Thank you for an energizing meeting with an amazing group of scientists in a beautiful volcano-strewn landscape. Wonderful event

This work was led by brilliant students Andrew Lu, Lukas Moeller, and Stephen Moore, and is a collaboration with
Hao Zhu and Dan Siegwart at UTSW.

If you have experience in animal cancer models and are interested in circuit therapeutics, please reach out.

In a mouse model of Ras-driven liver cancer, systemic treatment with the circuits (lower row) reduced tumor burden compared to untreated controls (upper row). Much more to explore.

We compared circuits (right) with Ras inhibitors (RMC-7977 and Sotorasib) by targeting mutant cells (magenta) co-cultured with wild-type Ras cells (green). Circuits were potent and selective.

We tried many, many, many circuit designs, eventually generating ones that sensitively discriminate Ras mutant cancer cells. We also generated protease-activated proteases to amplify weak oncogenic signals.

Why therapeutic circuits?
Sense-and-kill ≠ inhibit. Oncogene inhibition indirectly induces cell death, but is susceptible to resistance through compensatory signaling. Circuits directly rewire oncogenes to cell death --> less chance of resistance. Other benefits as well.

In this paradigm, engineered proteins are introduced into cancer and healthy cells using LNP-delivered mRNA. They then sense cancer markers (such as mutant Ras) and trigger engineered cell death effectors (caspases or gasdermins) only in cancer cells. (idealized schematic)