Mechanism of Action of DKN-01 in Gastroesophageal Adenocarcinoma

Samuel J. Klempner, MD, a medical oncologist at Massachusetts General Hospital, discusses the mechanism of action of the investigational agent DKN-01 in patients with gastroesophageal adenocarcinoma.

DKN-01, an intravenous monoclonal antibody which binds to DKK1 and neutralizes it, can potentially reduce the expression of DKK1. According to Klempner, DKK1 is highly expressed in esophageal and gastric cancers, and it is associated with worse disease prognosis and poor response to chemotherapy.

Elevated DKK1 can cause tumor growth through stimulation of PI3 kinase pathways. It can also have immunosuppressive pro-angiogenic effects in tumors. The Wnt/β-catenin pathway, which influences immune cell infiltration of the tumor microenvironment, is also affected by high DKK1 expression, leading to inhibition of natural killer (NK) cells and reducing antitumor activity.

In the ongoing phase 2a DisTinGuish trial (NCT04363801), DKN-01 showed promising efficacy and tolerability in patients with advanced esophageal cancer with DKK1 expression in combination with tislelizumab and capecitabine/oxaliplatin. DKK1 suppression can enable better treatment for a patient population known to have poorer overall survival.

TRANSCRIPTION:

0:08 | DKN-01 is a DKK1-neutralizing antibody, and this is of interest based on several lines of evidence. First, DKK1 is highly expressed in esophageal and gastric cancers.…It's been associated with a poor prognosis and a lesser benefit to frontline chemotherapy. So, this looks like a poor prognosis population that doesn't respond as well to standard therapies.

Then looking at what elevated DKK1 does, there are several effects. There are direct effects on tumor growth through PI3 kinase pathway stimulation. There are pro-angiogenic effects which we know are immunosuppressive, and then via modulation of β–catenin-dependent Wnt signaling, elevated DKK1 expression enhances the suppressive function of some of the immune cells in the microenvironment such as myeloid-derived suppressor cells, as well as inhibiting NK cell function, which we know is an important part of the anti-tumor immune response.