Michael Z. Lin, MD, PhD

Michael Z. Lin, MD, PhD
Stanford University Department of Neurobiology (Stanford, CA)
 

Year Funded:
2010

Focus:
Brain Cancer / Breast Cancer

Designing protein switches to control oncolytic RNA virus replication.

Vaccine-strain measles virus is a promising platform for the development of genetically programmable anti-cancer therapies. Measles vaccine virus has a natural preference for binding and infecting many types of tumor cells. With an impeccable safety record from decades of clinical use, the measles vaccine virus has already entered clinical trials for several cancers. 

Recently, genetic modifications to the measles vaccine virus that enhance its ability to replicate in cells have shown further improvements in tumor killing in preclinical testing. As this therapeutic virus platform is modified to be more lethal to cancer cells, however, it becomes important to be able to limit its replication to particular times and places in order retain its low toxicity to normal cells.  

We propose to develop two mechanisms for improving measles vaccine virus control and specificity. The first mechanism allows administration of an orally available nontoxic drug to rapidly shut off virus protein production. The second mechanism renders virus protein production dependent on a specific molecular abnormality commonly found in cancer cells. Both will be based on encoding in the virus genome rationally engineered protein switches to control the function of viral replication proteins. In preliminary work, we have successfully created prototypical control elements for both mechanisms.  

We propose to test the ability of these control elements to function in the context of the whole virus in order to control replication in time and by tumor type. If successful, the proposed work will establish a generalizable method by which replication of measles vaccine virus, and other RNA-based viruses, can be programmed for increased tumor specificity and safety.

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Michael Lin, PhD
Associate Professor, Neurobiology
Stanford University
290 Jane Stanford Way # S287
Stanford, California 94305-4005