It has long been understood that cancer cells have lost normal cellular growth control. Recent research has demonstrated a correlation between specific defects in cell cycle regulation and a variety of cancers. During Phase I of this SBIR grant, BitTech, Inc. developed in vivo phenotypic screens for cyclin/cyclin dependent kinase (cyclin/CDK) function. Cyclin/CDKs are the key regulators of eukaryotic cell cycle control, and three reporter genes were placed under control of a promoter which is regulated by a specific cyclin/CDK. Phase I research further demonstrated the feasibility of using the BitTech core technology for measuring effects on cyclins, CDKs or CDK inhibitor proteins (CKIs). During Phase II, the core technology will be further developed for use in targeted screening programs. Cell lines will be generated in which human cell cycle regulatory proteins, which are known to be mutant or aberrantly regulated in specific cancers, are incorporated as the molecular targets in the phenotypic screens. The test material for these high throughput screens may be expressed cDNA from various cell types, existing chemical libraries, new combinatorial libraries or products of rational design programs. Because these compounds will be discovered in screens which are highly specific for proteins which are mutant or aberrantly regulated in cancer cells, they (or analogues developed from the lead compound) are expected to exhibit improved efficacy and reduced side effects for the patients, compared to currently available therapies.
Current cancer therapies are frequently ineffective and have significant side effects for the patient. The in vivo screens for cyclin/CDK function are targeted to the key cell cycle regulatory proteins which are defective in certain cancers. Therefore, therapeutic compounds discovered with this technology are expected to exhibit improved efficiency and reduced side effects for the patient. Such therapies will decrease cancer-associated morbidity and health care costs.
| Bitter, Grant A; Schaeffer, Timothy N; Ellison, Aaron R (2002) Reporter gene regulation in Saccharomyces cerevisiae by the human p53 tumor suppressor protein. J Mol Microbiol Biotechnol 4:539-50 |
| Bitter, G A; Tsai, M M; Putzke, A P et al. (2000) Intergenic complementation truncation mutants of cyclin-dependent kinase. Mol Gen Genet 263:222-31 |
