Perifosine Plus Bortezomib and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma Previously Treated With Bortezomib: Results of a Multicenter Phase I/II Trial

Richardson, Paul G.; Wolf, Jeffrey; Jakubowiak, Andrzej; Zonder, Jeff; Lonial, Sagar; Irwin, David; Densmore, John; Krishnan, Amrita; Raje, Noopur; Bär, Michael; Martin, Tom; Schlossman, Robert; Ghobrial, Irène M.; Munshi, Nikhil C.; Laubach, Jacob P.; Allerton, J. P.; Hideshima, Teru; Colson, Kathleen; Poradosu, Enrique; Gardner, L.; Sportelli, Peter; Anderson, Kenneth C.

doi:10.1200/jco.2010.33.9788

Cited by 118 publications

(77 citation statements)

References 34 publications

(1 reference statement)

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“…Although high plasma concentrations up to 16.2 mM have been reached, tumor response rates to perifosine as a single agent have been modest (Gills & Dennis 2009). In contrast, preliminary reports of combination therapy with perifosine plus capecitabine in colon cancer and perifosine plus bortezomib and dexamethasone in multiple myeloma seem to be promising (Bendell et al 2011, Richardson et al 2011. However, to our knowledge, no clinical data on the effects of perifosine in NETs are yet available.…”

Section: Discussionmentioning

confidence: 47%

Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

Zitzmann

Vlotides²,

Brand³

et al. 2012

Endocrine-Related Cancer

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The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system show aberrant Akt activity. Several inhibitors of the phosphoinositide 3-kinase (PI(3)K)-Akt-mTOR signaling pathway are currently being evaluated in clinical phase II and III studies for the treatment of NETs with promising results. However, the molecular mechanisms and particularly the role of different Akt isoforms in NET signaling are not fully understood. In this study, we examine the effect of Akt inhibition on NET cells of heterogeneous origin. We show that the Akt inhibitor perifosine effectively inhibits Akt phosphorylation and cell viability in human pancreatic (BON1), bronchus (NCI-H727), and midgut (GOT1) NET cells. Perifosine treatment suppressed the phosphorylation of Akt downstream targets such as GSK3a/b, MDM2, and p70S6K and induced apoptosis. To further investigate the role of individual Akt isoforms for NET cell function, we specifically blocked Akt1, Akt2, and Akt3 via siRNA transfection. In contrast to Akt2 knockdown, knockdown of Akt isoforms 1 and 3 decreased phosphorylation levels of GSK3a/b, MDM2, and p70S6K and suppressed NET cell viability and colony-forming capacity. The inhibitory effect of simultaneous downregulation of Akt1 and Akt3 on tumor cell viability was significantly stronger than that caused by downregulation of all Akt isoforms, suggesting a particular role for Akt1 and Akt3 in NET signaling. Akt3 siRNA-induced apoptosis while all three isoform-specific siRNAs impaired BON1 cell invasion. Together, our data demonstrate potent antitumor effects of the panAkt inhibitor perifosine on NET cells in vitro and suggest that selective targeting of Akt1 and/or Akt3 might improve the therapeutic potential of Akt inhibition in NET disease.

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Section: Discussionmentioning

confidence: 47%

Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

Zitzmann

Vlotides²,

Brand³

et al. 2012

Endocrine-Related Cancer

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show abstract

“…Despite its promising performance in the preclinical models, Perifosine monotherapy does not show efficacy in clinical trials. Disappointingly, it has been showing poor results in advanced or metastatic breast cancer, head and neck cancer, pancreatic adenocarcinoma, and metastatic mela- (Table 3), Perifosine has had clinical success when used in combination regimens in metastatic colorectal cancer, relapsed or refractory multiple myeloma and glioma [130][131][132] . Perifosine in combination with paclitaxel leads to Akt/mTORC1 inhibition, along with a marked increase in ceramide and ROS generation and an increase in AMPK and JNK that results in apoptosis [133] .…”

Section: Akt Inhibitorsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

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“…60 In a phase I/II Trial using perifosine with bortezomib in 84 refractory/relapsed MM pts, of whom 100% had prior bortezomib treatment and 75% of whom had prior lenalidomide treatment, the ORR (defined as ≥minor response) was 40% and OS was 16 months among bortezomib refractory, and ORR was 55% with TTP of 8.8 months and median OS of 25 months among bortezomib-relapsed patients. 61 These encouraging results led to the initiation of a phase III study using bortezomib and dexamethasone with or without perifosine in bortezomib exposed patients with relapsed/ refractory MM. the use of panobinostat (LBH5989), a pan-HDAC inhibitor, in combination with Bortezomib in patients with relapsed/refractory MM, showed ≥partial response rate of 50% including 15% IF negative CR.…”

Section: Targetmentioning

confidence: 99%

Multiple myeloma: Implementing signaling pathways and molecular biology in clinical trials

Bazzi

Badros²

2010

Cancer Biology & Therapy

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Perifosine Plus Bortezomib and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma Previously Treated With Bortezomib: Results of a Multicenter Phase I/II Trial

Cited by 118 publications

References 34 publications

Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

Multiple myeloma: Implementing signaling pathways and molecular biology in clinical trials

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