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PloS One Jan 2011Platelet derived growth factor receptor (PDGFR) activity is deregulated in human GBM due to amplification and rearrangement of the PDGFR-alpha gene locus or...
BACKGROUND
Platelet derived growth factor receptor (PDGFR) activity is deregulated in human GBM due to amplification and rearrangement of the PDGFR-alpha gene locus or overexpression of the PDGF ligand, resulting in the activation of downstream kinases such as phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Aberrant PDGFR signaling is observed in approximately 25-30% of human GBMs, which are frequently molecularly classified as the proneural subclass. It would be valuable to understand how PDGFR driven GBMs respond to Akt and mTOR inhibition.
METHODOLOGY/PRINCIPAL FINDINGS
Using genetically engineered PTEN-intact and PTEN-deficient PDGF-driven mouse models of GBM that closely mimic the histology and genetics of the human PDGF subgroup, we investigated the effect of inhibiting Akt and mTOR alone or in combination in vitro and in vivo. We used perifosine and CCI-779 to inhibit Akt and mTOR, respectively. Here, we show in vitro data demonstrating that the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null primary glioma cell cultures is obtained when using both inhibitors in combination. We next investigated if the effects we observed in culture could be duplicated in vivo by treating mice with gliomas for 5 days. The in vivo treatments with the combination of CCI-779 and perifosine resulted in decreased Akt and mTOR signaling, which correlated to decreased proliferation and increased cell death independent of PTEN status, as monitored by immunoblot analysis, histology and MRI.
CONCLUSIONS/SIGNIFICANCE
These findings underline the importance of simultaneously targeting Akt and mTOR to achieve significant down-regulation of the PI3K pathway and support the rationale for testing the perifosine and CCI-779 combination in the human PDGF-subgroup of GBM.
Topics: Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Synergism; Glioblastoma; Mice; PTEN Phosphohydrolase; Phosphatidylinositol 3-Kinases; Phosphorylcholine; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Sirolimus
PubMed: 21267448
DOI: 10.1371/journal.pone.0014545 -
Pharmacological Research Sep 2022The serine/threonine kinase Akt is a major player in the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, and its modulation... (Review)
Review
The serine/threonine kinase Akt is a major player in the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, and its modulation impacts multiple cellular processes such as growth, proliferation, and survival. Several abnormalities in this pathway have been documented over the years, and these alterations were shown to have great implications in tumorigenesis and resistance to chemotherapy. Thus, multiple Akt inhibitors have been developed and tested in adult tumors, and some of them are currently undergoing phase I, II, and III clinical trials for distinct cancers that arise during adulthood. Despite that, the impact of these inhibitors is still not fully understood in pediatric tumors, and Akt-specific targeting seems to be a promising approach to treat children affected by cancers. This review summarizes recent available evidence of Akt inhibitors in pediatric cancers, from both preclinical and clinical studies. In short, we demonstrate the impact that Akt inhibition provides in tumorigenesis, and we suggest targeting the PI3K/Akt/mTOR signaling pathway, alone or in combination with other inhibitors, is a feasible tool to achieve better outcomes in pediatric tumors.
Topics: Adult; Carcinogenesis; Child; Humans; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 35987481
DOI: 10.1016/j.phrs.2022.106403 -
British Journal of Haematology Aug 2012The combination of lenalidomide-dexamethasone is active in multiple myeloma (MM). Preclinical data showed that the Akt inhibitor, perifosine, sensitized MM cells to...
The combination of lenalidomide-dexamethasone is active in multiple myeloma (MM). Preclinical data showed that the Akt inhibitor, perifosine, sensitized MM cells to lenalidomide and dexamethasone, providing the rationale for this Phase I, multicentre, single-arm study to assess the safety and determine the maximum-tolerated dose (MTD) of perifosine-lenalidomide-dexamethasone in relapsed and relapsed/refractory MM. Patients received escalating doses of perifosine 50-100 mg daily and lenalidomide 15-25 mg once daily on days 1-21 of each 28-d cycle, plus dexamethasone 20-40 mg weekly thereafter, as indicated. Thirty-two patients were enrolled across four dose cohorts. MTD was not reached, with 31 patients evaluable for safety/tolerability. The most common all-causality grade 1-2 adverse events were fatigue (48%) and diarrhoea (45%), and grade 3-4 neutropenia (26%), hypophosphataemia (23%), thrombocytopenia (16%), and leucopenia (13%). Among 30 evaluable patients, 73% (95% confidence interval, 57·5-89·2%) achieved a minimal response or better, including 50% with a partial response or better. Median progression-free survival was 10·8 months and median overall survival 30·6 months. Response was associated with phospho-Akt in pharmacodynamic studies. Perifosine-lenalidomide-dexamethasone was well tolerated and demonstrated encouraging clinical activity in relapsed and relapsed/refractory MM.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Kaplan-Meier Estimate; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Phosphatidylinositol 3-Kinase; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Recurrence; Thalidomide; Treatment Outcome
PubMed: 22640031
DOI: 10.1111/j.1365-2141.2012.09173.x -
World Journal of Clinical Oncology Oct 2016The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug... (Review)
Review
The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, ., MK-2206 and perifosine, or PI3K modulators, ., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy and , which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.
PubMed: 27777878
DOI: 10.5306/wjco.v7.i5.352 -
Frontiers in Oncology 2020Colorectal cancer (CRC) is a disease with constantly increasing incidence and high mortality. The treatment efficacy could be curtailed by drug resistance resulting from...
Colorectal cancer (CRC) is a disease with constantly increasing incidence and high mortality. The treatment efficacy could be curtailed by drug resistance resulting from poor drug penetration into tumor tissue and the tumor-specific microenvironment, such as hypoxia and acidosis. Furthermore, CRC tumors can be exposed to different pH depending on the position in the intestinal tract. CRC tumors often share upregulation of the Akt signaling pathway. In this study, we investigated the role of external pH in control of cytotoxicity of perifosine, the Akt signaling pathway inhibitor, to CRC cells using 2D and 3D tumor models. In 3D settings, we employed an innovative strategy for simultaneous detection of spatial drug distribution and biological markers of proliferation/apoptosis using a combination of mass spectrometry imaging and immunohistochemistry. In 3D conditions, low and heterogeneous penetration of perifosine into the inner parts of the spheroids was observed. The depth of penetration depended on the treatment duration but not on the external pH. However, pH alteration in the tumor microenvironment affected the distribution of proliferation- and apoptosis-specific markers in the perifosine-treated spheroid. Accurate co-registration of perifosine distribution and biological response in the same spheroid section revealed dynamic changes in apoptotic and proliferative markers occurring not only in the perifosine-exposed cells, but also in the perifosine-free regions. Cytotoxicity of perifosine to both 2D and 3D cultures decreased in an acidic environment below pH 6.7. External pH affects cytotoxicity of the other Akt inhibitor, MK-2206, in a similar way. Our innovative approach for accurate determination of drug efficiency in 3D tumor tissue revealed that cytotoxicity of Akt inhibitors to CRC cells is strongly dependent on pH of the tumor microenvironment. Therefore, the effect of pH should be considered during the design and pre-clinical/clinical testing of the Akt-targeted cancer therapy.
PubMed: 33344237
DOI: 10.3389/fonc.2020.581365 -
Annals of Clinical and Translational... Apr 2020Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic...
PURPOSE
Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well-tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti-tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose.
METHODS
Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg.
RESULTS
We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose-limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1).
CONCLUSION
Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.
Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Drug Therapy, Combination; Female; Glioblastoma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Phosphorylcholine; Prospective Studies; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases; Young Adult
PubMed: 32293798
DOI: 10.1002/acn3.51009 -
European Journal of Haematology Jan 2009Waldenström macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells (LPCs), along with... (Review)
Review
Waldenström macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells (LPCs), along with demonstration of an IgM monoclonal gammopathy in the blood. WM remains incurable, with 5-6 yr median overall survival for patients with symptomatic WM. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab, either in monotherapy or in combination. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. However, there are several limitations to these approaches. The complete response rate is low and the treatment free survival are short in many patients, no specific agent or regimen has been shown to be superior to another, and no treatment has been specifically approved for WM. As such, novel therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to develop new targeted therapeutics for this malignancy. These efforts have led to the development of proteasome inhibitors, of them bortezomib, several Akt/mTor inhibitors, such as perifosine and Rad001, and immunomodulatory agents such as thalidomide and lenalidomide. Many agents and monoclonal antibodies are currently being tested in clinical trials and seem promising. This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.
Topics: Antineoplastic Agents; Combined Modality Therapy; Diagnosis, Differential; Humans; Immunotherapy; Signal Transduction; Waldenstrom Macroglobulinemia
PubMed: 19087134
DOI: 10.1111/j.1600-0609.2008.01171.x -
Frontiers in Pharmacology 2020Autophagy is a highly conserved multistep process and functions as passage for degrading and recycling protein aggregates and defective organelles in eukaryotic cells.... (Review)
Review
Autophagy is a highly conserved multistep process and functions as passage for degrading and recycling protein aggregates and defective organelles in eukaryotic cells. Based on the nature of these materials, their size and degradation rate, four types of autophagy have been described, chaperone mediated autophagy, microautophagy, macroautophagy, and selective autophagy. One of the major regulators of this process is mTOR, which inhibits the downstream pathway of autophagy following the activation of its complex 1 (mTORC1). Alkylphosphocholine (APC) derivatives represent a novel class of antineoplastic agents that inhibit the serine-threonine kinase Akt ( protein kinase B), which mediates cell survival and cause cell cycle arrest. They induce autophagy through inhibition of the Akt/mTOR cascade. They interfere with phospholipid turnover and thus modify signaling chains, which start from the cell membrane and modulate PI3K/Akt/mTOR, Ras-Raf-MAPK/ERK and SAPK/JNK pathways. APCs include miltefosine, perifosine, and erufosine, which represent the first-, second- and third generation of this class, respectively. In a high fraction of human cancers, constitutively active oncoprotein Akt1 suppresses autophagy and . mTOR is a down-stream target for Akt, the activation of which suppresses autophagy. However, treatment with APC derivatives will lead to dephosphorylation (hence deactivation) of mTOR and thus induces autophagy. Autophagy is a double-edged sword and may result in chemotherapeutic resistance as well as cancer cell death when apoptotic pathways are inactive. APCs display differential autophagy induction capabilities in different cancer cell types. Therefore, autophagy-dependent cellular responses need to be well understood in order to improve the chemotherapeutic outcome.
PubMed: 32410999
DOI: 10.3389/fphar.2020.00547 -
Current Oncology Reports Mar 2009The PI3K/Akt/mTOR pathway is aberrantly active in most human cancers and contributes to cell growth, proliferation, and survival. Akt is a nodal regulator of cellular... (Review)
Review
The PI3K/Akt/mTOR pathway is aberrantly active in most human cancers and contributes to cell growth, proliferation, and survival. Akt is a nodal regulator of cellular survival pathways and an attractive target in cancer therapy. Many inhibitors of Akt are being developed. Perifosine is an oral Akt inhibitor currently being tested in phase 2 clinical trials. Unlike most kinase inhibitors, which target the adenosine triphosphate-binding region, perifosine targets the pleckstrin homology domain of Akt, thereby preventing its translocation to the plasma membrane. Single-agent activity with perifosine has been observed in sarcoma and Waldenström macroglobulinemia patients. However, the disappointing response rates of common solid tumors to perifosine as a single agent have diminished expectations and prompted further investigation into its mechanism of action. Perifosine exerts Akt-dependent and Akt-independent effects, and although many preclinical studies have documented Akt inhibition by perifosine, clinical validation of these findings is lacking. In this article, we review the clinical history of perifosine and discuss its many biologic activities.
Topics: Animals; Clinical Trials as Topic; Humans; Membrane Microdomains; Neoplasms; Phosphorylcholine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 19216841
DOI: 10.1007/s11912-009-0016-4 -
Expert Opinion on Drug Metabolism &... May 2012Perifosine is a novel targeted oral Akt inhibitor currently in Phase III clinical development for treatment of colorectal cancer (CRC, in combination with capecitabine)...
INTRODUCTION
Perifosine is a novel targeted oral Akt inhibitor currently in Phase III clinical development for treatment of colorectal cancer (CRC, in combination with capecitabine) and multiple myeloma (MM, in combination with bortezomib and dexamethasone).
AREAS COVERED
The mechanism, preclinical testing, and clinical activity of perifosine in CRC and MM are discussed, with supportive pharmacokinetic information presented. Appropriate literature searches were carried out for background and discussion purposes.
EXPERT OPINION
In preclinical models, perifosine has been shown to target phosphatidylinositol 3-kinase-Akt signaling. In CRC cell lines, preclinical studies indicate that perifosine may enhance the cytotoxic effects of fluorouracil, likely primarily through the nuclear transcription factor-kappa B pathway. A placebo-controlled Phase II randomized trial of capecitabine ± perifosine in previously treated patients with metastatic CRC showed the combination to be superior. In MM, Phase I/II clinical trials have established the optimal dosing schedule for perifosine and bortezomib in combination, and demonstrated that perifosine can sensitize to, or overcome resistance to, bortezomib, associated with prolonged responses and a favorable side effect profile. Ultimately, the favorable tolerability of perifosine will allow for its testing in combination with multiple targeted therapies to improve PFS and OS, which represent an important unmet need in these populations.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Capecitabine; Cell Line, Tumor; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Deoxycytidine; Dexamethasone; Drug Evaluation, Preclinical; Fluorouracil; Humans; Multiple Myeloma; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Pyrazines; Randomized Controlled Trials as Topic
PubMed: 22512706
DOI: 10.1517/17425255.2012.681376