Xin Zhou, PhD
Assistant Professor of Cancer Biology, Dana-Farber
Assistant Professor of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
Technology developed within the laboratory of Asst. Prof. Xin Zhou, PhD, of the Department of Cancer Biology at Dana-Farber capitalizes on the unique metabolic demands of cancer cells: their requirement for elevated levels of iron for rapid growth and spread. The approach relies on the concept of targeted protein degradation (TPD), an area of intense interest in drug discovery.
TPD works by removing specific disease-associated membrane-bound proteins from the surface of cells, many of which cannot be targeted and inhibited with traditional methods. The degradation approach offers a new way to entirely capture these previously ‘undruggable’ targets by internalizing them inside the cell where they – and the cancer cell – are destroyed. The technique reduces the toxicities associated with many other cancer treatments which often harm healthy tissue.
At the heart of Dr. Zhou’s innovation is a technology known as Transferrin Receptor Targeting Chimeras (TransTAC), which are bi-specific antibody molecules that leverage the natural behavior of the transferrin receptor – a pivotal protein overexpressed on the surface of cancer cells.
Found in abundance in several cancers, the transferrin receptor shuttles iron molecules into cancer cells, then quickly returns to the cell surface for another round. This process occurs at a rate of 500 receptors per second, fueling the rapid growth of cancer cells by aiding iron uptake.
TransTACs repurpose this naturally recycling receptor for targeted protein degradation by coupling an antibody binder to the receptor with another antibody engineered to target a specific cancer protein of interest. Examples include EGFR, PD-1, or CD20 – well-known proteins that are overexpressed in different cancer types.
One arm of the TransTAC homes in on the transferrin receptor on cancer cells while the other arm selectively binds to the target protein. The transferrin receptor, along with the tethered target, enters the cell. Dr. Zhou’s molecular design ensures that the target protein stays inside the cell where it will be destroyed while the transferrin receptor recycles. Critically, because tumor cells make more of the receptor than healthy cells, the approach improves the potential for avoiding the destruction of normal cells.
The innovation’s potential has been validated through the successful testing of multiple TransTAC degrader molecules, including an EGFR-targeting TransTAC for lung cancer developed in collaboration with Prof. Pasi Jänne MD, PhD, director, Lowe Center for Thoracic Oncology and director, Belfer Center for Applied Cancer Science. The technology’s efficiency in degrading a diverse range of cancer membrane proteins establishes new possibilities for targeted precision cancer therapy. Accelerator funding will enable Dr. Zhou and her team to develop additional TransTAC specific binders and enhance the overall IP portfolio of the technology.
Team Members
Pasi Jänne, MD, PhD
Senior Vice President for Translational Medicine, and David Livingston, MD Chair, Dana-Farber
Professor of Medicine, Harvard Medical School
