Blocking MYC Proteins Through Amphosteric Inhibition of AURKA
Novel Approaches to Blocking MYCN in Neuroblastoma
Modeling I131-MIBG Therapy for High Risk and Refractory Neuroblastoma

Gustafson Lab: Using basic biology to develop novel therapies for pediatric cancer.

A deep mechanistic understanding of targeted anti-cancer therapies is critical to success in the clinic.

Clay Gustafson, MD/PhD

UCSF Pediatric Oncology/ Helen Diller Cancer Center

New therapeutic development and clinical translation in cancer requires a solid understanding of basic tumor biology. The Gustafson lab focuses on new basic biological discoveries in cancer and leveraging these to develop novel therapies. We use in vitro cell systems, mouse models of cancer, and human tumor samples, with a particular focus on childhood cancers.

One focus has been the discovery and development of novel targeted therapies to treat MYC driven cancers, particularly neuroblastoma. Pathways which regulate MYC proteins are central to neuroblastoma, as well as a wide array of other pediatric and adult cancers. MYCN is prominently amplified in high-risk neuroblastoma, which accounts for 15% of over-all childhood cancer mortality and neuroblastoma is widely considered a model MYC-protein driven disease. Most recently we have discovered a new class of conformation-disrupting Aurora A inhibitors (CD-AURKi) with CD532 as our lead compound. These CD-AURKi potently inhibit Aurora Kinase A and downregulates MYCN protein in neuroblastoma cells. Using co-crystal structures, cell culture models, and structure-activity relationships, we have shown that CD532 acts via a novel allosteric mechanism whereby a kinase inhibitor is used to drug an undruggable transcription factor (Gustafson et al, 2014). There are ongoing efforts to further develop this class of drugs in the lab, potentially partnering with industry.

We are also translating drugs currently in development into the clinic. Thus far, we have performed pre-clinical testing and mechanistic studies for MYCN directed therapies in neuroblastoma including inhibitors of the PI3K/mTOR, BRD4, and Aurora A kinase pathways. We have ongoing efforts to develop novel, high-throughput assays to discover novel-novel drug combinations to treat childhood cancers.

Our lab is also involved in mouse modeling. We have several new projects to leverage our experience with mouse models of neuroblastoma for pre-clinical immunotherapy discovery and testing.

The major research goal of our laboratory is discover mechanisms of cancer signaling to leverage novel therapeutic development.

Gustafson Lab at UCSF Mission Bay

1550 4th St, Rock Hall Rm382
San Francisco, CA 94158

Phone: (415) 502-3602
Fax: (415) 476-5356