Brunhilde Felding-Habermann
Laurence Fitzgerald, Ph.D., CBCRP Core Funding Manager
The spread of breast cancer from the primary tumor to distant metastatic sites through the lymph and blood remains an element of tumor progression that is poorly understood and treated. Researchers know that tumor cells circulate in the blood of patients and there is much current interest in isolating these cells with the hope of obtaining prognostic information and better therapy selection. Brunhilde Felding-Habermann, Ph.D. from The Scripps Research Institute in La Jolla has taken a unique approach to study the process of metastasis that has evolved in two directions with CBCRP funding from three separate grants. Her initial interests were focused on the role of specific cell surface adhesion proteins, called integrins, for promoting the tumor cell-extracellular matrix interactions critical for metastasis. The specific integrin of interest is called the vitronectin receptor (avß3), which can exist in an “activated state” on aggressive tumor cells.
The activated vitronectin receptor has the ability to interact with circulating platelets in the blood. It is thought that the tumor cell-platelet interaction serves to form tiny clumps or “thrombi” that can interfere with the microcirculation in organs where metastasis will occur. In addition, the vitronectin receptor also is present on endothelial cells where it plays a critical role in the growth of new tumor-associated blood vessels through the process of angiogenesis. Thus, interfering selectively with activated forms of the vitronectin receptor would be expected to block both the metastasis of circulating tumor cells and tumor growth via inhibition of angiogenesis. Investigators at The Scripps Research Institute are developing small peptide inhibitors based on a three amino acid sequence, called Arg-Gly-Asp (RGD), which can block the active vitronectin receptor. Dr. Felding-Habermann’s strategy is to“ present” these inhibitory peptides as portions of antibody fragments to gain higher specificity, potency, and extended therapeutic effect in the blood. In 2005, the CBCRP funded Dr. Felding-Habermann to pursue her strategy to tackle breast cancer brain metastasis by producing the RGD peptide in the form of viral constructs that could be delivered to the brain through the nose. The research on integrins in cancer biology described above was performed in collaboration with Drs. David Cheresh, Zaverio Ruggeri, and Kim Janda at Scripps. Dr. Felding-Habermann is scheduled to give an update of her research at the Keystone Conference, Host Cell Interaction and Response to the Cancer Cell, on January 21-26, 2007.
Tumor cell metastasis might be
considered from a new perspective,
if the “stem cell theory” of breast
cancer proves correct. In this model
of breast cancer progression tumors
arise, not from mature (differentiated)
epithelial cells, but from “stem
cell-like” progenitors. Thus, the vast
majority of a primary tumor mass
from human patients represents differentiated
cancer cells. Only a small
fraction of the tumor is the residual
stem cell population that gives rise
to more tumor cells. Importantly, it
is from the population of tumor stem
cells that metastatic cells that colonize
distant organs are thought to be shed.
The CBCRP funded Dr. Felding-
Habermann along with co-PIs Dr.
John Yates at The Scripps Research
Institute and Dr. Evan Snyder from
The Burnham Institute in 2004 for a
project, Stem Cells in Breast Cancer
Metastasis. Currently, work is ongoing
to isolate stem cell fractions from
tumors and pleural (lung-derived)
effusions to compare their protein
composition and gain insight into
the “markers” that would predict
metastatic potential. Future therapies
selectively targeting cancer stem cells
are thought to have the potential to
cure the disease, especially in the
advanced, metastatic stages. This is in
contrast to current therapies without
complete cancer stem cell eradication,
which merely shrink tumors and
extend the time to disease recurrence.
Finally, Dr. Felding-Habermann’s
interests have evolved to focus on
neural stem cells. This approach is
a novel paradigm that utilizes these
neural stem cells as a delivery agent
for anti-cancer therapies to target
breast cancer metastases in the brain.
Dr. Felding-Habermann was educated in Germany and received her doctorate from Phillips University of Marburg. She received additional training at the Fred Hutchinson Cancer Research Center in Seattle and as a visiting scientist at Scripps. Prior to returning to Scripps in 1993, Dr. Felding- Habermann was Head of the Cell Adhesion Research Group in the Department of Immunopharmacology at E. Meck KgaA in Germany. She has been on the faculty at Scripps since 1995 and is currently an Associate Professor in the Department of Molecular and Experimental Medicine. In addition to CBCRP support, she has two ongoing NIH R01 grants.
