3 Afuresertib (GSK2110183), an oral AKT kinase inhibitor, in combination with carboplatin and paclitaxel in recurrent ovarian cancer

Blagden, Sarah P.; Hamilton, Anne; Mileshkin, Linda R.; Hall, M.; Meniawy, Tarek; Wong, Shirley; Anandra, S.; Buck, Martin; McAleer, Damien; Reedy, Beth Ann; Noble, Robert; Smith, D.; Morris, Stefanie; Gabra, Hani

doi:10.1016/s0959-8049(14)70129-7

Cited by 6 publications

(5 citation statements)

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“…Even among the limited number of recurrent samples analysed so far, there is an apparent diversity of acquired resistance mechanisms, including the activation of AKT signalling 58 , the reversion of germline mutations in BRCA1 and BRCA2 through intragenic second-site mutations that restore the open reading frame of defective transcripts 17,59,60 , the loss of BRCA1 methylation 17 , a shift to a higher stromal content (known as a desmoplastic phenotype) and overexpression of the drug transporter ABCB1 through promoter hijacking 17 . Targeting of AKT has recently shown promising clinical activity in combination with carboplatin and paclitaxel in a Phase Ib/II study of platinum-resistant ovarian cancer 61 . Expression of markers of autophagy is increased in dormant, drug-resistant tumour nodules found on the peritoneal surface in recurrent disease compared with primary disease 62 , suggesting that targeting autophagic processes may be important in overcoming dormancy in HGSOC.…”

Section: Understand Determinants Of Drug Responsementioning

confidence: 99%

Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer

et al. 2015

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High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This ‘roadmap’ for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015.

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Section: Understand Determinants Of Drug Responsementioning

confidence: 99%

Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer

et al. 2015

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“…Another potential targeted therapy is the inhibition of AKT signaling. One recent phase Ib/II study reported promising clinical activity of an oral AKT inhibitor (afuresertib) in combination with carboplatin and paclitaxel in platinum-resistant ovarian cancer [ 15 , 150 ].…”

Section: Targeted Therapiesmentioning

confidence: 99%

High-Grade Serous Ovarian Cancer: Basic Sciences, Clinical and Therapeutic Standpoints

Lisio

Goyeneche

et al. 2019

IJMS

440

404

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Among a litany of malignancies affecting the female reproductive tract, that of the ovary is the most frequently fatal. Moreover, while the steady pace of scientific discovery has fuelled recent ameliorations in the outcomes of many other cancers, the rates of mortality for ovarian cancer have been stagnant since around 1980. Yet despite the grim outlook, progress is being made towards better understanding the fundamental biology of this disease and how its biology in turn influences clinical behaviour. It has long been evident that ovarian cancer is not a unitary disease but rather a multiplicity of distinct malignancies that share a common anatomical site upon presentation. Of these, the high-grade serous subtype predominates in the clinical setting and is responsible for a disproportionate share of the fatalities from all forms of ovarian cancer. This review aims to provide a detailed overview of the clinical-pathological features of ovarian cancer with a particular focus on the high-grade serous subtype. Along with a description of the relevant clinical aspects of this disease, including novel trends in treatment strategies, this text will inform the reader of recent updates to the scientific literature regarding the origin, aetiology and molecular-genetic basis of high-grade serous ovarian cancer (HGSOC).

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“…Two patients achieved PFS of >6 months, with radiological objective tumor regressions of 26% and 11%, respectively. Preliminary results from a phase I study (NCT01653912) evaluating the clinical efficacy of the Akt inhibitor GSK2110183 in combination with carboplatin and paclitaxel in patients with platinum-resistant OC showed an ORR of 50% among patients treated at the MTD identified during the dose escalation phase (125 mg daily) [39] . These are particularly encouraging results because the trial recruited mainly platinum-resistant or refractory patients, in whom a RR to chemotherapy of 15% would be expected [40] .…”

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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3 Afuresertib (GSK2110183), an oral AKT kinase inhibitor, in combination with carboplatin and paclitaxel in recurrent ovarian cancer

Cited by 6 publications

References 0 publications

Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer

Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer

High-Grade Serous Ovarian Cancer: Basic Sciences, Clinical and Therapeutic Standpoints

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

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