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Seminars in Oncology Oct 2013The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens.... (Review)
Review
The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for transplant-eligible patients, and as part of consolidation and/or maintenance after front-line treatment, including in transplant-ineligible patients. Together, these and other strategies have contributed to a prolongation of progression-free survival (PFS) and overall survival (OS) in myeloma patients, and an increasing proportion are able to sustain a remission for many years. Despite these improvements, however, the vast majority of patients continue to suffer relapses, which suggests a prominent role for either primary, innate drug resistance, or secondary, acquired drug resistance. As a result, there remains a strong need to develop new proteasome inhibitors and immunomodulatory agents, as well as new drug classes, which would be effective in the relapsed and/or refractory setting, and overcome drug resistance. This review will focus on novel drugs that have reached phase III trials, including carfilzomib and pomalidomide, which have recently garnered regulatory approvals. In addition, agents that are in phase II or III, potentially registration-enabling trials will be described as well, to provide an overview of the possible landscape in the relapsed and/or refractory arena over the next 5 years.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Clinical Trials, Phase III as Topic; Disease-Free Survival; Drug Resistance, Neoplasm; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Immunologic Factors; Indoles; Multiple Myeloma; Oligopeptides; Panobinostat; Phosphorylcholine; Piperidines; Proteasome Inhibitors; Pyridines; Remission Induction; Thalidomide; Thiazoles; Treatment Outcome; Vorinostat
PubMed: 24135408
DOI: 10.1053/j.seminoncol.2013.07.007 -
Cancer Dec 2011Neuroblastoma (NB) tumors expressing high levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB or activated Akt are associated with decreased...
BACKGROUND
Neuroblastoma (NB) tumors expressing high levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB or activated Akt are associated with decreased event-free or overall survival in patients with NB. In the current study, the effect of perifosine, an Akt inhibitor, on the chemosensitivity of TrkB-expressing NB cells or tumors was evaluated.
METHODS
A tetracycline-regulated TrkB-expressing isogenic NB cell model system was tested. In this system, NB cells were treated with etoposide and/or perifosine both in vitro and in vivo. Inhibition of the target by perifosine was evaluated by Western blot analysis or kinase activity assay. Cell survival and tumor growth were investigated.
RESULTS
In vitro BDNF treatment induced Akt phosphorylation and rescued cells from etoposide-induced cell death in cells with high TrkB expression, but not in cells with low TrkB expression. Pretreatment of high TrkB-expressing TB3 cells with perifosine blocked BDNF/TrkB-induced Akt phosphorylation and inhibited BDNF's protection of TB3 cells from etoposide treatment. In vivo, tumors with high TrkB expression were found to have elevated levels of phosphorylated Akt and were less sensitive to etoposide treatment compared with tumors with low TrkB expression. Mice treated with a combination of perifosine and etoposide were found to have a statistically significant decrease in tumor growth compared with mice treated with either etoposide or perifosine alone. Activation of Akt through the BDNF/TrkB signaling pathway induced chemoresistance in NB in vivo.
CONCLUSIONS
Perifosine-induced inhibition of Akt increased the sensitivity of NB to chemotherapy. The results of the current study support the future clinical evaluation of an Akt inhibitor combined with cytotoxic drugs for the improvement of treatment efficacy.
Topics: Brain Neoplasms; Brain-Derived Neurotrophic Factor; Cell Line, Tumor; Drug Resistance, Neoplasm; Etoposide; Humans; Neuroblastoma; Phosphorylation; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Receptor, trkB; Tetracycline
PubMed: 21590687
DOI: 10.1002/cncr.26133 -
Cancer Chemotherapy and Pharmacology May 2015Central nervous system tumors are histologically and biologically heterogeneous. Standard treatment for malignant tumors includes surgery, radiation and chemotherapy,...
PURPOSE
Central nervous system tumors are histologically and biologically heterogeneous. Standard treatment for malignant tumors includes surgery, radiation and chemotherapy, yet surgical resection is not always an option and chemotherapeutic agents have limited benefit. Recent investigations have focused on molecularly targeted therapies aimed at critical tumorigenic pathways. Several tumor types, including high-grade gliomas and pediatric pontine gliomas, exhibit Akt activation. Perifosine, an orally bioavailable, synthetic alkylphospholipid and potent Akt inhibitor, has demonstrated activity in some preclinical models, but absent activity in a genetically engineered mouse model of pontine glioma. We evaluated the plasma and cerebrospinal fluid pharmacokinetics of orally administered perifosine in a non-human primate model to evaluate CNS penetration.
METHODS
Perifosine was administered orally to three adult rhesus monkeys as a single dose of 7.0 mg/kg perifosine. Serial paired plasma and CSF samples were collected for up to 64 days. Perifosine was quantified with a validated HPLC/tandem mass spectrometry assay. Pharmacokinetic parameters were estimated using non-compartmental methods. CSF penetration was calculated from the areas under the concentration-time curves.
RESULTS
Peak plasma concentrations (C max) ranged from 11.7-19.3 µM, and remained >1 µM for >28 days. Time to C max (T max) was 19 h. The median (range) AUCPl was 3148 (2502-4705) µM/h, with a median (range) terminal half-life (t 1/2) of 193 (170-221) h. Plasma clearance was 494 (329-637) mL/h/kg. Peak CSF concentrations were 4.1-10.1 nM (T max 64-235 h). CSF AUCs and t 1/2 were 6358 (2266-7568) nM/h and 277 (146-350) h, respectively. Perifosine concentrations in the CSF remained over nM for >35 days. The mean CSF penetration was 0.16 %.
CONCLUSION
CNS penetration of perifosine after systemic administration is poor. However, levels were measurable in both plasma and CSF for an extended time (>2 months) after a single oral dose.
Topics: Administration, Oral; Animals; Macaca mulatta; Male; Models, Animal; Phosphorylcholine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt
PubMed: 25740692
DOI: 10.1007/s00280-015-2711-1 -
Investigational New Drugs Oct 2013The PI3K-Akt pathway is frequently activated in acute leukemias and represents an important therapeutic target. UCN-01 and perifosine are known to inhibit Akt activation.
BACKGROUND
The PI3K-Akt pathway is frequently activated in acute leukemias and represents an important therapeutic target. UCN-01 and perifosine are known to inhibit Akt activation.
METHODS
The primary objective of this phase I study was to determine the maximum tolerated dose (MTD) of UCN-01 given in combination with perifosine in patients with advanced acute leukemias and myelodysplastic syndrome. Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and efficacy. Perifosine 150 mg every 6 h was given orally on day 1 followed by 100 mg once a day continuously in 28-day cycles. UCN-01 was given intravenously over 3 h on day 4 at three dose levels (DL1=40 mg/m(2); DL2=65 mg/m(2); DL3=90 mg/m(2)).
RESULTS
Thirteen patients were treated (DL1, n=6; DL2, n=4; DL3, n=3) according to a traditional "3+3" design. Two patients at the DL3 experienced dose-limiting toxicity including grade 3-4 pericardial effusion, hypotension, hyperglycemia, hyperkalemia, constitutional symptoms and grade 5 pneumonitis. Other frequent toxicities were grade 1-2 nausea, diarrhea, vomiting, fatigue and hyperglycemia. The MTD was determined to be UCN-01 65 mg/m(2) with perifosine 100 mg a day. No appreciable direct Akt inhibition could be demonstrated in patients' mononuclear cells using Western blot, however, reduced phosphorylation of the downstream target ribosomal protein S6 in leukemic blasts was noted by intracellular flow cytometry. No objective responses were observed on this study.
CONCLUSION
UCN-01 and perifosine can be safely administered, but this regimen lacked clinical efficacy. This approach may have failed because of insufficient Akt inhibition in vivo.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Leukemia; Leukocytes, Mononuclear; Male; Maximum Tolerated Dose; Middle Aged; Myelodysplastic Syndromes; Phosphorylcholine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Staurosporine; Treatment Outcome; Young Adult
PubMed: 23443507
DOI: 10.1007/s10637-013-9937-8 -
Journal of Pharmacological Sciences Jul 2020The optimum strategy for heart failure (HF) treatment has yet to be elucidated. This study intended to test the benefit of a combination of valsartan (VAL) and...
The optimum strategy for heart failure (HF) treatment has yet to be elucidated. This study intended to test the benefit of a combination of valsartan (VAL) and perifosine (PER), a specific AKT inhibitor, in protecting against pressure overload induced mouse HF. Mouse were subjected to aortic banding (AB) surgery to establish HF models and then were given vehicle (HF), VAL (50 mg/kg/d), PER (30 mg/kg/d) or combination of VAL and PER for 4 weeks. Mouse with sham surgery treated with VEH were used for control (VEH). VAL or PER treatment could significantly alleviate mouse heart weight, attenuate cardiac fibrosis and improve cardiac function. The combination treatment of VAL and PER presented much better benefit compared with VAL or PER group respectively. PER treatment significantly inhibited AKT/GSK3β/mTORC1 signaling. Besides the classic AT1 inhibition, VAL treatment significantly inhibited MAPK (ERK1/2) signaling. Furthermore, VAL and PER treatment could markedly prevent neonatal rat cardiomyocyte hypertrophy and the activation of neonatal rat cardiac fibroblast. Combination of VAL and PER also presented superior beneficial effects than single treatment of VAL or PER in vitro experiments respectively. This study presented that the combination of valsartan and PER may be a potential treatment for HF prevention.
Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Glycogen Synthase Kinase 3 beta; Heart Failure; MAP Kinase Signaling System; Male; Mice, Inbred C57BL; Organ Size; Phosphorylcholine; Pressure; Proto-Oncogene Proteins c-akt; Signal Transduction; Valsartan
PubMed: 32414690
DOI: 10.1016/j.jphs.2020.04.001 -
Acta Ophthalmologica Nov 2013Recently, there has been an increase in the use of targeted therapies for cancer treatments. Nevertheless, the ocular side-effects of the commonly used targeted agents... (Review)
Review
Recently, there has been an increase in the use of targeted therapies for cancer treatments. Nevertheless, the ocular side-effects of the commonly used targeted agents are generally under-reported and not well studied in the literature. We conducted multiple searches in databases, including Medline, EMBASE, Cochrane Library and conference proceedings, using the following strings: 'name of targeted therapeutic agent (both generic and commercial names)' AND 'eye OR ocular OR vision OR ophthalmological'. Various targeted agents have been found to be associated with ocular side-effects due to their specific targeting of activities in the eye. Imatinib commonly causes periorbital oedema, epiphora and occasionally conjunctival haemorrhage. Cetuximab causes corneal lesions, meibomian gland dysfunction, periorbital and lid dermatitis, blepharitis and conjunctivitis. Erlotinib is related to various ocular toxicities, mainly on the ocular surface, and perifosine has been reported to be associated with severe keratitis. Bevacizumab could potentially disrupt intrinsic ocular circulation and lead to the development of thromboembolic events; there are rare reported cases of optic neuritis or optic neuropathy. Other targeted agents, such as trastuzumab, sunitinib and crizotinib, also have specific ocular toxicities. In conclusion, ocular effects of targeted agents are not uncommon in cancer patients receiving targeted therapy. Ophthalmologists should have high indexes of suspicion to diagnose and treat these complications promptly.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Bevacizumab; Cetuximab; Crizotinib; Erlotinib Hydrochloride; Eye Diseases; Humans; Imatinib Mesylate; Molecular Targeted Therapy; Neoplasms; Phosphorylcholine; Piperazines; Pyrazoles; Pyridines; Pyrimidines; Quinazolines; Trastuzumab
PubMed: 22970709
DOI: 10.1111/j.1755-3768.2012.02518.x -
Radiographics : a Review Publication of... Oct 2011Glioblastoma is a highly malignant brain tumor that relentlessly defies therapy. Efforts over the past decade have begun to tease out the biochemical details that lead... (Review)
Review
Glioblastoma is a highly malignant brain tumor that relentlessly defies therapy. Efforts over the past decade have begun to tease out the biochemical details that lead to its aggressive behavior and poor prognosis. There is hope that this new understanding will lead to improved treatment strategies for patients with glioblastoma, in the form of targeted, molecularly based therapies that are individualized to specific changes in individual tumors. However, these new therapies have the potential to fundamentally alter the biologic behavior of glioblastoma and, as a result, its imaging appearance. Knowledge about common genetic alterations and the resultant cellular and tissue changes (ie, induced angiogenesis and abnormal cell survival, proliferation, and invasion) in glioblastomas is important as a basis for understanding imaging findings before treatment. It is equally critical that radiologists understand which genetic pathway is targeted by each specific therapeutic agent or class of agents in order to accurately interpret changes in the imaging appearances of treated tumors.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Brain Neoplasms; Cell Proliferation; Cell Survival; Erlotinib Hydrochloride; Gefitinib; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Magnetic Resonance Imaging; Neoplasm Invasiveness; Neovascularization, Pathologic; Phosphorylcholine; Protein Kinase Inhibitors; Quinazolines
PubMed: 21997991
DOI: 10.1148/rg.316115512 -
Cancer Research Mar 2010Brainstem gliomas (BSG) are a rare group of central nervous system tumors that arise mostly in children and usually portend a particularly poor prognosis. We report the...
Brainstem gliomas (BSG) are a rare group of central nervous system tumors that arise mostly in children and usually portend a particularly poor prognosis. We report the development of a genetically engineered mouse model of BSG using the RCAS/tv-a system and its implementation in preclinical trials. Using immunohistochemistry, we found that platelet-derived growth factor (PDGF) receptor alpha is overexpressed in 67% of pediatric BSGs. Based on this observation, we induced low-grade BSGs by overexpressing PDGF-B in the posterior fossa of neonatal nestin tv-a mice. To generate high-grade BSGs, we overexpressed PDGF-B in combination with Ink4a-ARF loss, given that this locus is commonly lost in high-grade pediatric BSGs. We show that the likely cells of origin for these mouse BSGs exist on the floor of the fourth ventricle and cerebral aqueduct. Irradiation of these high-grade BSGs shows that although single doses of 2, 6, and 10 Gy significantly increased the percent of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei, only 6 and 10 Gy significantly induce cell cycle arrest. Perifosine, an inhibitor of AKT signaling, significantly induced TUNEL-positive nuclei in this high-grade BSG model, but in combination with 10 Gy, it did not significantly increase the percent of TUNEL-positive nuclei relative to 10 Gy alone at 6, 24, and 72 hours. Survival analysis showed that a single dose of 10 Gy significantly prolonged survival by 27% (P = 0.0002) but perifosine did not (P = 0.92). Perifosine + 10 Gy did not result in a significantly increased survival relative to 10 Gy alone (P = 0.23). This PDGF-induced BSG model can serve as a preclinical tool for the testing of novel agents.
Topics: Animals; Brain Stem Neoplasms; Combined Modality Therapy; Disease Models, Animal; Genetic Engineering; Glioma; Inbreeding; Mice; Mice, Inbred BALB C; Phosphorylcholine; Receptor, Platelet-Derived Growth Factor alpha
PubMed: 20197468
DOI: 10.1158/0008-5472.CAN-09-2503 -
Frontiers in Oncology 2021Metastatic brain tumors are regarded as the most advanced stage of certain types of cancer; however, chemotherapy has played a limited role in the treatment of brain...
Metastatic brain tumors are regarded as the most advanced stage of certain types of cancer; however, chemotherapy has played a limited role in the treatment of brain metastases. Here, we established murine models of brain metastasis using cell lines derived from human brain metastatic tumors, and aimed to explore the antitumor efficacy of perifosine, an orally active allosteric Akt inhibitor. We evaluated the effectiveness of perifosine by using it as a single agent in ectopic and orthotopic models created by injecting the DU 145 and NCI-H1915 cell lines into mice. Initially, the injected cells formed distant multifocal lesions in the brains of NCI-H1915 mice, making surgical resection impractical in clinical settings. We determined that perifosine could distribute into the brain and remain localized in that region for a long period. Perifosine significantly prolonged the survival of DU 145 and NCI-H1915 orthotopic brain tumor mice; additionally, complete tumor regression was observed in the NCI-H1915 model. Perifosine also elicited much stronger antitumor responses against subcutaneous NCI-H1915 growth; a similar trend of sensitivity to perifosine was also observed in the orthotopic models. Moreover, the degree of suppression of NCI-H1915 tumor growth was associated with long-term exposure to a high level of perifosine at the tumor site and the resultant blockage of the PI3K/Akt signaling pathway, a decrease in tumor cell proliferation, and increased apoptosis. The results presented here provide a promising approach for the future treatment of patients with metastatic brain cancers and emphasize the importance of enriching a patient population that has a higher probability of responding to perifosine.
PubMed: 34804943
DOI: 10.3389/fonc.2021.754365 -
European Review For Medical and... Apr 2018It is to study the stimulation and possible active mechanism of miRNA-21 on AGS proliferation of gastric cancer.
OBJECTIVE
It is to study the stimulation and possible active mechanism of miRNA-21 on AGS proliferation of gastric cancer.
MATERIALS AND METHODS
AGS gastric cancer cells were cultivated in vitro and then divided into the blank control group, the PGE2 (prostaglandin E2) group, the anti-miRNA-21 group and the PGE2 + anti-miRNA-21 group and the MTT and the flow cytometry methods were adopted to test the effect of PGE2 or/and anti-miRNA-21 intervention on AGS cell proliferation and apoptosis and the differences to miRNA-21 expression. In addition, the cells were also divided into the blank control group, the PGE2 group, the PGE2 + Perifosine group, the PGE2 + anti-miRNA-21 group and the PGE2 + anti-miRNA-21 + Perifosine group and the MTT and flow cytometry methods were adopted to test the effect of Perifosine intervention on AGS cell proliferation and apoptosis and on PTEN and p-AktmRNA and protein expressions.
RESULTS
Compared with the control group, AGS cell proliferation activity increased significantly, the apoptosis rate decreased and the miRNA-21tmRNA and protein expression increased in the PGE2 group (p < 0.05); compared with the PGE2 group, the AGS cell proliferation rate decreased, the apoptosis rate increased and the miRNA-21mRNA and protein expressions decreased (p < 0.05) in the anti-miRNA-21 group and the PGE2 + anti-miRNA-21 group. In addition, after intervention of Perifosine, the AGS cell proliferation rate decreased, the apoptosis rate increased, the PTEN mRNA and protein expressions increased and the pAktmRNA and protein expressions decreased (p < 0.05).
CONCLUSIONS
miRNA-21 may promote the growth of gastric cancer cells by adjusting and controlling PTEN/Akt signal passage mediated PEG2.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Dinoprostone; Humans; MicroRNAs; PTEN Phosphohydrolase; Stomach Neoplasms
PubMed: 29687845
DOI: 10.26355/eurrev_201804_14717