Mutation and Protein Expression Biomarkers Correlate with Response to AKT Inhibition in a Phase I Trial of the Oral Pan AKT Inhibitor GSK2141795 (GSK795) in Patients (pts) with Platinum Resistant Ovarian Cancer

Gunqor, H.; Stronach, Euan A.; Curry, Ed; Saleem, Afnan; Agarwal, Roshan; Blagden, Sarah P.; Babar, Syed; Mills, GB; Morris, Shannon R.; Gabra, Hani

doi:10.1016/s0959-8049(11)70123-x

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“…In a recently completed Phase II study evaluating the efficacy of the pan-Akt inhibitor MK2206 in recurrent platinum resistant ovarian cancer (NCT01283035), 4/5 patients reported stable disease, while 1/5 had progressive disease. A Phase I trial with another pan-Akt inhibitor GSK795, also demonstrated moderate results, with stable disease in 16% of patients and some evidence of tumor shrinkage [ 46 ]. The results from the current study suggest that a contributor to the modest efficacy of the pan-Akt inhibitors in ovarian cancer is the incongruous effects of the individual Akt isoforms.…”

Section: Discussionmentioning

confidence: 99%

Akt isoform specific effects in ovarian cancer progression

et al. 2016

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Ovarian cancer remains a significant therapeutic problem and novel, effective therapies are needed. Akt is a serine-threonine kinase that is overexpressed in numerous cancers, including ovarian. Mammalian cells express three Akt isoforms which are encoded by distinct genes. Although there are several Akt inhibitors in clinical trials, most indiscriminately target all isoforms. Current in vitro data and animal knockout experiments suggest that the Akt isoforms may have divergent roles. In this paper, we determined the isoform-specific functions of Akt in ovarian cancer cell proliferation in vitro and in ovarian cancer progression in vivo. For in vitro experiments, murine and human ovarian cancer cells were treated with Akt inhibitors and cell viability was assessed. We used two different in vivo approaches to identify the roles of Akt isoforms in ovarian cancer progression and their influence on the primary tumor and tumor microenvironment. In one experiment, wild-type C57Bl6 mice were orthotopically injected with ID8 cells with stable knockdown of Akt isoforms. In a separate experiment, mice null for Akt 1-3 were orthotopically injected with WT ID8 cells (Figure 1). Our data show that inhibition of Akt1 significantly reduced ovarian cancer cell proliferation and inhibited tumor progression in vivo. Conversely, disruption of Akt2 increased tumor growth. Inhibition of Akt3 had an intermediate phenotype, but also increased growth of ovarian cancer cells. These data suggest that there is minimal redundancy between the Akt isoforms in ovarian cancer progression. These findings have important implications in the design of Akt inhibitors for the effective treatment of ovarian cancer.

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Section: Discussionmentioning

confidence: 99%