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Journal of Neuro-oncology Sep 2019Perifosine (PRF) is an oral alkylphospholipid with antineoplastic effects and reasonable tolerability. It inhibits signaling through the PI3/AKT axis and other cascades...
PURPOSE
Perifosine (PRF) is an oral alkylphospholipid with antineoplastic effects and reasonable tolerability. It inhibits signaling through the PI3/AKT axis and other cascades of biologic importance in glioblastoma, and has promising pre-clinical activity in vitro and in vivo. Therefore, we conducted a phase II open-label single-arm clinical trial of perifosine for patients with recurrent glioblastoma (GBM).
METHODS
We planned to accrue up to 30 adults with recurrent GBM with a minimum Karnofsky Performance Status of 50 following radiotherapy but without other restrictions on the number or types of prior therapy. Concurrent p450 stimulating hepatic enzyme inducing anticonvulsants were prohibited. Patients were treated with a loading dose of 600 mg PRF (in 4 divided doses on day 1) followed by 100 mg daily until either disease progression or intolerable toxicity. The primary endpoint was the 6-month progression free survival (PFS6) rate, with at least 20% considered promising. Accrual was continuous but if 0 of the first 12 patients with GBM reached PFS6, then further accrual would terminate for futility. Patients with other high grade gliomas were accrued concurrently to an exploratory cohort.
RESULTS
Treatment was generally well tolerated; gastrointestinal toxicities were the most common side effects, although none resulted in treatment discontinuation. However, there was limited to no efficacy in GBM (n = 16): the PFS6 rate was 0%, median PFS was 1.58 months [95% CI (1.08, 1.84)], median overall survival was 3.68 months [95% CI (2.50, 7.79)], with no radiographic responses. There was a confirmed partial response in one patient with anaplastic astrocytoma (n = 14).
CONCLUSIONS
PRF is tolerable but ineffective as monotherapy for GBM. Preclinical data suggests synergistic effects of PRF in combination with other approaches, and further study is ongoing.
Topics: Adult; Aged; Brain Neoplasms; Female; Follow-Up Studies; Glioblastoma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Phosphorylcholine; Prognosis; Prospective Studies; Proto-Oncogene Proteins c-akt; Survival Rate; Young Adult
PubMed: 31325145
DOI: 10.1007/s11060-019-03243-7 -
Investigational New Drugs Aug 2012The novel AKT inhibitor perifosine possesses myelopoiesis-stimulating effects in rodents. We studied the in vitro effects of the novel agents perifosine, bortezomib and...
The novel AKT inhibitor perifosine possesses myelopoiesis-stimulating effects in rodents. We studied the in vitro effects of the novel agents perifosine, bortezomib and lenalidomide in addition to adriamycin against normal human hematopoietic progenitor cells (HPC) using different clonogenic and non-clonogenic assays. All agents inhibited colony-forming unit (CFU) formation, perifosine inhibiting mainly CFU-granulocyte/macrophage formation and the other agents burst-forming unit-erythroid formation. Perifosine combined with lenalidomide or adriamycin tended to act antagonistically in suppressing CFU formation. Despite their inhibition of CFU formation, perifosine, bortezomib and lenalidomide induced only slight or moderate cytotoxicity in CD34(+) selected HPC, as assessed using different assays such as flow cytometry-based detection of activated caspases and immunohistochemistry studies (e.g., Ki-67 staining). In contrast to its myelopoiesis-stimulating effects in rodents, perifosine--like bortezomib and lenalidomide--suppresses the clonogenic potential of HPC from healthy donors in vitro and thus probably plays no role in preventing neutropenia or in shorting its duration after intensive chemotherapy. However, all these novel agents typically induce only slight or moderate suppression of the clonogenic potential or loss of viability of normal HPC at clinically achievable plasma concentrations, assuming that hematoxicity is manageable and functional HPC can be collected after treatment with these compounds.
Topics: Annexin A5; Antigens, CD34; Boronic Acids; Bortezomib; Caspases; Colony-Forming Units Assay; Doxorubicin; Flow Cytometry; Health; Hematopoietic Stem Cells; Humans; Immunohistochemistry; Lenalidomide; Phosphorylcholine; Pyrazines; Staining and Labeling; Thalidomide; Tissue Donors; Trypan Blue
PubMed: 21750922
DOI: 10.1007/s10637-011-9705-6 -
Clinical Cancer Research : An Official... Dec 2007It is critical to develop methods to quantify the early pharmacodynamic effects of targeted therapeutics in vivo to make drug development more efficient and ensure...
PURPOSE
It is critical to develop methods to quantify the early pharmacodynamic effects of targeted therapeutics in vivo to make drug development more efficient and ensure biologically relevant dosing. Furthermore, an ability to identify patients likely to respond to targeted therapeutics would decrease the size, duration, and cost of clinical trials, resulting in more efficient translation to improved patient outcomes. Recent studies suggest that perifosine inhibits the phosphatidylinositol-3'-kinase (PI3K) pathway by preventing cell membrane recruitment of the AKT pleckstrin homology domain.
EXPERIMENTAL DESIGN
A novel functional proteomics technology, reverse phase protein array, was used to establish and quantify pharmacodynamic markers of perifosine efficacy.
RESULTS
Perifosine selectively prevents AKT recruitment to the membrane and blocks activation of downstream effectors. Perifosine inhibited breast, ovarian, and prostate cancer models. Growth inhibition was associated with apoptosis. Activation of AKT as a consequence of genomic aberrations predicted perifosine efficacy. In cell lines and xenografts, there was a highly statistically significant correlation between the degree of antitumor efficacy of different perifosine doses and quantified down-regulation of phosphorylation of AKT and of its downstream targets, particularly S6.
CONCLUSIONS
Because of a strong correlation between proportional modulation of PI3K pathway biomarkers and quantified perifosine efficacy, it is likely that early measurement of such pharmacodynamic biomarkers with reverse phase protein array will optimize selection of responding patients and guide perifosine dosing. Furthermore, PI3K pathway activation status may allow baseline selection of patients most likely to respond to perifosine alone or in combination with other therapies.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Activation; Female; Humans; Immunoblotting; Mice; Mice, Nude; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphorylcholine; Protein Array Analysis; Proto-Oncogene Proteins c-akt; Transfection; Xenograft Model Antitumor Assays
PubMed: 18094426
DOI: 10.1158/1078-0432.CCR-07-0760 -
British Journal of Haematology Sep 2007Over time, Waldenström macroglobulinaemia (WM) has evolved conceptually from a clinical syndrome to a distinct clinicopathological entity. Progress is being made in... (Review)
Review
Over time, Waldenström macroglobulinaemia (WM) has evolved conceptually from a clinical syndrome to a distinct clinicopathological entity. Progress is being made in standardization of the disease definition and treatment response criteria, although nosologic controversies persist. According to the Second International Workshop on WM, the disease is defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in the bone marrow, with an associated immunoglobulin (Ig) M paraprotein. Disease symptoms are often divided into those related to tumour infiltration and those related to the rheological effects of the monoclonal IgM. As with other low-grade lymphomas, asymptomatic patients are observed only, with treatment reserved for symptomatic patients. There is no standard treatment for WM and choices include rituximab, alkylating agents, purine nucleoside analogues, alone or in combination, as well as autologous peripheral blood stem cell transplant in eligible patients. Novel treatments, such as bortezomib, oblimersen sodium, perifosine and others are being evaluated.
Topics: Antineoplastic Combined Chemotherapy Protocols; Diagnosis, Differential; Humans; Plasmapheresis; Splenectomy; Waldenstrom Macroglobulinemia
PubMed: 17672883
DOI: 10.1111/j.1365-2141.2007.06724.x -
Cellular Physiology and Biochemistry :... 2017The alkylphospholipid perifosine is used for the treatment of malignancy. The substance is effective by triggering suicidal tumor cell death or apoptosis. Side effects...
BACKGROUND/AIMS
The alkylphospholipid perifosine is used for the treatment of malignancy. The substance is effective by triggering suicidal tumor cell death or apoptosis. Side effects of perifosine include anemia. At least in theory, perifosine-induced anemia could result from stimulation of suicidal erythrocyte death or eryptosis. Hallmarks of eryptosis are cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Cellular mechanisms participating in the orchestration of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, increase of ceramide abundance, as well as activation of staurosporine sensitive protein kinase C and/or of SB203580 sensitive p38 kinase. The present study explored, whether perifosine induces eryptosis and, if so, whether its effect involves and/or requires Ca2+ entry, oxidative stress, ceramide and kinase activation.
METHODS
Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was estimated from hemoglobin concentration in the supernatant.
RESULTS
A 24 hours exposure of human erythrocytes to perifosine (2.5 µg/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased average forward scatter, significantly increased the percentage of shrunken erythrocytes, and significantly decreased the percentage of swollen erythrocytes. Perifosine significantly increased the percentage of hemolytic erythrocytes. Perifosine significantly increased Fluo3-fluorescence, but decreased DCFDA fluorescence and ceramide abundance. The effect of perifosine on annexin-V-binding was significantly blunted by removal of extracellular Ca2+ and by addition of staurosporine (1 µM), but not by addition of SB203580 (2 µM).
CONCLUSIONS
Perifosine triggers eryptosis, an effect at least in part due to Ca2+ entry and activation of staurosporine sensitive kinases.
Topics: Aniline Compounds; Calcium; Cell Size; Ceramides; Eryptosis; Erythrocyte Membrane; Erythrocytes; Flow Cytometry; Hemolysis; Humans; Imidazoles; Phosphatidylserines; Phosphorylcholine; Pyridines; Reactive Oxygen Species; Staurosporine; Xanthenes
PubMed: 28472790
DOI: 10.1159/000475977 -
Clinical Cancer Research : An Official... Nov 2014To evaluate safety and activity of perifosine and sorafenib combination therapy in patients with lymphoproliferative diseases.
PURPOSE
To evaluate safety and activity of perifosine and sorafenib combination therapy in patients with lymphoproliferative diseases.
EXPERIMENTAL DESIGN
Patients with relapsed and refractory lymphoproliferative diseases received perifosine (50 mg twice daily) for 1 month. Patients achieving less than partial response (PR) after perifosine alone were administered the combination therapy [perifosine plus sorafenib (400 mg twice daily)] until progressive disease (PD) or unacceptable toxicity occurred. The pERK and pAKT in peripheral blood lymphocytes as well as serum cytokine levels were investigated as predictive biomarkers of response.
RESULTS
Forty patients enrolled in this study. After 1 month of perifosine alone, 36 who achieved less than PR went on to combination therapy, whereas four patients with chronic lymphocytic leukemia (CLL) who achieved PR continued with perifosine alone for a median of 10 months (range, 4-21). The most common drug-related toxicities were grade 1-2 anemia (17%), thrombocytopenia (9%), diarrhea (25%), joint pain (22%), and hand-foot skin reaction (25%). Three patients experienced grade 3 pneumonitis. Eight patients (22%) achieved PR, 15 (42%) achieved stable disease, and 13 (36%) experienced PD. A 28% PR rate was recorded for 25 patients with Hodgkin lymphoma. Among all patients, median overall survival and progression-free survival were 16 and 5 months, respectively. Early reductions in pERK and pAKT significantly correlated with the probability of clinical response.
CONCLUSIONS
Perifosine and sorafenib combination therapy is feasible with manageable toxicity and demonstrates promising activity in patients with Hodgkin lymphoma. The predictive value of pERK and pAKT should be confirmed in a larger patient cohort.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Lymphoproliferative Disorders; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Recurrence; Sorafenib; Treatment Outcome; Young Adult
PubMed: 25239609
DOI: 10.1158/1078-0432.CCR-14-0770 -
Experimental Hematology Jul 2007Alkyl-lysophospholipids are a novel class of antitumor agents. Perifosine is a novel alkyl-lysophospholipid that can induce apoptosis in multiple myeloma (MM) tumor...
OBJECTIVES
Alkyl-lysophospholipids are a novel class of antitumor agents. Perifosine is a novel alkyl-lysophospholipid that can induce apoptosis in multiple myeloma (MM) tumor cells, both in vitro and in vivo. We investigated the effects of perifosine on the peripheral blood, bone marrow, and spleen of mice inoculated with subcutaneous plasmacytomas.
METHODS
Immunocompromised mice were inoculated with myeloma cell lines and treated with oral perifosine in either a daily or weekly schedule, or with vehicle only. When plasmacytomas reached 2 cm, mice were sacrificed. Terminal blood was analyzed with a Coulter counter, and counts were confirmed by light microscopy. Marrow and spleen were also analyzed by light microscopy.
RESULTS
In control mice, mean hemoglobin was 12 g/dL, white blood cell (WBC) count 7 x 10(9)/L, and mean platelet count was 292 x 10(9)/L. In contrast, the respective values for mice treated with perifosine weekly were 11 g/dL, 9 x 10(9)/L, and 944 x 10(9)/L; and for mice treated with perifosine daily were 10 g/dL, 11 x 10(9)/L, and 752 x 10(9)/L. The increase in WBCs was due, predominantly, to a neutrophilia. Compared to control mice, perifosine treatment induced marrow hypercellularity and splenic white pulp expansion.
CONCLUSIONS
These findings have clinical relevance because myeloid suppression is a dose-limiting toxicity of many cytotoxic agents, and myeloid hyperplasia is usually only observed in the setting of growth factor stimulation. Coupled with its remarkable in vitro MM cytotoxicity, these results strongly support the use of perifosine in clinical trials for patients with MM.
Topics: Animals; Apoptosis; Cell Line; Female; Hematopoiesis; Humans; Hyperplasia; Leukocytosis; Mice; Multiple Myeloma; Myeloid Cells; Phosphorylcholine; Thrombocytosis
PubMed: 17588472
DOI: 10.1016/j.exphem.2007.03.020 -
Acta Pharmaceutica Sinica. B Oct 2023It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E (GSDME)-deficient cells, but pyroptosis in GSDME-sufficient cells. The high GSDME...
It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E (GSDME)-deficient cells, but pyroptosis in GSDME-sufficient cells. The high GSDME expression and apoptosis resistance of pancreatic ductal adenocarcinoma (PDAC) cells shed light on another attractive strategy for PDAC treatment by promoting pyroptosis. Here we report a hGLuc-hGSDME-PCA system for high-throughput screening of potential GSDME activators against PDAC. This screening system neatly quantifies the oligomerization of GSDME-N to characterize whether pyroptosis occurs under the stimulation of chemotherapy drugs. Based on this system, ponatinib and perifosine are screened out from the FDA-approved anti-cancer drug library containing 106 compounds. Concretely, they exhibit the most potent luminescent activity and cause drastic pyroptosis in PDAC cells. Further, we demonstrate that perifosine suppresses pancreatic cancer by promoting pyroptosis caspase-3/GSDME pathway both and . Collectively, this study reveals the great significance of hGLuc-hGSDME-PCA in identifying compounds triggering GSDME-dependent pyroptosis and developing promising therapeutic agents for PDAC.
PubMed: 37799380
DOI: 10.1016/j.apsb.2023.07.018 -
Investigational New Drugs Aug 2005Clinical use of anti-cancer alkylphospholipids is limited by gastrointestinal toxicity. However, new interest has emerged since it was shown that these drugs enhance the... (Comparative Study)
Comparative Study
Clinical use of anti-cancer alkylphospholipids is limited by gastrointestinal toxicity. However, new interest has emerged since it was shown that these drugs enhance the cytotoxic effect of conventional chemotherapy and radiotherapy in preclinical models. The aim of this study was to characterize the pharmacokinetic profile of perifosine, an oral analog of alkylphosphocholine (APC), and to compare in vitro drug uptake with in vivo drug accumulation in three human-derived squamous cell carcinomas (A431, HNXOE and KB). In vitro, KB cells showed a remarkably high uptake and sensitivity for perifosine compared with A431 and HNXOE cells. In vivo, perifosine reached a clinically relevant plasma concentration in mice after a single oral dose of 40 mg/kg. Perifosine was not metabolized and displayed slow elimination, with a terminal half-life of 137 (+/- 20) hours and an apparent volume of distribution of 11.3 l/kg. Comparable tumor accumulation was observed for A431 and HNXOE tumors, whereas perifosine uptake by KB xenografts was substantially higher. Tissue distribution occurred throughout the whole body reaching high perifosine levels in the gastro-intestinal tract, while heart and brain tissue contained relatively low levels. Based on its stability and relatively high tumor uptake in vivo, perifosine is an attractive candidate for further evaluation, e.g. as radiosensitizer.
Topics: Administration, Oral; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Female; Head and Neck Neoplasms; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Phosphorylcholine; Tissue Distribution; Vulvar Neoplasms
PubMed: 16012787
DOI: 10.1007/s10637-005-1436-0 -
Acta Tropica Oct 2008Miltefosine has been established as the first oral administration drug against cutaneous and visceral leishmaniasis. Other alkyl-phospholipids such as edelfosine have... (Comparative Study)
Comparative Study
Miltefosine has been established as the first oral administration drug against cutaneous and visceral leishmaniasis. Other alkyl-phospholipids such as edelfosine have been tested against Leishmania showing an in vitro antiparasitic activity. Perifosine in vitro activity has been previously demonstrated against different Leishmania species including Leishmania amazonensis. In this study edelfosine and perifosine were orally administered to BALB/c mice at doses of 1 and 2.5 mg/kg/day during 28 days and 5 mg/kg/day during 14 days, starting the treatment 2 weeks after the first treatment scheme. Lesion sizes and parasitic burden as well as viability were determined in order to establish the treatment effectiveness. An assay to compare miltefosine at standard dose of 2.5 mg/kg/day during 28 days to an in vivo treatment with perifosine at the most effective treatment scheme observed in this study 5 mg/kg/day during 14 days, was also developed. Perifosine showed the higher activity in the in vivo assay and is showing as a new possibility within the alkyl-phospholipids group for the treatment against cutaneous leishmaniasis caused by L. amazonensis.
Topics: Administration, Oral; Animals; Antiprotozoal Agents; Female; Leishmania mexicana; Leishmaniasis, Cutaneous; Mice; Mice, Inbred BALB C; Phospholipid Ethers; Phosphorylcholine; Survival Analysis
PubMed: 18801328
DOI: 10.1016/j.actatropica.2008.08.005