel
lymph node sampling. These antibodies will be developed for
primary biomarker diagnostics using multiplex assays and as a
therapeutic option for late stage metastatic cancers.
Selected Publications
Rodriguez-Pinto D, Sparkowski J, Keough MP, Phoenix KN, Vumbaca
F, Han DK,Gundelfinger ED, Beesley P, Claffey KP.
Identification of novel tumor antigens with patient-derived
immune-selected antibodies. Cancer Immunol Immunother. 2009
Feb;58(2):221-34. Epub 2008 Jun 21.
Phoenix KN, Vumbaca F, Claffey KP. Therapeutic metformin/AMPK
activation promotes the angiogenic phenotype in the
ERalpha negative MDA-MB-435 breast cancer model. Breast Cancer
Res Treat. 2009 Jan;113(1):101-11. Epub 2008 Feb 7.
Vumbaca F, Phoenix KN, Rodriguez-Pinto D, Han DK, Claffey KP.
Double-stranded RNA-binding protein regulates vascular
endothelial growth factor mRNA stability, translation, and
breast cancer angiogenesis. Mol Cell Biol. 2008
Jan;28(2):772-83. Epub 2007 Nov 26.
Backer MV, Patel V, Jehning BT, Claffey KP, Backer JM.
Surface immobilization of active vascular endothelial growth
factor via a cysteine-containing tag. Biomaterials. 2006
Nov;27(31):5452-8. Epub 2006 Jul 14.
Neurath KM, Keough MP, Mikkelsen T, Claffey KP. AMP-dependent
protein kinase alpha 2 isoform promotes hypoxia-induced VEGF
expression in human glioblastoma. Glia. 2006 May;53(7):733-43.
Muñoz-Nájar UM, Neurath KM, Vumbaca F, Claffey KP. Hypoxia
stimulates breast carcinoma cell invasion through MT1-MMP and
MMP-2 activation. Oncogene. 2006 Apr 13;25(16):2379-92.
Belinsky GS, Claffey KP, Nambiar PR, Guda K, Rosenberg DW.
Vascular endothelial growth factor and enhanced angiogenesis do
not promote metastatic conversion of a newly established
azoxymethane-induced colon cancer cell line. Mol Carcinog. 2005
Jun;43(2):65-74.
Kluk MJ, Grant-Kels JM, Kerr P, Hoss D, Berke A, Claffey KP,
Murphy M. Melanoma on the move: the progression of melanoma:
novel concepts with histologic correlates. Am J Dermatopathol.
2004 Dec;26(6):504-10. Review. No abstract available.
Agarwal A, Muñoz-Nájar U, Klueh U, Shih SC, Claffey KP.
N-acetyl-cysteine promotes angiostatin production and vascular
collapse in an orthotopic model of breast cancer. Am J Pathol.
2004 May;164(5):1683-96.
Claffey KP. Molecular profiling of angiogenic markers: a step
towards interpretive analysis of a complex biological function.
Am J Pathol. 2002 Jul;161(1):7-11. No abstract available.
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.
rev. 3/09 |
