Perifosine

Perifosine is an inhibitor of Akt [1].

Perifosine is a synthetic antitumor alkylphospholipid. It induces cell apoptosis through inhibiting the activity of Akt. Perifosine shows antitumor activity in various cell lines including NSCLC, MM, epithelial carcinoma, prostate carcinoma and leukemia cells. In H460 cells, perifosine decreased cell survival and induced apoptosis with IC50 values of 1μM and 10 μM, respectively. The treatment of perifosine was also found to induce cleavage of caspase-8, caspase-9, caspase-3 and PARP in this cell line. In MM.1S cells, perifosine induced sub-G1 phase population increase from 15% to 57% at 10 μM and induced cleavage of caspase-8, caspase-9 and PARP in a dose-dependent manner. In mice inoculated with MM.1S cells, oral administration of perifosine significantly reduced MM tumor growth and increased survival [1, 2].

References:
[1] Elrod H A, Lin Y D, Yue P, et al. The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway. Molecular cancer therapeutics, 2007, 6(7): 2029-2038.
[2] Hideshima T, Catley L, Yasui H, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood, 2006, 107(10): 4053-4062.

Perifosine Mechanisms of Action in Leishmania Species.[Pubmed:28096161]

Antimicrob Agents Chemother. 2017 Mar 24;61(4). pii: AAC.02127-16.

Here the mechanism by which Perifosine induced cell death in Leishmania donovani and Leishmania amazonensis is described. The drug reduced Leishmania mitochondrial membrane potential and decreased cellular ATP levels while increasing phosphatidylserine externalization. Perifosine did not increase membrane permeabilization. We also found that the drug inhibited the phosphorylation of Akt in the parasites. These results highlight the potential use of Perifosine as an alternative to miltefosine against Leishmania.

Proteome and Acetylome Analysis Identifies Novel Pathways and Targets Regulated by Perifosine in Neuroblastoma.[Pubmed:28165023]

Sci Rep. 2017 Feb 6;7:42062.

Perifosine, an Akt inhibitor, has been shown to be effective in controlling neuroblastoma tumor growth. However, studies indicate that in addition to the ability to inhibit Akt, other mechanisms contribute to Perifosine's anti-tumor activity. To gain insight into Perifosine anti-tumor activity in neuroblastoma we have studied changes in the proteome and acetylome after Perifosine treatment in SK-N-AS neuroblastoma cells using SILAC labeling, affinity enrichment, high-resolution and LC-MS/MS analysis. Bioinformatic analysis indicates that, a total of 5,880 proteins and 3,415 lysine acetylation sites were quantified in SK-N-AS cells and 216 differentially expressed proteins and 115 differentially expressed lysine acetylation sites were obtained. These differentially expressed proteins and lysine acetylated proteins were involved in a number of different biological functions, metabolic pathways and pathophysiological processes. This study details the impact of Perifosine on proteome and lysine acetylome in SK-N-AS cells and expands our understanding of the mechanisms of Perifosine action in neuroblastoma.

A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors.[Pubmed:28035748]

Pediatr Blood Cancer. 2017 Jul;64(7).

BACKGROUND: The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of Perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination. PROCEDURE: We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of Perifosine (25-75 mg/m(2) /day) and temsirolimus (25-75 mg/m(2) IV weekly) were investigated. RESULTS: Twenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for Perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved. CONCLUSIONS: The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.

A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: Long-term progression-free survival of patients with resistant neuroblastoma.[Pubmed:27649927]

Int J Cancer. 2017 Jan 15;140(2):480-484.

AKT plays a pivotal role in driving the malignant phenotype of many cancers, including high-risk neuroblastoma (HR-NB). AKT signaling, however, is active in normal tissues, raising concern about excessive toxicity from its suppression. The oral AKT inhibitor Perifosine showed tolerable toxicity in adults and in our phase I trial in children with solid tumors (clinicaltrials.gov NCT00776867). We now report on the HR-NB experience. HR-NB patients received Perifosine 50-75 mg m(-2) day(-1) after a loading dose of 100-200 mg m(-2) on day 1, and continued on study until progressive disease. The 27 HR-NB patients included three treated for primary refractory disease and 24 with disease resistant to salvage therapy after 1-5 (median 2) relapses; only one had MYCN-amplified HR-NB. Pharmacokinetic studies showed muM concentrations consistent with cytotoxic levels in preclinical models. Nine patients (all MYCN-non-amplified) remained progression-free through 43+ to 74+ (median 54+) months from study entry, including the sole patient to show a complete response and eight patients who had persistence of abnormal (123) I-metaiodobenzylguanidine skeletal uptake but never developed progressive disease. Toxicity was negligible in all 27 patients, even with the prolonged treatment (11-62 months, median 38) in the nine long-term progression-free survivors. The clinical findings (i) confirm the safety of therapeutic serum levels of an AKT inhibitor in children; (ii) support Perifosine for MYCN-non-amplified HR-NB as monotherapy after completion of standard treatment or combined with other agents (based on preclinical studies) to maximize antitumor effects; and (iii) highlight the welcome possibility that refractory or relapsed MYCN-non-amplified HR-NB is potentially curable.