Addressing the cancer cells' ability to develop resistance to treatments, a team of Toulouse researchers has developed a novel approach. They have created a molecule named 'biodegrader,' engineered from a small intracellular antibody coupled with a natural cellular enzyme (SPOP). This biodegrader acts as a destruction tag, specifically recognizing cytidine deaminase (CDA), an enzyme responsible for deactivating key anti-cancer drugs such as gemcitabine and cytarabine.
This innovative strategy aims to eliminate the CDA protein, which can inactivate up to 90% of gemcitabine, rather than merely blocking it. The biodegrader triggers the degradation of CDA by the cell's protein recycling system. This method offers the advantage of working catalytically, with a single biodegrader potentially contributing to the destruction of multiple CDA molecules, while demonstrating high specificity for CDA.
Laboratory experiments conducted on pancreatic, lung, and acute myeloid leukemia cancer cells have yielded encouraging results. The combination of the biodegrader with gemcitabine or cytarabine made these cells more sensitive to treatments, slowing their proliferation and increasing apoptosis (programmed cell death).
Preclinical studies on tumor models in mice have also demonstrated the effectiveness of this approach. The biodegrader + gemcitabine combination significantly reduced tumor volume in pancreatic cancer models and led to near-complete tumor regression in lung cancer models. However, these results remain preclinical and require further validation in humans.
A major challenge lies in the biodegrader's ability, as an intracellular protein, to penetrate cells. Researchers have successfully tested pseudo-viral particles (VLPs) loaded with messenger RNA encoding the biodegrader. While promising, this delivery method showed incomplete degradation of CDA in mouse tumors, necessitating future optimizations regarding RNA stability, biodegrader activity, and homogeneous tumor distribution.
The significance of this research extends beyond CDA alone. It paves the way for a new strategy in combating resistance to anti-cancer treatments by programming the targeted destruction of proteins that promote this resistance. This approach could be extended to other treatments and enzymes involved in tumor resistance, thereby transforming a weakness of cancer cells into a potential attack point.
