Two posters on KRX-0401 (Perifosine) were presented at the 102nd annual meeting of the American Association for Cancer Research currently ongoing at the Orange County Convention Center in Orlando, Florida. Perifosine, a novel, potentially first-in-class, oral anti-cancer agent that inhibits Akt activation in the phosphoinositide 3-kinase (PI3K) pathway, is currently in Phase III clinical trials for refractory advanced colorectal cancer and multiple myeloma.

Both of Phase III programs are being conducted under Special Protocol Assessment (SPA) agreements with the FDA, and with Fast Track designations obtained for both indications. Perifosine is also in Phase 1 and 2 clinical development for several other tumor types. KRX-0401 (Perifosine) is being developed by Keryx Biopharmaceuticals.

Antitumor activity of novel Akt inhibitor, perifosine in gastric cell lines
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.

Perifosine demonstrated antitumor activity in several gastric cancer cell lines. Furthermore, perifosine enhanced the antitumor activity of 5-FU including 5-FU resistant cell lines. 5-FU is the active metabolite of the pro-drug Xeloda(TM) (capecitabine), which is approved for the treatment of metastatic colorectal cancer and breast cancer in the U.S., as well as advanced gastric cancer in certain countries outside of the U.S.

Antitumor and antivascular activity of CD34+ cells
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.

Advertisement #3

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.

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.

KRX-0401 (perifosine) is in-licensed by Keryx from AEterna Zentaris Inc. in the United States, Canada and Mexico.

For more information:
Poster #1965: 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).

Poster #640: 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), A. Giacomini, S. L. Locatelli, M. Righi, L. Cleris, P.D. Longoni, M. Milanesi, M. Francolini, M. Magni, M. Di Nicola, A. M. Gianni, C. Carlo-Stella (Fondazione IRCCS Istituto Nazionale Tumori and University of Milan, Milan, Italy).

Advertisement #5