Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Cullinane, Carleen × Author: Hicks, Rodney × Author: Johnstone, Ricky × Author: Pearson, Richard × End date: 2019 × Start date: 2010 ×

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    An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice
    Kinross, KM ; Montgomery, KG ; Kleinschmidt, M ; Waring, P ; Ivetac, I ; Tikoo, A ; Saad, M ; Hare, L ; Roh, V ; Mantamadiotis, T ; Sheppard, KE ; Ryland, GL ; Campbell, IG ; Gorringe, KL ; Christensen, JG ; Cullinane, C ; Hicks, RJ ; Pearson, RB ; Johnstone, RW ; McArthur, GA ; Phillips, WA (AMER SOC CLINICAL INVESTIGATION INC, 2012-02)
    Mutations in the gene encoding the p110α subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3caH1047R mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous adenocarcinomas and granulosa cell tumors. Both mutational events were required for early, robust Akt activation. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. These results demonstrate that the Pik3caH1047R mutation with loss of Pten is enough to promote ovarian cell transformation and that we have developed a model system for studying possible therapies.
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    Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors
    Sheppard, KE ; Cullinane, C ; Hannan, KM ; Wall, M ; Chan, J ; Barber, F ; Foo, J ; Cameron, D ; Neilsen, A ; Ng, P ; Ellul, J ; Kleinschmidt, M ; Kinross, KM ; Bowtell, DD ; Christensen, JG ; Hicks, RJ ; Johnstone, RW ; McArthur, GA ; Hannan, RD ; Phillips, WA ; Pearson, RB (ELSEVIER SCI LTD, 2013-12)
    BACKGROUND: Ovarian cancer is the major cause of death from gynaecological malignancy with a 5year survival of only ∼30% due to resistance to platinum and paclitaxel-based first line therapy. Dysregulation of the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) and RAS/extracellular signal-regulated kinase (ERK) pathways is common in ovarian cancer, providing potential new targets for 2nd line therapy. METHODS: We determined the inhibition of proliferation of an extensive panel of ovarian cancer cell lines, encompassing all the major histotypes, by the dual PI3K/mTOR inhibitor PF-04691502 and a MEK inhibitor, PD-0325901. In addition, we analysed global gene expression, mutation status of key PI3K/mTOR and RAS/ERK pathway members and pathway activation to identify predictors of drug response. RESULTS: PF-04691502 inhibits proliferation of the majority of cell lines with potencies that correlate with the extent of pathway inhibition. Resistant cell lines were characterised by activation of the RAS/ERK pathway as indicated by differential gene expression profiles and pathway activity analysis. PD-0325901 suppressed growth of a subset of cell lines that were characterised by high basal RAS/ERK signalling. Strikingly, using PF-04691502 and PD-0325901 in combination resulted in synergistic growth inhibition in 5/6 of PF-04691502 resistant cell lines and two cell lines resistant to both single agents showed robust synergistic growth arrest. Xenograft studies confirm the utility of combination therapy to synergistically inhibit tumour growth of PF-04691502-resistant tumours in vivo. CONCLUSIONS: These studies identify dual targeted inhibitors of PI3K/mTOR in combination with inhibitors of RAS/ERK signalling as a potentially effective new approach to treating ovarian cancer.