Our lab studies cancer-specific transcription factor (TF) dependencies, the master regulators of gene expression that tumors become addicted to, yet normal cells can live without. These transcription factors have long been considered “undruggable,” and we develop new strategies to target them, turning a cancer’s reliance on a TF into a therapeutic vulnerability and, ultimately, better treatments. In Ewing sarcoma, our primary disease model, we discovered that the cells are selectively dependent on the transcription factor ETV6, and we now apply this framework to additional transcription-factor-driven cancers. Every cancer-specific dependency is a therapeutic opportunity. We pursue this through three complementary directions:

Research Directions

1

Targeting essential protein interactions of TF dependencies

Cancer-dependent transcription factors act through interactions with partner proteins. We map these interactions and pinpoint the ones tumor cells cannot live without, then disrupt them as a therapeutic strategy.

2

Ligand modulation of transcription factors

Transcription factors have long been considered difficult to drug. We are exploring how small molecules and metabolites can bind and modulate these factors, aiming to pharmacologically tune their activity and unlock new therapeutic targets.

3

Modeling the tumor microenvironment to identify acquired dependencies

Using custom microfluidic “sarcoma-on-a-chip” devices, we reconstruct the tumor microenvironment to uncover the acquired dependencies and resistance mechanisms it creates, and reveal new vulnerabilities to target therapeutically.