Investigators at the German Cancer Research Center in Heidelberg (DKFZ) and the Mannheim Medical Faculty of the University of Heidelberg have released data on an antibody they created that blocks a receptor that stimulates the formation of new blood vessels in tumors and metastasis. Findings from the new stud—published recently in EMBO Molecular Medicine through an article entitled “Preclinical validation of a novel metastasis‐inhibiting Tie1 function‐blocking antibody”—showed that the antibody prevented the growth of metastases in mice with breast or lung cancer—thus providing a potential new principle for slowing down the metastatic dissemination of cancer cells.
“The angiopoietin (Ang)–Tie pathway has been intensely pursued as candidate second‐generation anti‐angiogenic target,” the authors explained. “While much of the translational work has focused on the ligand Ang2, the clinical efficacy of Ang2‐targeting drugs is limited and failed to improve patient survival. In turn, the orphan receptor Tie1 remains therapeutically unexplored, although its endothelial‐specific genetic deletion has previously been shown to result in a strong reduction in metastatic growth.”
Just like healthy tissue, tumors depend on nutrients that they receive via the bloodstream. However, since cancer cells proliferate rapidly and the tumors grow correspondingly fast, a bottleneck can develop here—if new blood vessels do not sprout at the same time. In addition, these new blood vessels are transport routes through which cancer cells reach distant organs where they grow into metastases. One goal in cancer therapy is, therefore, to prevent angiogenesis, i.e., the formation of new blood vessels, in order to deprive the tumor of nutrients and slow down metastasis. Drugs suppressing angiogenesis have already been in clinical use for more than a decade—albeit with limited efficacy.
Two years ago, German scientists from Heidelberg and Mannheim discovered a new target through which this could work: the receptor molecule, Tie1. It is produced in the endothelial cells, i.e., in the cell layer that lines the blood vessels from the inside. It is also known that Tie1 is produced in greater quantities during tumor development and during the growth of blood vessels in the tumor.
“We do not know the binding partner of Tie1 and therefore cannot yet say in detail how the receptor works,” noted lead study investigator Mahak Singhal, PhD, a DKFZ senior scientist.
But scientists have found out that as cancer progresses, Tie1 helps the blood vessels and tumors to accelerate their growth. In addition, Tie1 destabilizes the walls of the blood vessels and thus promotes the development of metastases. If Tie1 is genetically knocked out in mice, this suppresses both tumor growth and metastasis.
“We report a novel Tie1 function‐blocking antibody (AB‐Tie1‐39), which suppressed postnatal retinal angiogenesis. During primary tumor growth, neoadjuvant administration of AB‐Tie1‐39 strongly impeded systemic metastasis,” the authors wrote. “Furthermore, the administration of AB‐Tie1‐39 in a perioperative therapeutic window led to a significant survival advantage as compared to control‐IgG‐treated mice. Additional in vivo experimental metastasis and in vitro transmigration assays concurrently revealed that AB‐Tie1‐39 treatment suppressed tumor cell extravasation at secondary sites.”
Tie1 is, therefore, an interesting target for cancer therapy. The scientists consequently set out experiments to generate and test several antibodies directed against Tie1. In fact, they were able to identify a promising candidate. If mice with breast or lung tumors were treated with the antibody, cancer growth was slowed down. However, there was no noticeable effect on the formation of blood vessels in the tumors. Importantly, the treated animals showed significantly fewer metastases compared to untreated mice with breast or lung tumors.
This implies that although the antibody is not able to prevent angiogenesis in the tumor effectively, it has the potential to slow down the formation of metastases during cancer therapy.
“However, we have only observed the therapeutic potential of the antibody in experimental animals,” concluded senior study investigator Hellmut Augustin, PhD, who is concerned about not raising premature hopes. “Many experiments and studies are still needed before it may one day actually be used to treat cancer patients.”