Pathogenesis
Pathogenesis Funding Data:
| Proportion of CBCRP's Total | ||
| Grants awarded in 2003: |
12 |
24% |
| Funded amount: |
$1,866,461 |
16% |
Pathogenesis Portfolio Summary:
Although cancer is often described as a “genetic disease”, there are many competing theories to explain the gene alterations and mutations that initiate cancer and those that promote disease progression. W. Wayt Gibbs, writing in the July 2003 issue of Scientific American, summarized this cancer confusion as, “...it is more useful to think of cancer as the consequence of a chaotic process, a combination of Murphy's Law and Darwin's Law: anything that can go wrong will, and in a competitive environment, the best adapted survive and prosper.” In a more scientifically detailed fashion, William Hahn at Dana-Farber Cancer Institute in Boston and Robert Weinberg at MIT have pointed to six key cellular events that are “hallmarks of cancer” (recently reviewed in: N Engl J Med., 2003 348:674). Taken together these cellular events attempt to account for the sporadic nature of cancer, the biological and pathological heterogeneity seen in patients, immortality of cancer cells, numerous gene and chromosomal alterations, uncontrolled growth, motility and metastasis events, and resistance to therapy. Since no single approach can successfully explain cancer, researchers are employing a variety of technologies and methods. These range from cell and animal models of breast cancer; complex genomic and proteomic techniques to identify and relate multiple genetic changes in various forms of the disease; and the application to cancer of new discoveries in basic cell biology, DNA repair, cell cycle, growth signaling, and gene regulation processes. Still, in breast cancer the response to hormones, especially estrogen, remains a key underlying theme. Researchers now think that estrogen may operate in ways outside the “classical” estrogen receptor pathway. New thinking is also emerging for the growth factor receptor EGFR and the Her oncogenes. There is much interest in “cross-talk” between signaling pathways, previously thought to be distinct. Finally, the inherited breast cancer risk genes, BRCA1 and 2, are being studied in more advanced ways to better explain how DNA defects, repair processes, and cell growth/death pathways are interrelated and become defective in cancer.
Angiogenesis, invasion, and metastasis continue to be areas of promising investigation, despite the reality that angiogenesis-blockers have not lived up to expectations. From a basic research perspective, there is still a tremendous amount of information needed on how cancer spreads to develop and use targeted therapies. Min-Ying (Lydia) Su from the University of California, Irvine, is funded for an innovative STEP award to use an MRI-based approach to study angiogenic markers in the earliest phases of breast cancer progression—from hyperplasia through DCIS. Dr. Su and colleagues hope to identify and classify the early cancers that are most likely to undergo angiogenesis and progress to life-threatening stages. Verena Kallab from the University of California, San Francisco, is funded for a postdoctoral fellowship to study circulating tumor cells from patients with advanced disease. Dr. Kallab will study the cytotoxic effects of breast tumor therapy on circulating tumor cells and how key cancer biomarkers on these cells correspond with the primary tumor. Finally, Nadim Jessani from the Scripps Research Institute is a graduate student in the lab of CBCRP-funded investigator, Benjamin Cravatt. Mr. Jessani is funded through a dissertation award to apply a novel proteomics (i.e., study of the whole protein component profile of a cell or tissue) method to detect the “active” proteases present in human tumors grown in mice. Proteases, such as metalloproteinases, are key modulators of cell invasion, so knowing the active proteases is much more useful than cataloging them at the gene-level.
Cancer has long been characterized by uncontrolled cell growth, responses to growth modulators and, more recently, resistance to cell death responses. Even when an effective drug, such as Herceptin© is developed, the benefit to individual patients varies, because cancer cells differ in susceptibility and develop resistance. Tsui-Ting Ching at the University of California, San Francisco, is funded for a postdoctoral fellowship to study gene variation and gene methylation patterns in cell samples from patients with elevated Her-2. Dr. Ching hopes to identify gene/methylation patterns that underlie Herceptin resistance, since only about 30% of patients with elevated Her-2 respond well to this therapy. On the same general theme of drug resistance, Kristiina Vuori from The Burnham Institute is funded for a STEP award to investigate why about 40% of the patients treated with Tamoxifen have tumors that don't respond well to this therapy. Dr. Vuori and colleagues are focusing on a docking protein, called “Cas” that may function as an assembly point for anti-estrogen resistance signaling pathways. Nola Hylton at the University of California, San Francisco, is funded for a Career Enrichment award to study the role of p53 as a regulator of radiation-induced cell death in a mouse cancer model. Dr. Hylton will be trained in the techniques of basic science and transfer this knowledge to her current expertise in MRI and radiology. Finally, Steven Martin from the University of California, Berkeley, received an innovative IDEA award to investigate how an oncogene, called Src, regulates cell signaling though growth factors to influence the breast tissue architecture associated with early malignant events. Loss of cell polarity is a key morphological change in cancer development, and Dr. Martin will study the connection to Src by using specific inhibitors and a 3-D tissue culture system in the laboratory of his colleague, Mina Bissell at the Lawrence Berkeley National Laboratory.
When breast cancer is detected clinically, it has already been present for many years; first in pre-neoplastic and then in small, developmental stages. We have too little information on what is happens at the etiological (i.e, causative) and biological (i.e, genetic) levels during breast cancer progression. Paul Henderson at the Lawrence Livermore National Laboratory is funded for a novel approach to measure oxidative damage to DNA. Using breast cancer cell lines and tumors in animals, Dr. Henderson can feed cells or animals an oxidative damage-reporting marker for detecting and measuring DNA damage. This approach will enable the measurement of the ability of cells to either develop lesions or repair the damage. Another study will explore the role of BRCA1 in DNA repair. In recent years the role of the BRCA1 gene in DNA repair has become better defined, but we still need more information on its multiple roles in coordinating the cell cycle, protein degradation, and gene regulation. Quan Zhu at the Salk Institute for Biological Studies is funded as a postdoctoral fellow in the laboratory of Inder Verma. Dr. Zhu will use new gene expression vectors to enable the many BRCA1 functional domains to be studied independently in a mouse model of breast cancer. A third study will explore a paradox in breast cancer biology and the clinic—why about 1/3 of patients at diagnosis are estrogen receptor negative (ER-). Keon Wook Kang has been awarded a postdoctoral fellowship to study the ER+ to ER- transformation using a special mouse model in his mentor's, Eva Lee, lab at the University of California, Irvine. Another perplexing issue in breast cancer is understanding the biological basis of why some DCIS progresses to invasive cancer and some does not. Ruria Namba from the University of California, Davis, is funded as a postdoc in the laboratory of Jeffrey Gregg to study DCIS-like hyperplasic outgrowths from pre-malignant mouse mammary tumors for the expression of altered genes and biomarkers of breast cancer. Finally, Euan Slorach from the University of California, San Francisco, was awarded a postdoctoral fellowship to study a novel gene, called Melb1, which is associated with embryonic and mammary development. Dr. Slorach will study this gene for its role in breast tumor development in the context of knockout mice lacking Melb1.
Pathogenesis Grants Funded in 2003:
Understanding Herceptin Resistance with Dual Function Array
Tsui-Ting Ching
University of California, San Francisco
Postdoctoral Fellowship Award
2 years; $80,000
Role of Oxidative DNA Damage to Breast Tumor Progression
Paul Henderson
Lawrence Livermore National Laboratory
New Investigator Award
3 years; $592,566
Study of the Apoptotic Phenotype as a Hallmark of Malignancy
Nola Hylton
University of California, San Francisco
Career Enrichment Award
1 year; $155,409.00
Activity Based Profiling of Breast Cancer Xenografts
Nadim Jessani
Scripps Research Institute
Dissertation Award
2 years; $60,000
Characterization of Circulating Tumor Cells in Breast Cancer
Verena Kallab
University of California, San Francisco
Postdoctoral Fellowship Award
2 years; $80,000
Mechanism of Estrogen Receptor Loss in Breast Cancer
Keon Wook Kang
University of California, Irvine
Postdoctoral Fellowship Award
1 years; $39,086
SRC Signaling in Breast Cancer
Steven Martin
University of California, Berkeley
IDEA
1 year; $75,000
Molecular Analysis of DCIS Progression in a Mouse Model
Ruria Namba
University of California, Davis
Postdoctoral Fellowship Award
2 years; $80,000
Novel Genes in Mammary Gland Development and Cancer
Euan Slorach
University of California, San Francisco
Postdoctoral Fellowship Award
2 years; $80,000
Angiogenesis in Hyperplasia to In-Situ Breast Cancers
Min-Ying (Lydia) Su
University of California, Irvine
STEP Award
2 years; $250,000
Overcoming Tamoxifen-Resistance in Breast Cancer
Kristiina Vuori
The Burnham Institute
STEP Award
2 years; $288,0000
Molecular Analysis of BRCA1 Function
Quan Zhu
Salk Institute for Biological Studies
Postdoctoral Fellowship Award
2 years; $86,400
