Aeterna Zentaris presents two posters on perifosine at AACR meeting

Apr 5 2011

Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZ) (the "Company")  today announced that two posters on its lead anticancer agent, perifosine, were presented at the 102^nd annual meeting of the American Association for Cancer Research currently held at the Orange County Convention Center in Orlando, Florida.

Poster #1965:

Entitled, "Antitumor activity of novel Akt inhibitor, perifosine in gastric cell lines",Tae Soo Kim, Hyo Song Kim, Bo Ram Kwan, Chan Hee Park, Hei-Cheul Jeung, Woo Ick Jang, Juergen Engel, Hyun Cheol Chung, Jae Kyung Roh, Sun Young Rha, (Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea).

Results

Perifosine showed single agent anti-proliferative activity in a variety of gastric cancer cell lines. In 8/13 cell lines resistant to 5-FU, perifosine showed a synergistic antiproliferative activity with 5-FU. In 72% of cell lines, high basal levels of pAkt were detected. Treatment with perifosine reduced tumor growth in nude mice inoculated subcutaneously with the YCC 2 gastric cancer cell line. Finally, an MTT based microarray analysis was performed to identify pharmacogenomic classifiers for synergy in 5-FU resistant cell lines.

Conclusions

Perifosine demonstrated antitumor activity in several gastric cancer cell lines. Furthermore, perifosine enhanced the antitumor activity of 5-FU in parts of the cell lines - including 5-FU resistant cell lines. 5-FU is the active metabolite of the prodrug Xeloda, which is approved for the treatment of advanced gastric cancer in many countries including Japan and Korea.

Poster #640:

Entitled "The Akt inhibitor Perifosine strongly enhances the antitumor and antivascular activity of CD34+ cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)" , Arianna Giacomini, Silvia L. Locatelli, Marco Righi, Loredana Cleris, Paolo D. Longoni, Marco Milanesi, Maura Francolini, Michele Magni, Massimo Di Nicola, Alessandro M. Gianni, Carmelo Carlo-Stella (Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori Milano and University of Milan, Milan, Italy).

Results

Pro-apoptotic TRAIL receptors present on tumor cells are known to represent a potential pharmaceutical target for cancer treatment. Perifosine stimulated the expression of pro-apoptotic TRAIL receptors on the multiple myeloma KMS-11 cell line, substantially reduced the levels of phosphorylated Akt and significantly enhanced the sensitivity of these cells for trail induced apoptosis. The same molecular effects were noted in the non-Hodgkin lymphoma cell line SU-DHL-4V. In this TRAIL resistant cell line, perifosine treatment substantially enhanced the cytotoxicity of TRAIL treatment to similar levels observed in the TRAIL sensitive multiple myeloma cell line.

The synergistic activity was confirmed in NOD/SCID mice xenograft models, where perifosine induced a down-modulation of Akt expression as well as TRAIL receptor upregulation in tumor cells and tumor endothelial cells.

Conclusion

Perifosine markedly enhanced the antitumor activity of the cellular TRAIL based treatment and was able to overcome TRAIL resistance both in vitro and in vivo. The results are in line with other studies demonstrating the synergistic effects of perifosine with cytotoxic drugs, including bortezomib and 5-FU.

Juergen Engel, Ph.D. Aeterna Zentaris President and Chief Executive Officer, commented, "Gastric cancer represents a significant threat especially in Asia. This preclinical work demonstrates the potential of perifosine especially in combination with Xeloda for the treatment of gastric cancer. Moreover, both posters are in line with previous data and the clinical observations emphasizing the benefit of combining perifosine with cytotoxic drugs in different oncological indications."