Pathogenesis: Understanding the Disease
Pathogenesis Funding Data:
Proportion of CBCRP's Total |
||
Grants awarded in 2002: |
31 |
46% |
Funded Amount: |
$6,159,554 |
42% |
Pathogenesis Portfolio Summary:
The underlying cellular, genetic, and biological processes of breast cancer continue to be major topics of research interest and CBCRP funding for 2002. Some key questions that are being addressed in our funded research include:
- Why do cancer cells have the ability to divide beyond the point where normal breast cells become stable?
- What is the underlying biology that explains why many breast cancer cells do not respond well to drug treatment, or develop drug resistance?
- What are the genetic differences between various forms of breast cancer?
- Can a more detailed understanding of heterogeneity in breast cancer lead to better disease biomarkers and targeted, individualized therapies?
- What are the key genetic and protein biomarkers of disease status and risk for progression?
Because of the large number of Pathogenesis grants funded in 2002, we will provide highlights only for selected projects. Gerry Boss and Anne Wallace at the University of California, San Diego, are funded for a three-year Translational Research Collaboration to study whether a newly patented test for a key signaling protein, called Ras, might provide prognostic information on biopsy samples. Ras inhibitors are in clinical development, but there is not a validated assay to match patients with these drugs. Jan Schnitzer from the Sidney Kimmel Cancer Center is funded for an innovative STEP grant to discover new proteins on the blood vessel lining cells (endothelial cells) that are specific to breast cancer and might be the target of new therapeutics. This research would open new opportunities to target the tumor's blood supply. Jonathan Pollack from Stanford University is funded as a new investigator to use powerful DNA array technology to pinpoint DNA amplifications or deletions in clinical samples. Herceptin become most clinically useful when a test became available to determine those women having Her-2 gene amplifications. Dr. Pollack would greatly expand on this approach and simultaneously associate gene expression information and gene copy number.
Next, proteomics is an emerging discipline that complements genetic analysis by studying the protein content and abundance within cells and, in the case of breast cancer, determining how protein differences are associated with progression and key biological properties. Benjamin Cravatt and his postdoctoral fellow, Arul Joseph at the Scripps Research Institute, are funded in separate grants to apply a novel proteomics assay to analyze the invasive proteases of breast cancer cells. Their methods can catalog the active proteases and simultaneously point the way to inhibiting their activity.
The narrow focus in basic science's approach to breast cancer is illustrated best by the fact that the bulk of research is performed using less than ten model cell lines, and these model cells do not mirror key clinical aspects of the disease. Shanaz Dairkee at the California Pacific Medical Center is using CBCRP funding to think outside the box and develop a potential breakthrough technique to immortalize breast cancer cells directly from newly diagnosed patients. If successful, this method might bring individualized therapy a big step closer.
Finally, the CBCRP funds career development and allows
researchers to bring approaches completely outside current breast cancer
research to bear on our understanding the disease. Patrick Lupardus
at Stanford University received a Dissertation Award to study a
key DNA repair process using a frog model system. The inability of cancer
cells to monitor their DNA properly is a key factor in allowing the massive
genetic changes seen at diagnosis. A postdoctoral fellow, Cheryl
Van Buskirk at the California Institute of Technology, is studying
a nematode, called C. elegans, to see how the cellular processing
of a key growth factor receptor (EGFR) is regulated. Kelly Boatright
at The Burnham Institute received a Dissertation Award to enter
breast cancer research by studying why chromosome separation is defective
in breast cancer.
Pathogenesis Grants Funded in 2002:
The newly funded grants for CBCRP's Pathogenesis priority issue are organized into five sub-topics.
1. Outbreak—How Cancer Spreads: Angiogenesis, Invasion, and Metastasis
Breast tumors becomes life-threatening by acquiring the ability to stimulate blood vessel growth, initiating cell movement and invasion, and ultimately spreading to distant organs. The CBCRP funded four new grants in 2002 under this sub-topic.
HOX Transcriptional Regulation of Angiogenesis
Charboneau, Aubri
University of California, San Francisco
Postdoctoral Fellowship
2 years, $80,000
The Role of Matrix Metalloproteinase 13 in Breast Cancer
Egeblad, Mikala
University of California, San Francisco
Postdoctoral Fellowship
2 years, $80,000
Method to Profile Active Metalloproteases in Breast Cancer
Joseph, Arul
Scripps Research Institute
Postdoctoral Fellowship
2 years, $86,400
Identifying Accessible Targets in Human Breast Tumors
Schnitzer, Jan
Sidney Kimmel Cancer Center
STEP Award
2 years, $496,000
2. Too Much Cell Growth: Defective Messages and Internal Signaling
Cancer is defined as the growth of abnormal cells. Therefore, much current research effort is directed at underlying growth processes of intracellular signaling, cell division control checkpoints, growth receptor function (e.g., Her-2 and EGFR), and programmed cell death (apoptosis). This research will give insight into tumor formation and the ability of cells to survive drug treatment and the immune response. The CBCRP funded nine new grants in 2002 under this sub-topic.
Cell Killing Effect of Orphan Receptor TR3 in Breast Cancer
Bruey-Sedano, Nathalie
The Burnham Institute
Postdoctoral Fellowship
2 years, $86,400
Novel Ligands as Probes of Estrogen Receptor Signaling
Clegg, Nicola
University of California, San Francisco
Dissertation Award
2 years, $50,941
Cyclin E Affects Growth Arrest in Breast Cancer Cells
Dhillon, Navdeep
University of California, Davis
Dissertation Award
2 years, $50,386
A Novel Anti-estrogen Resistance Mechanism in Breast Cancer
Ely, Kathryn
The Burnham Institute
IDEA Award
1.5 years, $144,000
Potential Role of a Novel Repressor Complex in Breast Cancer
Liu, JianXiang
University of California, San Diego
Postdoctoral Fellowship
2 years, $80,000
Structure and Function of the Bax Apoptosis Regulator
Marassi, Francesca
The Burnham Institute
STEP Award
2 years, $297,000
DNA Damage Response Pathways in Breast Cancer Cells
Maroto, Beatriz
Scripps Research Institute
Postdoctoral Fellowship
2 years, $86,400
Regulation of Estrogen Response by Corepressors
Privalsky, Martin
University of California, Davis
STEP Award
2 years, $149,942
Analysis of EGFR Transcript Splicing in C. Elegans
Van Buskirk, Cheryl
California Institute of Technology
Postdoctoral Fellowship
2 years, $86,400
3. Mistakes on the Master Blueprint: Molecular Genetics and Gene Regulation
Breast cancer is characterized by major chromosomal deletions, duplications, and rearrangements. These genetic mutations might someday form the basis of detection, treatment, and analysis of disease severity. Many of these genetic alterations are thought to accumulate as a result of defects in DNA monitoring functions and normal repair processes. The CBCRP funded four new grants in 2002 under this sub-topic.
Alterations in the Separase/Securin Balance in Breast Cancer
Boatright, Kelly
The Burnham Institute
Dissertation Award
2 years, $60,000
Identifying Sources of Genomic Instability in Breast Cancer
Cimprich, Karlene
Stanford University
IDEA Award
1.5 years, $118,432
The Detailed Structure of a Model Breast Cancer Genome
Collins, Colin
University of California, San Francisco
STEP Award
2 years, $194,840
Global Gene Regulation by SATB1 in Metastatic Breast Cancer
Kohwi-Shigematsu, Terumi
Lawrence Berkeley National Laboratory
IDEA Award
1 year, $161,513
4. Searching the Unknown: Novel Breast Cancer Genes
It has been estimated that up to 4,000 of the 30,000-35,000 human genes might represent causative agents for initiation and progression of various human diseases. The relevant number for breast cancer is thought to be 100-200, perhaps less. Each new suspected genetic piece of the puzzle needs to be validated as relevant to breast cancer and accurately placed with respect to the biology of the disease. The CBCRP funded four new grants in 2002 under this sub-topic.
Profiling Enzyme Activities in Models of Human Breast Cancer
Cravatt, Benjamin
Scripps Research Institute
STEP Award
2 years, $369,508
Regulation of the Rad1 Checkpoint Complex in Breast Cancer
Lupardus, Patrick
Stanford University
Dissertation Award
2 years, $60,000
Cloning of the X Chromosome's Putative Tumor Suppressor Gene
Malkhosyan, Sergei
The Burnham Institute
STEP Award
2 years, $297,000
Locating Novel Breast Cancer Genes using DNA Microarrays
Pollack, Jonathan
Stanford University
New Investigator Award
3 years, $470,796
5. Unraveling the Path to Breast Cancer: Tumor Progression
Breast cancer develops though many stages for a decade or more before detection. What happens during this progression period, and are there new opportunities to arrest the disease? This topic also incorporates work on the biology of the normal breast and enables new treatment concepts based on an understanding of clinical heterogeneity of breast cancer. The CBCRP funded ten new grants in 2002 under this sub-topic.
The Role of PTEN in Progression of Ductal Carcinoma in Situ
Bose, Shikha
Cedars-Sinai Medical Center
New Investigator
2 years, $306,000
Prognostic Value of Ras Activation in Breast Cancer
Boss, Gerry & Wallace, Anne
University of California, San Diego
Translational Research Collaboration, Full Award
3 years, $499,796
Infinite Expansion of Breast Tumor Samples in Culture
Dairkee, Shanaz
California Pacific Medical Center
STEP Award
2 years, $311,400
Does the BLM Gene Co-regulate BRCA1 in DNA Damage Response?
Davalos, Albert
Lawrence Berkeley National Laboratory
Postdoctoral Fellowship
2 years, $80,672
Molecular Pathogenesis of Metastatic Breast Cancer
Debs, Robert
California Pacific Medical Center
STEP Award
2 years, $311,400
Studies of Telomere Capping Dysfunction in Breast Cancer
Gilley, David
Lawrence Berkeley National Laboratory
New Investigator
3 years, $502,975
Fatty Acid Synthase and Breast Cancer
Knowles, Lynn
The Burnham Institute
Postdoctoral Fellowship
2 years, $86,400
Identification and Prognostic Value of ERβ in Breast Cancer
Leitman, Dale
University of California, San Francisco
STEP Award
2 years, $150,000
Three-Dimensional Modeling of Breast Cancer Progression
Ortiz de Solorzano, Carlos
Lawrence Berkeley National Laboratory
STEP Award
2 years, $336,328
BRCA1-dependent Ubiquitin Ligase Activity in Breast Cancer
Xia, Yan
Salk Institute for Biological Studies
Postdoctoral Fellowship
2 years, $86,400
