First Round

(Abstracts provided by applicants)

Yeast Cell-Based Screen for Breast Cancer Therapeutics
Grant Bitter, Principal Investigator BitTech, Inc., Agoura Hills, CA	R43 CA 84148-01
The majority of human breast cancers express estrogen receptor alpha (ER+ phenotype). Although adjuvant treatment with tamoxifen reduces tumor recurrence and increases survival in approximately 60% of these patients, prolonged use invariably leads to resistance. For the 40% of hormone independent ER+ breast cancers, as well as the ER+ tamoxifen resistant metastases, effective therapeutics are currently lacking. Recently, a novel mechanism of activating estrogen receptor alpha (ER) was elucidated. Cyclin D1 was shown to stimulate the in vivo transcription of reporter genes activated by the ER. This stimulation by cyclin D1 occurred independently of CDK4, the ER was not phosphorylated and, importantly, reporter gene activation occurred in the absence of estrogen. It had previously been well documented that cyclin D1 is overexpressed in approximately 50% of all breast cancers. Therefore, expression of growth response genes mediated by cyclin D1/ER may be involved in the proliferation of hormone independent, ER+ breast cancers and tamoxifen resistant metastases. Compounds which inhibit transcriptional activation of genes by cyclin D1/ER may therefore prevent proliferation of these breast cancer cells. During Phase I research, Saccharomyces cerevisiae yeast strains in which reporter genes are activated by human cyclin D1/ER will be developed. This technology will be utilized in high-throughput screening programs during Phase II. Compounds discovered in such screens may be developed into effective therapeutics for hormone independent breast cancers. PROPOSED COMMERCIAL APPLICATIONS: Breast cancer is the second leading cause of cancer deaths in women in the United States, and the leading cause of cancer deaths in women aged 30 to 70 years. The technology developed during Phase I research will be used in Phase II for discovery of compounds which may be effective therapeutics for the more than 40% of ER+ breast cancers which do not respond to current endocrine therapies.

Whole Animal Model for Heptocellular Carcinoma
George Serbedzija, Principal Investigator Phylonix Pharmaceuticals, Cambridge, MA	R43 CA 85118-01
the last 50 years, cancer has become a leading cause of death in the developed world. Hepatocellular carcinoma is the most common primary liver tumor and in countries where hepatitis B infection is prevalent, it is a leading cause of death. Cancer research involving cell transplantation primarily use mice. These assays are slow and require immunosuppressed mice to prevent cell rejection. Clonogenic assays in which cells are cultured in a petri dish or culture flask are also used for drug screening. Cells, however, frequently fail to divide in culture and results are also not predictive of drug performance in humans. This Phase I SBIR aims to develop a whole animal model for screening drugs against hepatocellular carcinoma using zebrafish (Danio rerio) embryos. The transparency of the embryo and the ease with which drugs can be introduced into the zebrafish are inherent advantages of the zebrafish model. PROPOSED COMMERCIAL APPLICATIONS: Therapeutic approaches for cancer generate in excess of $10B in worldwide revenue. By providing a rapid, high throughput, automated method for screening drugs, the zebrafish assay will facilitate drug development and reduce the costs associated with it.

Whole Animal Assay for Angiogenesis Inhibition
George Serbedzija, Principal Investigator Phylonix Pharmaceuticals, Cambridge, MA	R43 CA 85034-01
Because angiogenesis is necessary for tumor growth, inhibition of blood vessel formation is an excellent target for cancer therapy. The inherent complexities of current animal models, however, complicate screening of compounds for anti-angiogenic activity. In Phase I research, zebrafish (Danio rerio) embryos will be used to develop a rapid whole animal assay for screening potential drug candidates for anti-angiogenic activity. The inherent advantages of the zebrafish make it highly suitable for use for drug screening. Zebrafish embryos can be generated and maintained inexpensively and are amenable to automated analysis. Introduction of drugs into the embryo is simple. Because the embryos are transparent, drug and toxicity effects can be easily detected. Following staining, blood vessels and organs can be examined under the microscope without further sample preparation. Rapid embryonic development also facilitates rapid detection of drug effects. The zebrafish is particularly well suited for screening of potential inhibitors of angiogenesis because blood vessel patterning is highly characteristic in the developing embryo. Preliminary studies indicate that chemicals introduced into the developing embryo induce observable, dose-dependent responses. Phase I research will compare results obtained using the zebrafish model with other vertebrate models. PROPOSED COMMERCIAL APPLICATIONS: By providing a rapid, high throughput, automated method for screening drugs, the zebrafish assay will help to streamline flee drug development process for cancer and heart disease. In 1997 the worldwide market for drug screens for cancer and heart disease was $500M.