Pharmacokinetic (PK)/pharmacodynamic (PD) analysis of escalating repeat doses of the AKT inhibitor GSK2141795 (GSK795) in patients (pts) with ovarian cancer.

Gungor, Hatice; Saleem, Azeem; Agarwal, Roshan; Blagden, Sarah P.; Michael, A.; Stronach, Euan A.; Chen, M.; Pickford, Emily; Rama, Nona; Lewis, Yuet; Carme, S. C.; Salinas, Cristian; Smith, Deborah A.; Krachey, Elizabeth C.; Santiago-Walker, Ademi; Gunn, RN; El‐Bahrawy, Mona; Babar, Syed; Morris, Shannon R.; Gabra, Hani

doi:10.1200/jco.2011.29.15_suppl.5064

Cited by 13 publications

(13 citation statements)

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“…GSK795 is an oral ATP-competitive pan-Akt inhibitor, and a small phase I pharmacodynamic and pharmacokinetic study in advanced platinum-resistant OC showed reduced fluorodeoxyglucose (FDG) metabolism in the majority of tumors [38] . Among 5 patients treated at high dose levels, paired pre- and post-treatment tumor biopsies demonstrated down-regulation of pAkt and the tumor proliferative marker Ki67.…”

Section: Other Inhibitors Of the Pi3k Pathwaymentioning

confidence: 99%

The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges

2015

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The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer, including ovarian cancer (OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin (mTOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective mTOR complex-1 (mTORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual mTORC1/mTORC2, Akt, and PI3K inhibitors. Although it is likely that inhibition of the PI3K/Akt/mTOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and/or phosphatase and tensin homolog (PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3K signaling network, PI3K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3K pathway in OC and provide an up-to-date review of clinical trials of novel PI3K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.

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Section: Other Inhibitors Of the Pi3k Pathwaymentioning

confidence: 99%

The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges

2015

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“…GSK795 is an oral ATP-competitive pan-Akt inhibitor in early stages of development and a small phase I pharmacodynamic and pharmacokinetic study was conducted in order to characterize the relationship between AKT inhibition by GSK795 and downstream effects in patients with advanced platinum resistant ovarian cancer [44]. Twelve patients were enrolled.…”

Section: Akt Inhibitorsmentioning

confidence: 99%

The PI3K/Akt/mTOR Pathway in Ovarian Cancer: Biological Rationale and Therapeutic Opportunities

Leary¹,

Auclin²,

Pautier³

et al. 2013

Ovarian Cancer - A Clinical and Translational Update

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“…At present, there are several clinical trials focused on the examination of new agents, such as AZD-8055 (NCT00731263), OSI-027 (NCT00698243), and INK128 (NCT02142803), in a variety of human hematological malignancies and solid tumors, including breast cancer. Also some studies were conducted using GSK795 in patients with advanced platinum-resistant ovarian and showed interesting results as tumor regressions and CA125 decreases [161]. Phase I study are ongoing to evaluate the safety and toxicity profile of AZD2014 in combination with paclitaxel in patients with ovarian cancer (NCT02193633).…”

Section: Atp-competitive Inhibitorsmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Pathway in Cancer Cells

Guimarães¹,

Tessarollo²,

Lyra-Júnior³

et al. 2015

Updates on Cancer Treatment

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Pharmacokinetic (PK)/pharmacodynamic (PD) analysis of escalating repeat doses of the AKT inhibitor GSK2141795 (GSK795) in patients (pts) with ovarian cancer.

Cited by 13 publications

References 0 publications

The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges

The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges

The PI3K/Akt/mTOR Pathway in Ovarian Cancer: Biological Rationale and Therapeutic Opportunities

Targeting the PI3K/AKT/mTOR Pathway in Cancer Cells

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