A phase I safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor XL765 (SAR245409) in combination with erlotinib (E) in patients (pts) with advanced solid tumors.

Cohen, Richard B.; Engelman, J. A.; Martı́nez, Pablo; Nishida, Yukihiro; Gendreau, Steve; Wu, Bor-Wen; Felip, Enriqueta

doi:10.1200/jco.2010.28.15_suppl.3015

Cited by 16 publications

(12 citation statements)

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“…Target pathway inhibition was clearly demonstrated. In combination with erlotinib, XL765-related adverse events remained unchanged but 4 of 21 patients had a partial response, 3 of whom had previously progressed on erlotinib [104]. When XL765 was combined with temozolamide in a Phase I study for patients with glioblastoma, response rates were generally low but one patient with a PTEN mutation remained on drug in excess of 1 year.…”

Section: Cal-101mentioning

confidence: 90%

New phosphatidylinositol 3-kinase inhibitors for cancer

Bowles

Jimeno

2011

Expert Opinion on Investigational Drugs

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Section: Cal-101mentioning

confidence: 90%

New phosphatidylinositol 3-kinase inhibitors for cancer

Bowles

Jimeno

2011

Expert Opinion on Investigational Drugs

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“…Numerous PI3K-targeted compounds, many of which are dual PI3K and mTOR inhibitors, are being introduced into clinical trials. Dual inhibitors like NVP-BEZ235 (39) and XL765 (40) are currently undergoing phase I clinical investigation for treatment of solid tumors. Preclinical data show that NVP-BEZ235 has strong anti-proliferative activity against tumor xenografts that have abnormal PI3K signaling, including loss of PTEN function or gain-of-function PI3K mutations (41).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of NVP-BKM120—A Selective Pan Class I PI3 Kinase Inhibitor Showed Differential Forms of Cell Death Based on p53 Status of Glioma Cells

Koul

Shen

et al. 2012

Clinical Cancer Research

148

124

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Purpose The aim of this study was to show preclinical efficacy and clinical development potential of NVP-BKM120, a selective pan class I phosphatidylinositol-3 kinase (PI3K) inhibitor in human glioblastoma (GBM) cells in vitro and in vivo. Experimental Design The effect of NVP-BKM120 on cellular growth was assessed by CellTiter-Blue assay. Flow cytometric analyses were carried out to measure the cell-cycle, apoptosis, and mitotic index. Mitotic catastrophe was detected by immunofluorescence. The efficacy of NVP-BKM120 was tested using intracranial U87 glioma model. Results We tested the biologic effects of a selective PI3K inhibitor NVP-BKM120 in a set of glioma cell lines. NVP-BKM120 treatment for 72 hours resulted in a dose-dependent growth inhibition and effectively blocked the PI3K/Akt signaling cascade. Although we found no obvious relationship between the cell line's sensitivity to NVP-BKM120 and the phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) statuses, we did observe a differential sensitivity pattern with respect to p53 status, with glioma cells containing wild-type p53 more sensitive than cells with mutated or deleted p53. NVP-BKM120 showed differential forms of cell death on the basis of p53 status of the cells with p53 wild-type cells undergoing apoptotic cell death and p53 mutant/deleted cells having a mitotic catastrophe cell death. NVP-BKM120 mediates mitotic catastrophe mainly through Aurora B kinase. Knockdown of p53 in p53 wild-type U87 glioma cells displayed microtubule misalignment, multiple centrosomes, and mitotic catastrophe cell death. Parallel to the assessment of the compound in in vitro settings, in vivo efficacy studies using an intracranial U87 tumor model showed an increased median survival from 26 days (control cohort) to 38 and 48 days (treated cohorts). Conclusion Our present findings establish that NVP-BKM120 inhibits the PI3K signaling pathways, leading to different forms of cell death on the basis of p53 statuses. Further studies are warranted to determine if NVP-BKM120 has potential as a glioma treatment.

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“…Eleven patients have been reported to be on study for ≥ 16 weeks and seven patients on treatment for ≥ 24 weeks.The maximum tolerated dose for single-agent XL765 is reported as 50 mg BID. XL765 exhibited potent pharmacodynamic activity in solid tumours and surrogate tissues at generally well tolerated doses [126]. XL765 in combination with the DNA methylating agent temozolomide is well tolerated at doses up to 40 mg QD.…”

Section: Clinical Trials In Cancermentioning

confidence: 99%

Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors

Shuttleworth

Silva²,

Cecil³

et al. 2011

CMC

100

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The phosphoinositide 3-kinases (PI3Ks) constitute an important family of lipid kinase enzymes that control a range of cellular processes through their regulation of a network of signal transduction pathways, and have emerged as important therapeutic targets in the context of cancer, inflammation and cardiovascular diseases. Since the mid-late 1990s, considerable progress has been made in the discovery and development of small molecule ATP-competitive PI3K inhibitors, a number of which have entered early phase human trials over recent years from which key clinical results are now being disclosed. This review summarizes progress made to date, primarily on the discovery and characterization of class I and dual class I/IV subtype inhibitors, together with advances that have been made in translational and clinical research, notably in cancer.

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A phase I safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor XL765 (SAR245409) in combination with erlotinib (E) in patients (pts) with advanced solid tumors.

Cited by 16 publications

References 0 publications

New phosphatidylinositol 3-kinase inhibitors for cancer

New phosphatidylinositol 3-kinase inhibitors for cancer

Antitumor Activity of NVP-BKM120—A Selective Pan Class I PI3 Kinase Inhibitor Showed Differential Forms of Cell Death Based on p53 Status of Glioma Cells

Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors

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