Clay Gustafson, MD, PhD

Assistant Professor
Department of Pediatrics (Hematology/Oncology)

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 goals of our laboratory is discover mechanisms of cancer signaling to leverage novel therapeutic development.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Immunology
Research Summary: 
Novel targeted therapeutic development for neuroblastoma and other MYC driven cancers

Websites

Featured Publications: 

Drugging MYCN through an allosteric transition in Aurora kinase A.

Cancer cell

Gustafson WC, Meyerowitz JG, Nekritz EA, Chen J, Benes C, Charron E, Simonds EF, Seeger R, Matthay KK, Hertz NT, Eilers M, Shokat KM, Weiss WA

Paracrine signaling through MYCN enhances tumor-vascular interactions in neuroblastoma.

Science translational medicine

Chanthery YH, Gustafson WC, Itsara M, Persson A, Hackett CS, Grimmer M, Charron E, Yakovenko S, Kim G, Matthay KK, Weiss WA

Downregulation of MYCN through PI3K Inhibition in Mouse Models of Pediatric Neural Cancer.

Frontiers in oncology

Cage TA, Chanthery Y, Chesler L, Grimmer M, Knight Z, Shokat K, Weiss WA, Gustafson WC

Targeting MYCN in neuroblastoma by BET bromodomain inhibition.

Cancer discovery

Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J, Chanthery YH, Nekritz EA, Zeid R, Gustafson WC, Greninger P, Garnett MJ, McDermott U, Benes CH, Kung AL, Weiss WA, Bradner JE, Stegmaier K