Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor‐targeted therapy

Cho, Daniel C.; Hutson, Thomas E.; Samlowski, Wolfram E.; Sportelli, Peter; Somer, Brad; Richards, Paul; Sosman, Jeffrey A.; Puzanov, Igor; Michaelson, M. Dror; Flaherty, Keith T.; Figlin, Robert A.; Vogelzang, Nicholas J.

doi:10.1002/cncr.27668

Cited by 42 publications

(21 citation statements)

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“…Limited potentially beneficial effects of perifosine treatment for colorectal cancer and multiple myeloma were reported (21). Nevertheless, grades 3-4 adverse effects (e.g., anemia, hand-foot syndrome, or pulmonary embolism) (21,22) limit the clinical applicability of perifosine.…”

Section: Schmid Et Almentioning

confidence: 99%

Sirolimus treatment of severe PTEN hamartoma tumor syndrome: case report and in vitro studies

et al. 2013

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Section: Schmid Et Almentioning

confidence: 99%

Sirolimus treatment of severe PTEN hamartoma tumor syndrome: case report and in vitro studies

et al. 2013

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“…Several anticancer protein inhibitors, such as perifosine (an AKT inhibitor) and tipifarnib (an RAS and Wnt inhibitor), are currently undergoing clinical trials to investigate their potential as antineoplastic drugs 10,11. Typically, it takes an average of 7 years for these drugs to be approved after they undergo evaluation in clinical trials 12.…”

Section: Introductionmentioning

confidence: 99%

Candidate cancer-targeting agents identified by expression-profiling arrays

Termglinchan¹,

Wanichnopparat²,

Teeyapant³

et al. 2013

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BackgroundOne particularly promising component of personalized medicine in cancer treatment is targeted therapy, which aims to maximize therapeutic efficacy while minimizing toxicity. However, the number of approved targeted agents remains limited. Expression microarray data for different types of cancer are resources to identify genes that were upregulated. The genes are candidate targets for cancer-targeting agents for future anticancer research and targeted treatments.Methods and findingsThe gene expression profiles of 48 types of cancer from 2,141 microarrays reported in the Gene Expression Omnibus were analyzed. These data were organized into 78 experimental groups, on which we performed comprehensive analyses using two-tailed Student’s t-tests with significance set at P < 0.01 to identify genes that were upregulated compared with normal cells in each cancer type. The resulting list of significantly upregulated genes was cross-referenced with three categories of protein inhibitor targets, categorized by inhibitor type (‘Targets of US Food and Drug Administration (FDA)-approved anticancer drugs’, ‘Targets of FDA-approved nonantineoplastic drugs’, or ‘Targets of non-FDA-approved chemical agents’). Of the 78 experimental groups studied, 57 (73%) represent cancers that are currently treated with FDA-approved targeted treatment agents. However, the target genes for the indicated therapies are upregulated in only 33 of these groups (57%). Nevertheless, the mRNA expression of the genes targeted by FDA-approved treatment agents is increased in every experimental group, including all of the cancers without FDA-approved targeted treatments. Moreover, many targets of protein inhibitors that have been approved by the FDA as therapies for nonneoplastic diseases, such as 3-hydroxy-3-methylglutaryl-CoA reductase and cyclooxygenase-2 and the targets of many non-FDA-approved chemical agents, such as cyclin-dependent kinase 1 and DNA-dependent protein kinase, are also overexpressed in many types of cancer.ConclusionThis research demonstrates a clinical correlation between bioinformatics data and currently approved treatments and suggests novel uses for known protein inhibitors in future antineoplastic research and targeted therapies.

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“…Examples of the former include the p110 inhibitor acetic acid (1S,4E,10R,11R,13S,14R)- [4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10,13-dimethyl-3,7,17-trioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxacyclopenta[a]phenanthren-11-yl ester (PX-866) and of the latter, perifosine or 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo [3,4-f] [1,6]naphthyridin-3(2H)-one hydrochloride (MK2206) (Ihle et al, 2009;Locatelli et al, 2013). These agents are undergoing clinical evaluation in a variety of tumor types (Cho et al, 2012;Hong et al, 2012). PX-866 is a derivative of wortmannin, and acts as a suicide inhibitor of p110a/b/d/g.…”

Section: Introductionmentioning

confidence: 99%

Sorafenib/Regorafenib and Phosphatidyl Inositol 3 Kinase/Thymoma Viral Proto-Oncogene Inhibition Interact to Kill Tumor Cells

et al. 2013

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The present studies were undertaken to determine whether the multikinase inhibitors sorafenib/regorafenib cooperated with clinically relevant , phosphatidyl inositol 3 kinase (PI3K)-thymoma viral proto-oncogene (AKT) inhibitors to kill tumor cells. In liver, colorectal, lung, breast, kidney, and brain cancer cells, at clinically achievable doses, sorafenib/regorafenib and the PI3K inhibitor acetic acid (1S,4E,10R,11R,13S,14R)-[4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10, 13-dimethyl-3,7,17-trioxo-1,3,4, 7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester (PX-866) cooperated in a greater than additive fashion to kill tumor cells. Cells lacking phosphatase and tensin homolog were as sensitive to the drug combination as cells expressing the protein. Similar data were obtained using the AKT inhibitors perifosine and 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4-f] [1,6]naphthyridin-3(2H)-one hydrochloride (MK2206). PX-866 treatment abolished AKT/glycogen synthase kinase 3 (GSK3) phosphorylation, and cell killing correlated with reduced activity of AKT and mammalian target of rapamycin (mTOR). Expression of activated AKT and to a lesser extent activated mTOR reduced drug combination lethality. Expression of B-cell lymphoma-extra large or dominant negative caspase 9, but not cellular FLICE (FADD-like IL-1b-converting enzyme)-inhibitory protein short, protected cells from the drug combination. Treatment of cells with PX-866 increased protein levels of p62, lysosome-associated membrane protein 2 (LAMP2), and microtubule-associated protein light chain (LC) 3 and LC3II that correlated with a large increase in LC3-green fluorescent protein (GFP) vesicle numbers. Exposure of PX-866 treated cells to sorafenib reduced p62 and LAMP2 levels, decreased the ratio of LC3 to LC3II, and reduced LC3-GFP vesicle levels. Knockdown of Beclin1 or autophagy-related 5 suppressed drug toxicity by ∼40%. In vivo, sorafenib and PX-866 or regorafenib and MK2206 cooperated to suppress the growth of established HuH7 and HCT116 tumors, respectively. Collectively our data demonstrate that the combination of sorafenib family kinase inhibitors with inhibitors of the PI3K/AKT pathway kills tumor cells in vitro and in vivo.

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Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor‐targeted therapy

Cited by 42 publications

References 20 publications

Sirolimus treatment of severe PTEN hamartoma tumor syndrome: case report and in vitro studies

Sirolimus treatment of severe PTEN hamartoma tumor syndrome: case report and in vitro studies

Candidate cancer-targeting agents identified by expression-profiling arrays

Sorafenib/Regorafenib and Phosphatidyl Inositol 3 Kinase/Thymoma Viral Proto-Oncogene Inhibition Interact to Kill Tumor Cells

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