Alireza Ghanbarpour, Ph.D. 

ABSTRACT

This project introduces ReCAP, a host-independent protein degradation platform using bacterial AAA+ proteases to target undruggable proteins like KRAS and c-MYC. Through directed evolution and antibody-adaptor chimeras, ReCAP enables selective degradation in mammalian cells. It addresses limitations of current degradation technologies and offers a modular, programmable strategy for precision oncology. The work spans six years of investigation and includes plans for NIH and DARPA funding and SBIR/STTR commercialization.

Lay Summary: 
Many cancers are driven by abnormal proteins called oncoproteins, which help tumor cells grow and spread. These proteins are often “undruggable” because they lack suitable binding sites or quickly develop resistance to existing treatments. This project proposes a new strategy: instead of blocking oncoproteins, it aims to destroy them using a programmable system derived from bacterial protein machines.

The system, called ReCAP (Reprogrammed ClpX for Antigen-specific Proteolysis), is based on ClpXP—a bacterial protease that can shred unwanted proteins. The project will reprogram ClpXP to target specific oncoproteins like KRAS and MYC using two methods: (1) engineering ClpX to recognize these proteins directly, and (2) attaching antibody fragments to ClpX via adaptors that guide the target proteins to the system. This dual targeting approach enhances precision and flexibility. The system will be tested in human cells to ensure it selectively eliminates cancer-causing proteins without harming normal ones. If successful, ReCAP could become a powerful tool for personalized cancer therapy and may be adapted to treat other diseases caused by harmful proteins.