Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Hicks, Rodney × End date: 2012 × Start date: 2012 ×

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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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    Should positron emission tomography/computed tomography be the first rather than the last test performed in the assessment of cancer?
    Hicks, RJ (BMC, 2012-09-28)
    Cancer is a major cause of illness and death in Western society and is associated with a heavy concomitant economic burden. Although use of imaging comprises only a small proportion of the fiscal impact of cancer, its use has been increasing over recent decades, causing concern amongst funders of health care and efforts to constrain the use of new imaging tests with a relatively high unit cost. In clinical practice, positron emission tomography/computed tomography (PET/CT) is generally performed when less expensive tests have left some uncertainty regarding appropriate management. In this setting, its utility relates to provision of incremental diagnostic information. However, given that superior diagnostic information can positively affect patient management, wherein the majority of costs reside, it may be both more efficient and cost effective to go directly to the most accurate investigation in certain situations. For PET/CT, the ability to provide more accurate assessment of metastatic status than is available from conventional diagnostic paradigms provides a rationale for its independent rather than incremental use in patients presenting with either a high likelihood of malignancy or proven malignancy of a locally advanced nature and an accordingly high risk of metastatic disease. A randomized trial design is described that could be used to test this hypothesis.
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