High Throughput Lethality Screen in Drosophila Against Tumor Metastasis

DESCRIPTION (provided by applicant): Cancer continues to be a growing health issue. Overall five-year survival rates have changed only marginally over the past three decades and success rates in putting cancer drugs through the clinic have not improved. Th ese facts highlight an unmet need not only for new therapies but, more importantly, for novel approaches toward the discovery of safe anti-cancer agents that can more effectively negotiate the increasingly complex obstacles of clinical trials. Medros has a long term goal of impacting the field of cancer not only by putting better drugs into the clinic, but doing so by developing a different approach to drug discovery. This Phase I proposal emphasizes the concept of whole-organism screening, a common paradig m in the early days of the pharmaceutical industry. Our advancing knowledge of cancer has emphasized how the multifactorial problem of tumorigenesis relies on many features that cannot be recapitulated ex vivo, in particular with regards to tumor metastasi s. However, a whole-animal screening approach utilizing mammals is not practical due to the immense cost and time required. In response to these issues, Medros was founded on a proprietary platform optimized for high-throughput drug screening in vivo by mo deling disease in the fruit fly Drosophila. An important proof-of-concept for this approach came from our academic collaborators, who have used this approach to demonstrate activity of a drug now in Phase III clinical trials for Medullary Thyroid Carcinoma . In this Proposal, Medros will further develop its proprietary platform by establishing a more sophisticated and complex multi-hit cancer model. Our collaborators have demonstrated that activation of Src and Ras - two oncogenic pathways present in many tu mors -results in aggressive tumors that are lethal to the developing flies. The major objectives of this Phase I proposal are (i) to optimize use of this lethality for high-throughput compound screening and (ii) to perform a pilot screen for compounds that block Ras/Src-mediated tumorigenesis and improve whole-animal survival. Medros' ultimate vision is to validate a more fully in vivo approach to drug discovery from fly to rodent to man. PUBLIC HEALTH RELEVANCE:Cancer is a growing global problem. It is the second leading cause of death in this country, accounting for nearly one in four deaths. This proposal develops a novel whole animal approach with Drosophila to screen drug libraries for tumor invasion and metastasis. Our goal is to identify promising com pounds that will reduce the risk of the most dangerous aspect for most solid tumors: tumor cell invasion and metastasis.