Unique pathway that homes cancer drugs to tumors is like no other
In a new study published in Nature Communications, Erkki Ruoslahti, M.D., Ph.D., and his research team, with Hongbo Pang, Ph.D., as the lead author, identify the unique pathway that enhances the delivery of anti-cancer drugs to tumors. The pathway, called CendR, is a previously unknown variation of endocytosis—the process by which cells engulf nutrients and extracellular molecules. When activated, the CendR system improves the therapeutic efficacy of existing anti-cancer drugs while minimizing the collateral damage of normal cells and tissue. The findings advance our understanding of the biology of the cell by establishing a new type of trans-tissue transport pathway.
“Our lab previously discovered a class of peptides (short sequences of amino acids) called CendR peptides that preferentially home to tumor blood vessels and penetrate through the blood-vessel wall into tumor tissue,” said Ruoslahti. “CendR peptides are unique in that they promote the accumulation of anti-tumor drugs that are co-administered but not chemically coupled to the peptide, enhancing the overall anti-tumor efficacy. Now, we have identified the transport mechanism whereby CendR peptides penetrate the tumor and how this process is regulated. Combined, the pathway and CendR peptides are called the CendR system.”
In this study, the research team found that the CendR pathway is triggered by CendR peptides that activate a receptor called neuropilin-1 (NRP1), and the process is activated when nutrients are scarce. Since NRP1 is frequently over-expressed in tumors, and tumors—because of their frantic growth—are chronically starved for nutrients, it’s possible that the CendR system may help tumor cells survive by increasing the amount of nutrients taken up by tumor cells.
Tumor Targeting The conventional way of delivering targeted drugs to tumors is to couple the drug to a targeting probe, such as a tumor-homing peptide or antibody. “Our studies, showing that the CendR system creates large endocytotic vesicles that can take along extracellular fluid near the cell surface, explain why the co-administration is effective,” said Ruoslahti. If the extracellular fluid contains a drug, the drug is swept up into the transport pathway. This unique property of the CendR system enhances the therapeutic efficacy of the anti-cancer drugs by activating the pathway in tumors, but not elsewhere in the body.
“We look forward to continuing our studies into the molecular basis of this novel endocytotic mechanism, its ability to transfer CendR cargo between cells, and the underlying mechanism of control through nutrient regulation. We are also using high-throughput and imaging technologies to find more CendR-like peptides with related properties,” added Ruoslahti.
Hongbo Pang, Ph.D., is a postdoctoral research fellow in Dr. Ruoslahti’s laboratory. Dr. Ruoslahti is a distinguished professor in the Tumor Microenvironment and Metastasis Program at Sanford-Burnham.
A link to the paper can be found at: http://www.nature.com/ncomms/2014/141003/ncomms5904/full/ncomms5904.html.