The role of CD95 in cancer: promoter or suppressor?

CANbridge Life Sciences, a Beijing-based biotech company, in-licensed China rights to Apogenix’s lead candidate, APG101. The drug is a fusion protein that consists of the extracellular domain of CD95 and the Fc domain of IgG1 and blocks the interaction between CD95 and its ligand. Apogenix has completed a Phase II trial in patients with recurrent glioblastoma[1].

What interests me is the exact function of CD95 in cancer. CD95 (also known as Fas receptor) is a death receptor on the surface of cells that mediates apoptosis. Cancer cells often downregulate CD95 to evade apoptosis. Thus CD95 agonists were considered to kill cancer cells[2]. However, severe liver toxicity was observed in mice due to CD95-mediated apoptosis of hepatocytes.

In 2010, scientists from the University of Chicago speculated that CD95 could actually promote the growth of tumors[3]. The discovery seems unbelievable because CD95 had previously been defined as a tumor suppressor.

APG101 indeed showed a clinical benefit in patients with relapsed glioblastoma in the Phase II trial. PFS rates at 6 months were 20.7% for reirradiation + APG101 and 3.8% for reirradiation alone (p=0.048). Median PFS was 4.5 months vs. 2.5 months (p=0.0162). Median OS for both two arms were 11.5 months.

In the Phase II trial, there was no difference  in median OS. Many scientists still believe CD95 is a tumor suppressor[4,5]. Apogenix announced Phase II results in March 2012, but Phase III study hasn’t been initiated until now. The median OS of 11.5 months in second-line setting is not that attractive.

[1] Clin Cancer Res. 2014, 20(24), 6304-6313.
[2] Brain Pathol. 1998, 8(2), 285-293.
[3] Nature. 2010, 465(7297), 492-496.
[4] J Immunol. 2012, 188(9), 4441-4449.
[5] J Biol Chem. 2012, 287(30), 25530-25540.

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