Aerpio Therapeutics, a clinical-stage biopharmaceutical company recently announced that collaborators from Massachusetts General Hospital, Harvard Medical School, New York University and the Massachusetts Institute of Technology have published data on Tie2 activator, AKB-9778, in the Journal of the National Cancer Institute.

This data highlighted the clinically relevant changes to tumour vasculature upon administration of AKB-9778 in preclinical models of breast cancer, which delayed tumour growth, slowed metastatic progression and enhanced responses to radiotherapy.

AKB-9778 is a first-in-class inhibitor of VE-PTP (vascular endothelial  - protein tyrosine phosphatase also known as human protein tyrosine phosphatase beta [HPTPß]) that works to activate Tie2, a receptor on vascular endothelial cells that stabilizes blood vessels, preventing abnormal blood vessel growth and vascular leak.

“Certain abnormalities of tumour vasculature are known determinants of aggressive tumour behaviour, insensitivity to standard therapies and poor prognosis,” said Rakesh K Jain, A Werk Cook Professor of Tumour Biology (Radiation Oncology), Department of Radiation Oncology, Harvard Medical School director; director of Steele Laboratory, Massachusetts General Hospital and principal investigator of the study. “Use of AKB-9778 represents a novel approach to prevent or alleviate the abnormalities of tumour vasculature by activating Tie2 through the inhibition of VE-PTP. We demonstrated that through its effect on tumour vasculature, AKB-9778 can delay tumour growth, slow metastatic progression and enhance responses to cytotoxic treatments, representing a potential adjunct therapy for patients with cancer.”

Tie2 signaling is regulated on the cell surface by the receptors angiopoietin (Ang)-1 and Ang-2. Ang-1 activates Tie2 signaling, whereas Ang-2 inhibits Tie2 signaling. Many tumours express high levels of Ang-2, which now has become a target of interest in cancer research. However, VE-PTP is able to inhibit Tie2 signaling downstream of the Ang-1 and Ang-2 receptors, mitigating the cell’s response to either pharmacological activation of Ang-1 or inhibition of Ang-2.

“Indeed, the role of Tie2 is becoming more of a focus in oncology, and these latest data highlight the broad potential that AKB-9778 may have to impact the vasculature in a variety of indications, including cancer,” said Kevin Peters, MD, chief scientific officer and VP of Research and Development at Aerpio.”A number of compounds under investigation target Ang-2. However, Ang-2 inhibition may not result in optimal Tie2 activation and, perhaps due to that, may not be the best approach to targeting the angiopoietin/ Tie2 pathway. In contrast, AKB-9778 is able to activate Tie2, even in the context of increased Ang-2, and has marked  positive effects on tumour vasculature as a result. Aerpio’s lead development programme for AKB-9778 is focused on stabilizing the vasculature of patients with diabetic macular edema and a phase I/II clinical trial is currently underway.”

Aerpio Therapeutics, Inc. is developing innovative therapies for vascular diseases by targeting the Tie2 pathway.