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Perifosine

Perifosine is an orally active alkyl-phosphocholine compound with potential antineoplastic activity. Targeting cellular membranes, perifosine modulates membrane permeability, membrane lipid composition, phospholipid metabolism, and mitogenic signal transduction, resulting in cell differentiation and inhibition of cell growth. This agent also inhibits the anti-apoptotic mitogen-activated protein kinase (MAPK) pathway and modulates the balance between the MAPK and pro-apoptotic stress-activated protein kinase (SAPK/JNK) pathways, thereby inducing apoptosis. Perifosine has a lower gastrointestinal toxicity profile than the related agent miltefosine. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Perifosine is being developed by Keryx Biopharmaceuticals who have licenced it from Æterna Zentaris Inc. In 2010 perifosine has reached phase II. In one phase II trial for metastatic colon cancer perifosine doubled time to progression. In 2011 it was in a phase III trial for colorectal cancer, and another for multiple myeloma. Perifosine has orphan drug status in the U.S. for the treatment of multiple myeloma and neuroblastoma, and for multiple myeloma in the EU. [source: http://en.wikipedia.org/wiki/Perifosine].

Current developer:     Asta Medica (Originator), Zentaris (Originator), Access Pharmaceuticals (Licensee), National Cancer Institute (Codevelopment), Nippon Kayaku (Codevelopment); Keryx Biopharmaceuticals and AEterna Zentaris

Highlight on recent research using perifosine

Phase II trials: Perifosine plus capecitabine showed promising clinical activity  in patients with metastatic colorectal cancer (data published in 2011):  In a multicenter, double-blind phase II trial, we compared the efficacy and safety of perifosine plus capecitabine (P-CAP) with placebo plus capecitabine (CAP) in patients with metastatic colorectal cancer (mCRC) who had progressed after as many as two prior therapies.  P-CAP showed promising clinical activity compared with CAP in previously treated patients with mCRC. A phase III trial is underway comparing P-CAP with CAP in patients with refractory mCRC. [source: J Clin Oncol. 2011 Nov 20;29(33):4394-400.).

Phase I/II trials: Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma (data published in 2011): Preclinical data show that the novel signal transduction modulator, perifosine, enhances the cytotoxicity of dexamethasone and bortezomib. Clinical data suggest that perifosine in combination with dexamethasone has activity in relapsed or relapsed/refractory MM.  An overall response rate (ORR; defined as minimal response or better) of 41% was demonstrated with this combination in 73 evaluable patients, including an ORR of 65% in bortezomib-relapsed patients and 32% in bortezomib-refractory patients. Therapy was generally well tolerated; toxicities, including gastrointestinal adverse effects and fatigue, proved manageable. No treatment-related mortality was seen. Median progression-free survival was 6.4 months, with a median overall survival of 25 months (22.5 months in bortezomib-refractory patients).  Perifosine-bortezomib ± dexamethasone demonstrated encouraging activity in heavily pretreated bortezomib-exposed patients with advanced MM. A phase III trial is underway comparing perifosine-bortezomib plus dexamethasone with bortezomib-dexamethasone in patients with relapsed/refractory MM previously treated with bortezomib. [source J Clin Oncol. 2011 Nov 10;29(32):4243-9.]

Phase II trials: perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia. (data published in 2010): The median age was 65 years (range, 44-82). The median number of prior therapy lines was two (range, one to five). Of the 37 patients, 4 achieved partial response (11%), 9 minimal response (24%), and 20 showed stable disease (54%). The median progression-free survival was 12.6 months. Additionally, beta2 microglobulin of >3.5 mg/dL was associated with poor event-free survival (P = 0.002). Perifosine was generally well tolerated; adverse events related to therapy were cytopenias (grade 3-4, 13%), gastrointestinal symptoms (grade 1-2, 81%), and arthritis flare (all grades, 11%). Translational studies using gene expression profiling and immunohistochemistry showed that perifosine inhibited pGSK activity downstream of Akt, and inhibited nuclear factor kappaB activity. Perifosine resulted in at least a minimal response in 35% of patients and a median progression-free survival of 12.6 months in patients with relapsed or relapsed/refractory WM, as well as in vivo inhibition of pGSK activity. The results of this study warrant further evaluation of perifosine in combination with rituximab or other active agents in patients with WM. (source: Clin Cancer Res. 2010 Feb 1;16(3):1033-41.)

1: Liu R, Liu D, Xing M. The Akt Inhibitor MK2206 Synergizes, but Perifosine Antagonizes, the BRAFV600E Inhibitor PLX4032 and the MEK1/2 Inhibitor AZD6244 in the Inhibition of Thyroid Cancer Cells. J Clin Endocrinol Metab. 2011 Nov 16. [Epub ahead of print] PubMed PMID: 22090271.

2: Richardson PG, Wolf J, Jakubowiak A, Zonder J, Lonial S, Irwin D, Densmore J, Krishnan A, Raje N, Bar M, Martin T, Schlossman R, Ghobrial IM, Munshi N, Laubach J, Allerton J, Hideshima T, Colson K, Poradosu E, Gardner L, Sportelli P, Anderson KC. Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial. J Clin Oncol. 2011 Nov 10;29(32):4243-9. Epub 2011 Oct 11. PubMed PMID: 21990396.

3: Bendell JC, Nemunaitis J, Vukelja SJ, Hagenstad C, Campos LT, Hermann RC, Sportelli P, Gardner L, Richards DA. Randomized Placebo-Controlled Phase II Trial of Perifosine Plus Capecitabine As Second- or Third-Line Therapy in Patients With Metastatic Colorectal Cancer. J Clin Oncol. 2011 Nov 20;29(33):4394-400. Epub 2011 Oct 3. PubMed PMID: 21969495.

4: Sun H, Yu T, Li J. Co-administration of perifosine with paclitaxel synergistically induces apoptosis in ovarian cancer cells: more than just AKT inhibition. Cancer Lett. 2011 Nov 1;310(1):118-28. Epub 2011 Jun 29. PubMed PMID: 21775054.

5: Wang FZ, Fei HR, Li XQ, Shi R, Wang DC. Perifosine as potential anti-cancer agent inhibits proliferation, migration, and tube formation of human umbilical vein endothelial cells. Mol Cell Biochem. 2011 Jul 19. [Epub ahead of print] PubMed PMID: 21769450.

6: Schmidt-Hieber M, Dabrowski R, Aicher B, Lohneis P, Busse A, Tietze-Buerger C, Reufi B, Thiel E, Blau IW. In vitro effects of perifosine, bortezomib and lenalidomide against hematopoietic progenitor cells from healthy donors. Invest New Drugs. 2011 Jul 13. [Epub ahead of print] PubMed PMID: 21750922.

7: Li Z, Oh DY, Nakamura K, Thiele CJ. Perifosine-induced inhibition of akt attenuates brain-derived neurotrophic factor/TrkB-induced chemoresistance in neuroblastoma in vivo. Cancer. 2011 Dec 1;117(23):5412-22. doi: 10.1002/cncr.26133. Epub 2011 May 16. PubMed PMID: 21590687; PubMed Central PMCID: PMC3158972.

8: Gao Y, Ishiyama H, Sun M, Brinkman KL, Wang X, Zhu J, Mai W, Huang Y, Floryk D, Ittmann M, Thompson TC, Butler EB, Xu B, Teh BS. The alkylphospholipid, perifosine, radiosensitizes prostate cancer cells both in vitro and in vivo. Radiat Oncol. 2011 Apr 15;6:39. PubMed PMID: 21496273; PubMed Central PMCID: PMC3096921.

9: Pitter KL, Galbán CJ, Galbán S, Tehrani OS, Li F, Charles N, Bradbury MS, Becher OJ, Chenevert TL, Rehemtulla A, Ross BD, Holland EC, Hambardzumyan D. Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-deficient PDGF-driven murine glioblastoma. PLoS One. 2011 Jan 18;6(1):e14545. Erratum in: PLoS One. 2011;6(1). doi: 10.1371/annotation/66641ad6-afb9-4d3c-ade6-73fcd5aab061. Saeed-Tehrani, Omid [corrected to Tehrani, Omid Saeed]. PubMed PMID: 21267448; PubMed Central PMCID: PMC3022633.

10: Fu L, Lin YD, Elrod HA, Yue P, Oh Y, Li B, Tao H, Chen GZ, Shin DM, Khuri FR, Sun SY. c-Jun NH2-terminal kinase-dependent upregulation of DR5 mediates cooperative induction of apoptosis by perifosine and TRAIL. Mol Cancer. 2010 Dec 20;9:315. PubMed PMID: 21172010; PubMed Central PMCID: PMC3018404.

11: Schmidt-Hieber M, Dabrowski R, Weimann A, Aicher B, Lohneis P, Busse A, Thiel E, Blau IW. In vitro cytotoxicity of the novel antimyeloma agents perifosine, bortezomib and lenalidomide against different cell lines. Invest New Drugs. 2010 Nov 16. [Epub ahead of print] PubMed PMID: 21080211.

12: Fei HR, Chen G, Wang JM, Wang FZ. Perifosine induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines by blockade of Akt phosphorylation. Cytotechnology. 2010 Oct;62(5):449-60. Epub 2010 Sep 15. PubMed PMID: 20842425; PubMed Central PMCID: PMC2993858.

13: Muñoz-Martínez F, Torres C, Castanys S, Gamarro F. CDC50A plays a key role in the uptake of the anticancer drug perifosine in human carcinoma cells. Biochem Pharmacol. 2010 Sep 15;80(6):793-800. Epub 2010 May 25. PubMed PMID: 20510206.

14: Li Z, Tan F, Liewehr DJ, Steinberg SM, Thiele CJ. In vitro and in vivo inhibition of neuroblastoma tumor cell growth by AKT inhibitor perifosine. J Natl Cancer Inst. 2010 Jun 2;102(11):758-70. Epub 2010 May 12. PubMed PMID: 20463309; PubMed Central PMCID: PMC2879416.

15: Engel JB, Schönhals T, Häusler S, Krockenberger M, Schmidt M, Horn E, Köster F, Dietl J, Wischhusen J, Honig A. Induction of programmed cell death by inhibition of AKT with the alkylphosphocholine perifosine in in vitro models of platinum sensitive and resistant ovarian cancers. Arch Gynecol Obstet. 2011 Mar;283(3):603-10. Epub 2010 Apr 20. PubMed PMID: 20405296.

16: Cirstea D, Hideshima T, Rodig S, Santo L, Pozzi S, Vallet S, Ikeda H, Perrone G, Gorgun G, Patel K, Desai N, Sportelli P, Kapoor S, Vali S, Mukherjee S, Munshi NC, Anderson KC, Raje N. Dual inhibition of akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol Cancer Ther. 2010 Apr;9(4):963-75. Epub 2010 Apr 6. PubMed PMID: 20371718; PubMed Central PMCID: PMC3096071.

17: Keenan JD, Fram NR, McLeod SD, Strauss EC, Margolis TP. Perifosine-related rapidly progressive corneal ring infiltrate. Cornea. 2010 May;29(5):583-5. PubMed PMID: 20335808.

18: Becher OJ, Hambardzumyan D, Walker TR, Helmy K, Nazarian J, Albrecht S, Hiner RL, Gall S, Huse JT, Jabado N, MacDonald TJ, Holland EC. Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma. Cancer Res. 2010 Mar 15;70(6):2548-57. Epub 2010 Mar 2. PubMed PMID: 20197468.

19: Celeghini C, Voltan R, Rimondi E, Gattei V, Zauli G. Perifosine selectively induces cell cycle block and modulates retinoblastoma and E2F1 protein levels in p53 mutated leukemic cell lines. Invest New Drugs. 2011 Apr;29(2):392-5. Epub 2010 Feb 4. PubMed PMID: 20130960.

20: Ghobrial IM, Roccaro A, Hong F, Weller E, Rubin N, Leduc R, Rourke M, Chuma S, Sacco A, Jia X, Azab F, Azab AK, Rodig S, Warren D, Harris B, Varticovski L, Sportelli P, Leleu X, Anderson KC, Richardson PG. Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia. Clin Cancer Res. 2010 Feb 1;16(3):1033-41. Epub 2010 Jan 26. PubMed PMID: 20103671; PubMed Central PMCID: PMC2885252.

21: Unger C, Berdel W, Hanauske AR, Sindermann H, Engel J, Mross K. First-time-in-man and pharmacokinetic study of weekly oral perifosine in patients with solid tumours. Eur J Cancer. 2010 Mar;46(5):920-5. Epub 2010 Jan 14. PubMed PMID: 20079628.

22: Voltan R, Celeghini C, Melloni E, Secchiero P, Zauli G. Perifosine plus nutlin-3 combination shows a synergistic anti-leukaemic activity. Br J Haematol. 2010 Mar;148(6):957-61. Epub 2009 Dec 1. PubMed PMID: 19958355.

23: Fu L, Kim YA, Wang X, Wu X, Yue P, Lonial S, Khuri FR, Sun SY. Perifosine inhibits mammalian target of rapamycin signaling through facilitating degradation of major components in the mTOR axis and induces autophagy. Cancer Res. 2009 Dec 1;69(23):8967-76. Epub 2009 Nov 17. PubMed PMID: 19920197; PubMed Central PMCID: PMC2789206.

24: Kumar A, Fillmore HL, Kadian R, Broaddus WC, Tye GW, Van Meter TE. The alkylphospholipid perifosine induces apoptosis and p21-mediated cell cycle arrest in medulloblastoma. Mol Cancer Res. 2009 Nov;7(11):1813-21. Epub 2009 Nov 3. PubMed PMID: 19887560.

25: Simons AL, Parsons AD, Foster KA, Orcutt KP, Fath MA, Spitz DR. Inhibition of glutathione and thioredoxin metabolism enhances sensitivity to perifosine in head and neck cancer cells. J Oncol. 2009;2009:519563. Epub 2009 Sep 2. PubMed PMID: 19746172; PubMed Central PMCID: PMC2738856.

26: Dogan SS, Esmaeli B. Ocular side effects associated with imatinib mesylate and perifosine for gastrointestinal stromal tumor. Hematol Oncol Clin North Am. 2009 Feb;23(1):109-14, ix. Review. PubMed PMID: 19248974.

27: Gills JJ, Dennis PA. Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep. 2009 Mar;11(2):102-10. Review. PubMed PMID: 19216841.

28: Zhang W, Liu W, Poradosu E, Ratain MJ. Genome-wide identification of genetic determinants for the cytotoxicity of perifosine. Hum Genomics. 2008 Sep;3(1):53-70. PubMed PMID: 19129090.

29: Tazzari PL, Tabellini G, Ricci F, Papa V, Bortul R, Chiarini F, Evangelisti C, Martinelli G, Bontadini A, Cocco L, McCubrey JA, Martelli AM. Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor Perifosine in acute myelogenous leukemia cells. Cancer Res. 2008 Nov 15;68(22):9394-403. PubMed PMID: 19010914; PubMed Central PMCID: PMC2597037.

30: Cabrera-Serra MG, Valladares B, Piñero JE. In vivo activity of perifosine against Leishmania amazonensis. Acta Trop. 2008 Oct;108(1):20-5. Epub 2008 Aug 29. PubMed PMID: 18801328.

31: David E, Sinha R, Chen J, Sun SY, Kaufman JL, Lonial S. Perifosine synergistically enhances TRAIL-induced myeloma cell apoptosis via up-regulation of death receptors. Clin Cancer Res. 2008 Aug 15;14(16):5090-8. PubMed PMID: 18698026.

32: Engel JB, Honig A, Schönhals T, Weidler C, Häusler S, Krockenberger M, Grunewald TG, Dombrowski Y, Rieger L, Dietl J, Wischhusen J. Perifosine inhibits growth of human experimental endometrial cancers by blockade of AKT phosphorylation. Eur J Obstet Gynecol Reprod Biol. 2008 Nov;141(1):64-9. Epub 2008 Aug 6. PubMed PMID: 18687514.

33: Floryk D, Thompson TC. Perifosine induces differentiation and cell death in prostate cancer cells. Cancer Lett. 2008 Aug 8;266(2):216-26. Epub 2008 Apr 18. PubMed PMID: 18395973; PubMed Central PMCID: PMC2525810.

34: Chiarini F, Del Sole M, Mongiorgi S, Gaboardi GC, Cappellini A, Mantovani I, Follo MY, McCubrey JA, Martelli AM. The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism. Leukemia. 2008 Jun;22(6):1106-16. Epub 2008 Apr 3. PubMed PMID: 18385752.

35: Chee KG, Longmate J, Quinn DI, Chatta G, Pinski J, Twardowski P, Pan CX, Cambio A, Evans CP, Gandara DR, Lara PN Jr. The AKT inhibitor perifosine in biochemically recurrent prostate cancer: a phase II California/Pittsburgh cancer consortium trial. Clin Genitourin Cancer. 2007 Dec;5(7):433-7. PubMed PMID: 18272025.

36: Shome D, Trent J, Espandar L, Hatef E, Araujo DM, Song CD, Kim SK, Esmaeli B. Ulcerative keratitis in gastrointestinal stromal tumor patients treated with perifosine. Ophthalmology. 2008 Mar;115(3):483-7. Epub 2008 Jan 16. PubMed PMID: 18201764.

37: Hennessy BT, Lu Y, Poradosu E, Yu Q, Yu S, Hall H, Carey MS, Ravoori M, Gonzalez-Angulo AM, Birch R, Henderson IC, Kundra V, Mills GB. Pharmacodynamic markers of perifosine efficacy. Clin Cancer Res. 2007 Dec 15;13(24):7421-31. PubMed PMID: 18094426.

38: Muñoz-Martínez F, Torres C, Castanys S, Gamarro F. The anti-tumor alkylphospholipid perifosine is internalized by an ATP-dependent translocase activity across the plasma membrane of human KB carcinoma cells. Biochim Biophys Acta. 2008 Feb;1778(2):530-40. Epub 2007 Oct 25. PubMed PMID: 18005660.

39: Vinall RL, Hwa K, Ghosh P, Pan CX, Lara PN Jr, de Vere White RW. Combination treatment of prostate cancer cell lines with bioactive soy isoflavones and perifosine causes increased growth arrest and/or apoptosis. Clin Cancer Res. 2007 Oct 15;13(20):6204-16. PubMed PMID: 17947488.

40: Papa V, Tazzari PL, Chiarini F, Cappellini A, Ricci F, Billi AM, Evangelisti C, Ottaviani E, Martinelli G, Testoni N, McCubrey JA, Martelli AM. Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells. Leukemia. 2008 Jan;22(1):147-60. Epub 2007 Oct 11. PubMed PMID: 17928881.

41: Elrod HA, Lin YD, Yue P, Wang X, Lonial S, Khuri FR, Sun SY. The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway. Mol Cancer Ther. 2007 Jul;6(7):2029-38. Epub 2007 Jun 29. PubMed PMID: 17604333.

42: Catley L, Hideshima T, Chauhan D, Neri P, Tassone P, Bronson R, Song W, Tai YT, Munshi NC, Anderson KC. Alkyl phospholipid perifosine induces myeloid hyperplasia in a murine myeloma model. Exp Hematol. 2007 Jul;35(7):1038-46. PubMed PMID: 17588472.

43: Leighl NB, Dent S, Clemons M, Vandenberg TA, Tozer R, Warr DG, Crump RM, Hedley D, Pond GR, Dancey JE, Moore MJ. A Phase 2 study of perifosine in advanced or metastatic breast cancer. Breast Cancer Res Treat. 2008 Mar;108(1):87-92. Epub 2007 Apr 26. PubMed PMID: 17458693.

44: Marsh Rde W, Rocha Lima CM, Levy DE, Mitchell EP, Rowland KM Jr, Benson AB 3rd. A phase II trial of perifosine in locally advanced, unresectable, or metastatic pancreatic adenocarcinoma. Am J Clin Oncol. 2007 Feb;30(1):26-31. PubMed PMID: 17278891.

45: Cabrera-Serra MG, Lorenzo-Morales J, Romero M, Valladares B, Piñero JE. In vitro activity of perifosine: a novel alkylphospholipid against the promastigote stage of Leishmania species. Parasitol Res. 2007 Apr;100(5):1155-7. Epub 2007 Jan 6. PubMed PMID: 17206506.

46: Bailey HH, Mahoney MR, Ettinger DS, Maples WJ, Fracasso PM, Traynor AM, Erlichman C, Okuno SH. Phase II study of daily oral perifosine in patients with advanced soft tissue sarcoma. Cancer. 2006 Nov 15;107(10):2462-7. PubMed PMID: 17058289.

47: Gajate C, Mollinedo F. Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood. 2007 Jan 15;109(2):711-9. Epub 2006 Sep 26. PubMed PMID: 17003375.

48: Vink SR, Schellens JH, Beijnen JH, Sindermann H, Engel J, Dubbelman R, Moppi G, Hillebrand MJ, Bartelink H, Verheij M. Phase I and pharmacokinetic study of combined treatment with perifosine and radiation in patients with advanced solid tumours. Radiother Oncol. 2006 Aug;80(2):207-13. Epub 2006 Aug 17. PubMed PMID: 16914220.

49: Geroldi D, Aldeghi A, Emanuele E. Perifosine may be of therapeutic usefulness in morbid obese females via inhibition of the PI3K/Akt signaling pathway. Med Hypotheses. 2007;68(1):236. Epub 2006 Aug 14. PubMed PMID: 16905273.

50: Nyåkern M, Cappellini A, Mantovani I, Martelli AM. Synergistic induction of apoptosis in human leukemia T cells by the Akt inhibitor perifosine and etoposide through activation of intrinsic and Fas-mediated extrinsic cell death pathways. Mol Cancer Ther. 2006 Jun;5(6):1559-70. PubMed PMID: 16818515.

51: de la Peña L, Burgan WE, Carter DJ, Hollingshead MG, Satyamitra M, Camphausen K, Tofilon PJ. Inhibition of Akt by the alkylphospholipid perifosine does not enhance the radiosensitivity of human glioma cells. Mol Cancer Ther. 2006 Jun;5(6):1504-10. PubMed PMID: 16818509.

52: Argiris A, Cohen E, Karrison T, Esparaz B, Mauer A, Ansari R, Wong S, Lu Y, Pins M, Dancey J, Vokes E. A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer. Cancer Biol Ther. 2006 Jul;5(7):766-70. Epub 2006 Jul 2. PubMed PMID: 16760642.

53: Vink SR, Lagerwerf S, Mesman E, Schellens JH, Begg AC, van Blitterswijk WJ, Verheij M. Radiosensitization of squamous cell carcinoma by the alkylphospholipid perifosine in cell culture and xenografts. Clin Cancer Res. 2006 Mar 1;12(5):1615-22. PubMed PMID: 16533789.

54: Knowling M, Blackstein M, Tozer R, Bramwell V, Dancey J, Dore N, Matthews S, Eisenhauer E. A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: A National Cancer Institute of Canada Clinical Trials Group trial. Invest New Drugs. 2006 Sep;24(5):435-9. PubMed PMID: 16528479.

55: Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C, Podar K, Munshi NC, Chauhan D, Richardson PG, Anderson KC. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006 May 15;107(10):4053-62. Epub 2006 Jan 17. PubMed PMID: 16418332; PubMed Central PMCID: PMC1895278.

56: Li X, Luwor R, Lu Y, Liang K, Fan Z. Enhancement of antitumor activity of the anti-EGF receptor monoclonal antibody cetuximab/C225 by perifosine in PTEN-deficient cancer cells. Oncogene. 2006 Jan 26;25(4):525-35. PubMed PMID: 16170346.

57: Posadas EM, Gulley J, Arlen PM, Trout A, Parnes HL, Wright J, Lee MJ, Chung EJ, Trepel JB, Sparreboom A, Chen C, Jones E, Steinberg SM, Daniels A, Figg WD, Dahut WL. A phase II study of perifosine in androgen independent prostate cancer. Cancer Biol Ther. 2005 Oct;4(10):1133-7. Epub 2005 Oct 1. PubMed PMID: 16138006.

58: Momota H, Nerio E, Holland EC. Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res. 2005 Aug 15;65(16):7429-35. PubMed PMID: 16103096.

59: Ernst DS, Eisenhauer E, Wainman N, Davis M, Lohmann R, Baetz T, Belanger K, Smylie M. Phase II study of perifosine in previously untreated patients with metastatic melanoma. Invest New Drugs. 2005 Dec;23(6):569-75. PubMed PMID: 16034524.

60: Vink SR, Schellens JH, van Blitterswijk WJ, Verheij M. Tumor and normal tissue pharmacokinetics of perifosine, an oral anti-cancer alkylphospholipid. Invest New Drugs. 2005 Aug;23(4):279-86. PubMed PMID: 16012787.

61: Rahmani M, Reese E, Dai Y, Bauer C, Payne SG, Dent P, Spiegel S, Grant S. Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species. Cancer Res. 2005 Mar 15;65(6):2422-32. PubMed PMID: 15781658.

62: Van Ummersen L, Binger K, Volkman J, Marnocha R, Tutsch K, Kolesar J, Arzoomanian R, Alberti D, Wilding G. A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer. Clin Cancer Res. 2004 Nov 15;10(22):7450-6. PubMed PMID: 15569974.

63: Dasmahapatra GP, Didolkar P, Alley MC, Ghosh S, Sausville EA, Roy KK. In vitro combination treatment with perifosine and UCN-01 demonstrates synergism against prostate (PC-3) and lung (A549) epithelial adenocarcinoma cell lines. Clin Cancer Res. 2004 Aug 1;10(15):5242-52. PubMed PMID: 15297428.

64: Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK. Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther. 2003 Nov;2(11):1093-103. PubMed PMID: 14617782.

65: Crul M, Rosing H, de Klerk GJ, Dubbelman R, Traiser M, Reichert S, Knebel NG, Schellens JH, Beijnen JH, ten Bokkel Huinink WW. Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours. Eur J Cancer. 2002 Aug;38(12):1615-21. PubMed PMID: 12142051.

66: Patel V, Lahusen T, Sy T, Sausville EA, Gutkind JS, Senderowicz AM. Perifosine, a novel alkylphospholipid, induces p21(WAF1) expression in squamous carcinoma cells through a p53-independent pathway, leading to loss in cyclin-dependent kinase activity and cell cycle arrest. Cancer Res. 2002 Mar 1;62(5):1401-9. PubMed PMID: 11888912.

67: Woo EW, Messmann R, Sausville EA, Figg WD. Quantitative determination of perifosine, a novel alkylphosphocholine anticancer agent, in human plasma by reversed-phase liquid chromatography-electrospray mass spectrometry. J Chromatogr B Biomed Sci Appl. 2001 Aug 15;759(2):247-57. PubMed PMID: 11499478.

68: Knebel NG, Grieb S, Winkler M, Locher M, van der Vlis E, Verheij ER. Quantification of perifosine, an alkylphosphocholine anti-tumour agent, in plasma by pneumatically assisted electrospray tandem mass spectrometry coupled with high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl. 1999 Jan 22;721(2):257-69. PubMed PMID: 10052698.