1. OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)
BIOGRAPHICAL SKETCH
Provide the follow ing information for the Senior/key personnel and other significant contributors.
Follow this format for each person. DO NOT EXCEED FIVE PAGES.
NAME: Brunhilde H. Felding
eRA COMMONS USER NAME (credential, e.g., agency login): BRUNIE
POSITION TITLE: Associate Professor (Tenure)
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing,
include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION
DEGREE
(if
applicable)
Completion
Date
MM/YYYY
FIELD OF STUDY
Justus-Liebig-University of Giessen, Germany
Phillips-University of Marburg, Germany
M.Sc.
Ph.D.
05/80
02/84
Biology
Biochemistry
A. Personal Statement
The goal of our research is to understand mechanisms of cancer progression and to develop new regimens for
prevention and treatment. Based on our preclinical models, our analyses of the initial steps of cancer metastasis
from the blood stream, particularly cancer spreading to the brain, tumor cell interaction with vascular cells, and
evidence of mechanisms that drive metastatic cancer cell proliferation within the brain, we are developing
therapeutic approaches to prevent and treat metastasis. Furthermore, our research on tumor cell metabolism and
mitochondrial activity are yielding novel strategies to suppress aggressiveness in cancer, and to make current
therapies more effective by interfering with treatment resistance. I have a broad background in cancer cell biology,
biochemistry, drug and therapeutic antibody development, and functional analyses of tumor progression. I have
specifically developed cell and animal models of breast cancer brain metastasis. This expertise and my experience
in antibody based approaches against metastasis, as well as strong partnerships with colleagues in antibody
engineering, chemistry, structural and computational biology, and bioinformatics provide the foundation for
development of new, effective approaches to block cancer progression and advance our projects toward clinical
translation for prevention and treatment of cancer metastasis.
B. Positions and Honors
1984-1987 Research Associate, Dept. of Physiological Chemistry, Phillips University Marburg, Germany
1987-1989 Research Associate, Fred Hutchinson Cancer Research Center and Biomembrane Inst., Seattle
1989-1991 Visiting Scientist, The Scripps Research Institute (TSRI), La Jolla
1991-1993 Head of Cell Adhesion Res. Group, Dept. of Immunopharmacology, E. Merck KgaA, Germany
1993-1995 Senior Research Associate, Dept. of Molecular & Experimental Medicine (MEM), TSRI, La Jolla
1995-2003 Assistant Professor, The Scripps Research Institute, La Jolla
2003-Pres. Associate Professor, The Scripps Research Institute, La Jolla
2007-Pres. Teaching Faculty, Kellogg School of Science and Technology, The Scripps Research Institute
2013 Tenure, The Scripps Research Institute, La Jolla
2010-2014 Board Member of the Metastasis Research Society
Other Professional Activities
Service on Scientific Review Panels:
2006 – 2011 Member of the NIH Tumor Progression and Metastasis (TPM) Study Section
2005 – 2006 Member of the NIH Onc-L (12)B Cancer Diagnostic and Treatment Study Section
2004 – 2006 Member of the Western 4B Review Panel of the American Heart Association
2002 – 2005 Member of the Pathology Review Panels of the Army DOD Breast Cancer Research Program
2005 – present Ad hoc reviewer for NIH study sections TPM Tumor Progression and
Metastasis, ZRG1 CB-J31 Shared Instrument, ZCA1 SRLB-C and SRB-1 Omnibus Study
Sections, CDP Chemo and Dietary Prevention, National Science Foundation, DoD Breast
Cancer Research Program, Arizona Biomedical Research Commission, Cancer Research UK,
2. Italian Association for Cancer Research, Swiss National Science Foundation, Dutch Cancer
Society, Erwin Schroedinger Science Program Austria
Service as reviewer for Scientific Journals including: Am J Pathol, Biochemistry, Blood, Breast Cancer Res,
Br J Hematol, Cancer Cell, Cancer Cell Intl, Cell, Cancer Discovery, Cancer Res, Clin Cancer Res, Clin Exp
Metastasis, Experimental Cell Biol, Expert Opin Invest Drugs, Endocrinology, Intl J Cancer, J Biol Chem, J
Cell Biology, J Clin Invest, Molecular Cancer Res, Nature, Nature Cell Biology, Nature Medicine, Oncogene,
Proc Natl Acad Sci USA, Science
C. Contribution to Science
Our goals are to understand mechanisms of cancer progression, define functional targets for inhibition, and
develop new, effective approaches for therapy.
1. Role of mitochondrial aberrations in breast cancer progression. Despite advances in clinical therapy, cancer
progression to metastasis remains the leading cause of death in breast cancer patients. Even though genes and
signaling pathways have been identified that support tumor development and progression, it is still not fully
understood which factors render cancer cells particularly aggressive. We recently identified a cause-and-effect
relationship between altered mitochondrial complex I function in breast cancer cells and their aggressive
phenotype. The mechanism is based on regulation of the tumor cell NAD+/NADH redox balance, mTORC1
activity, and autophagy. Conversely, we showed that nonlethal reduction of NAD+ levels by interfering with
nicotinamide phosphoribosyl transferase (NAMPT) expression renders tumor cells highly aggressive and
increases metastasis. We translated our results into a new therapeutic strategy where enhancement of the
NAD+/NADH balance through treatment with NAD+ precursors inhibits metastasis in xenograft studies, increases
animal survival, and strongly interferes with oncogene-driven breast cancer progression in the MMTV-PyMT
mouse model. Thus, we showed that aberration in mitochondrial complex I NADH dehydrogenase activity can
profoundly enhance the aggressiveness of human breast cancer cells, while therapeutic normalization of the
NAD+/NADH balance inhibits metastasis and interferes with disease progression, documenting a central role for
NAD+ metabolism in determining the phenotype of breast cancer cells.
• Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, LeBoeuf SE, Gay LJ, Yagi T, Felding-Habermann
B. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. 2013 J
Clin Invest 123(3):1068-81 PMID: 23426180, PMCID: PMC3582128
• Santidrian AF, LeBoeuf SE, Wold ED, Ritland M, Forsyth JS, Felding BH. Nicotinamide phosphoribosyl
transferase can affect metastatic activity and cell adhesive functions by regulating integrins in breast cancer.
2014 DNA Repair Nov,23:79-87 PMID: 25263164, PMCID: PMC4252795
2. Integrin activation can control metastatic activity. Studying tumor cell interactions with vascular cells in the
circulation, we discovered four major functional determinants of tumor metastasis. First, we found that platelets
are required for tumor cell arrest during blood flow, survival within the blood stream, and extravasation into target
organs of metastasis. Second, by identifying tumor cell and platelet receptors involved in their interaction, we
found that tumor cells can carry integrin adhesion receptors in distinct states of affinity, and that constitutive
expression of the high affinity conformer of integrin αvβ3 mediates binding to platelets, and strongly promotes
an invasive, metastatic phenotype. Third, we identified the activated form of integrin αvβ3 as a functional
contributor to metastasis in breast cancer and melanoma, and showed that specific targeting of high affinity αvβ3
inhibits metastatic disease in animal models. Fourth, we discovered that the cancer patient immune repertoire
contains antibodies that specifically bind and inhibit the high affinity conformer of αvβ3 by mimicking ligands
of the receptor. These findings are clinically relevant, because treatment with these antibodies can prevent
metastatic spreading and interfere with advanced metastatic disease. Thus, expression of high affinity integrin
conformers can drive cancer progression and be targeted for therapeutic intervention. Linking these discoveries
with our new insight on tumor cell metabolism revealed, that the expression and affinity state of key tumor cell
adhesion receptors involves dysregulation of cancer cell NAD+ salvage pathway activity.
• Felding-Habermann B, O’Toole TE, Smith JW, Fransvea E, Ruggeri ZM, Ginsberg MH, Hughes PE,
Pampori N, Shattil SJ, Saven A, Mueller BM. Integrin activation controls metastasis in human breast cancer.
PNAS 98(4):1853-8. Proc Natl Acad Sci USA 2001 PMID:11172040, PMCID: PMC29346
• Rolli M, Fransvea E, Pilch J, Saven A, Felding-Habermann B. Activated integrin αvβ3 cooperates with
metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells. Proc Natl Acad Sci USA
100(16):9482-7, 2003 PMID: 12874388 PMID: 12874388, PMCID: PMC170944
3. • Felding-Habermann B, Lerner RA, Lillo A, Zhuang S, Weber MR, Arrues S, Gao C, Mao S, Saven A,
Janda KD. Combinatorial antibody libraries from cancer patients yield ligand-mimetic ARG-Gly-Asp-
containing immunoglobulins that inhibit breast cancer metastasis. Proc Natl Acad Sci USA 101:17210-
17215, 2004. PMID: 15563590, PMCID: PMC534417
• Staflin K, Krueger JS, Hachmann J, Forsyth JS, Lorger M, Steiniger SC, Mee J, Pop C, Salvesen GS, Janda
KD, Felding-Habermann B. Targeting activated integrin alphavbeta3 with patient-derived antibodies
impacts late-stage multiorgan metastasis. Clin Exp Metastasis. 2010 Apr;27(4):217-31. Epub 2010 Mar 12.
PMID: 20225083, PMCID: 4830478
3. Mechanisms of breast cancer brain metastasis. Brain metastases resist treatment and are ultimately fatal. We
have contributed to pioneering research in the understudied field of brain metastasis by generating unique cell
and animal models that emulate the human disease. We discovered that tumor cells reside and must survive within
the cerebral microvasculature for 3-7 days before they can breach the blood brain barrier. During this time, the
tumor cells depend on platelet interaction, coagulation, and cytoprotective signaling pathways triggered by tumor
cell expressed tissue factor. Together with platelets, astrocyte recruitment supports mechanisms that open the
blood brain barrier to tumor cell invasion.
Based on comprehensive proteomic analyses and in vivo validation, we discovered that once arrived within the
brain parenchyma, brain metastatic cells adapt their metabolic activities and rely primarily on oxidative
phosphorylation for intracranial growth. Furthermore within the brain microenvironment, expression of high
affinity integrin αvβ3 provides tumor cells with a unique advantage, as it triggers signaling pathways for
proliferation and continuous, hypoxia independent VEGF protein production for highly efficient angiogenesis
and recruitment of blood supply. The mechanism is based on inhibition of translational repressor 4E-BP1, and it
is not executed at the primary tumor site.
• Chen EI, Hewel J, Krueger JS, Weber MR, Tiraby C, Kralli A, Becker K, Yates JR III, Felding-
Habermann B. Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res 67(4):
1472-1486, 2007. PMID: 17308085, [Accepted prior to April 7, 2008]
• Lorger M, Krueger JS, O’Neal M, Staflin K, Felding-Habermann B. Activation of tumor cell integrin
αvβ3 controls angiogenesis and metastatic growth in the brain. Proc Natl Acad Sci USA 2009, 106(26):
10666-71. PMID: 19541645, PMCID: PMC2697113
• Lorger M, Felding-Habermann B. Capturing changes in the brain microenvironment during initial steps of
brain metastasis. Am J Pathol 2010, 176(6): 2958-71. PMID: 20382702, PMCID: PMC2877856
• Lorger M, Lee H, Forsyth JS, Felding-Habermann B Comparison of in vitro and in vivo approaches to
studying brain colonization by breast cancer cells. J Neurooncol 2011 Feb 27 [Epub ahead of print]. PMID:
21359851
4. Development of antibodies for cancer therapy. To improve diagnosis and treatment of metastatic cancer, we
used combinatorial antibody library approaches and antibody engineering in two major advances. First, we
identified new targets on metastatic tumor cells and isolated unique, specific antibodies to tumor cell molecules
that were identified in our functional analyses. Second, we generated antibody drug conjugates and chemically
programmed antibodies, and documented their therapeutic efficacy against metastatic disease.
• Hutchins BM, Kazane SA, Staflin KI, Forsyth JS, Felding-Habermann B, Schultz PG, Smider VV. Site-
specific coupling and sterically controlled formation of multimeric antibody Fab fragments using unnatural
amino acids. J Mol Bio 2011, 406 (4):595-603. PMID: 21237172, PMCID: PMC4278757
• Hutchins BM, Kazane SA, Staflin K, Forsyth JS, Felding-Habermann B, Smider VV, Schultz PG Selective
Formation of Covalent Protein Heterodimers with an Unnatural Amino Acid. Chemistry and Biology 2011,
18(3):299-303. PMID: 21439474, PMCID: PMC3694407
• Goswami RK, Bajjuri KM, Forsyth JS, Das S, Hassenpflug W, Huang ZZ, Lerner RA, Felding-
Habermann B, Sinha SC. Chemically Programmed Antibodies Targeting Multiple Alpha(v) Integrins and
Their Effects on Tumor-Related Functions in Vitro. Bioconjug Chem. 2011 Aug 17;22(8):1535-44. PMID:
21774545, PMCID: PMC3277862
• Kularatne SA, Deshmukh V, Ma J, Tardif V, Lim RK, Pugh HM, Sun Y, Manibusan A, Sellers AJ, Barnett
RS, Srinagesh S, Forsyth JS, Hassenpflug W, Tian F, Javahishvili T, Felding-Habermann B, Lawson BR,
Kazane SA, Schultz PG. A CXCR4-Targeted site-specific antibody-drug conjugate. 2014 Angew Chem Int
Ed Engl. Oct 27; 53(44): 11863-7 PMID: 25213874, PMCID:PMC4331128
Complete List of Published Work in MyBibliography:
http://www.ncbi.nlm.nih.gov/sites/myncbi/brunhilde.felding.1/bibliography/40521637/public/?sort=date&direct
ion=ascending
4. D. ResearchSupport
Ongoing ResearchSupport
R01CA170737 Felding-Habermann (PI) 08/01/12 – 07/31/16
National Institutes of Health
Normalizing Breast Cancer Metabolism to Prevent Progression and Recurrence
We aim to investigate if treatments to normalize the cellular NAD+/NADH redox balance in combination with
standard therapy can prevent breast cancer progression and recurrence.
R01CA170140 Eliceiri/Felding-Habermann (MPI) 07/01/12 – 06/30/17
National Institutes of Health
Vascular Mechanisms regulating breast cancer brain metastasis
We aim to provide a functional basis for a better understanding of mechanisms through which cerebral vascular
normalization controls breast cancer brain metastasis. The results may validate src, endothelial FAK and
specific platelet functions as key targets for prevention and treatment of brain metastasis in breast cancer
patients.
R21CA198595 Felding/Smider (MPI) 07/01/15 – 06/30/17
National Institutes of Health
Antibody Fingerprinting of Triple Negative Breast Cancer by High Throughput FACS
We aim to identify clinically relevant molecular targets on triple negative breast cancer cells and provide
specific antibodies with therapeutic and diagnostic potential for future evaluation and development.
BC 123479 Felding (PI) 09/01/13 – 08/31/16
Department of Defense Breast Cancer Research Program (BCRP CDMRP)
Metabolomic Imaging of Early Breast Cancer Brain Metastasis to Identify Targets for Prevention
We aim to understand key metabolic requirements at critical stages of brain metastatic progression based on
comprehensive and targeted metabolomic analyses and in situ imaging of metabolite profiles.
BC132886P1 Smider/Felding (PIs) 09/30/14 – 09/29/17
Department of Defense Breast Cancer Research Program (BCRP CDMRP)
Antibodies Targeting EMT
We aim to generate and investigate antibodies that can interfere with epithelial to mesenchymal transition in
breast cancer.
Completed ResearchSupport
18IB-0022 Felding-Habermann (PI) 08/01/12 – 01/31/14
California Breast Cancer Research Program
Host hypoxia: A new approach to treating breast cancer brain metastasis
We studied a novel therapeutic approach to inhibit brain metastasis and investigate mechanisms involved.
17NB-0058 Felding-Habermann (PI) 08/01/09 – 07/31/13
California Beast Cancer Research Program
Combating Breast Cancer with the Wellderly Immune Repertoire
We aimed to understand mechanisms that drive progression in inflammatory breast cancer and to isolate
therapeutically relevant antibodies against this disease. Role: Co-PI
ASG-RC09-1601 Smider (PI) 07/01/09 – 06/30/13
American Cancer Society
Unnatural Amino Acids in Cancer Immunotherapy
We aimed to identify antibody fragments containing unnatural amino acids against cancer targets. Role: Co-PI
NIH UL1RR025774 Topol (PI) 07/01/11 – 6/30/12
National Institutes of Health, Scripps Translational Science Institute Pilot Study
Mitochondrial complex I alterations in breast cancer
We aimed to examine mitochondrial quality and oxidative mitochondrial DNA damage in breast cancer.
Role: Felding-Habermann (PI) of Pilot Award under this study
5. R01 CA120289 Sinha (PI) 03/01/07 – 02/29/12
NIH/NCI
Selective Antibody Conjugates
We aimed to develop novel cell-targeting antibody constructs to evaluate anti-tumor efficacy.
Role: Co-PI
W81XWH-08-1-0468 Felding-Habermann (PI) 07/01/08 – 06/30/11
CDMRP DOD Breast Cancer Research Program
Neural Stem Cell Delivery of Therapeutic Antibodies to treat Breast Cancer Brain Metastases
We aimed to establish and evaluate a neural stem cell based delivery system for therapeutic antibodies to reach
and treat brain metastases in breast cancer patients.
16IB-0052 Felding-Habermann (PI) 07/01/10 - 12/31/11
California Breast Cancer Research Program
Inhibiting Breast Cancer Brain Metastasis with Cilengitide
We aimed to evaluate a new therapy for human breast cancer brain metastasis in vivo.
R01 CA112287 Felding-Habermann (PI) 11/01/04 – 06/30/10
National Institutes of Health
Targeting Metastatic Breast Cancer with Human Antibodies
We aimed to isolate patient antibodies for inhibition of breast cancer invasion and metastasis.
UL1 RR025774 Topol (PI) 10/01/09 – 09/30/10
Scripps Translational Research Award
Investigation of New Inhibitors of Hyaluronidase-1 for Treatment of Cancer Progression
We aimed to investigate a role of Hyal-1 in cancer invasion and metastatic progression.
Role: Felding-Habermann (PI) of Pilot Award under this study
13NB-0180 Felding-Habermann (PI) 07/01/06 – 12/31/09
CA Breast Cancer Research Program
Neural Stem Cell Therapy for Breast Cancer Brain Metastases
We aimed to establish a neural stem cell model and analytical system for neural stem cell based targeting of
breast cancer brain metastases.