Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Campbell, Ian × Author: Sheppard, Karen ×

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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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    Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition
    Davis, SJ ; Sheppard, KE ; Anglesio, MS ; George, J ; Traficante, N ; Fereday, S ; Intermaggio, MP ; Menon, U ; Gentry-Maharaj, A ; Lubinski, J ; Gronwald, J ; Pearce, CL ; Pike, MC ; Wu, A ; Kommoss, S ; Pfisterer, J ; du Bois, A ; Hilpert, F ; Ramus, SJ ; Bowtell, DDL ; Huntsman, DG ; Pearson, RB ; Simpson, KJ ; Campbell, IG ; Gorringe, KL (AMER ASSOC CANCER RESEARCH, 2015-06)
    Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of amplified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number amplified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling.
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    Functional Analysis of Genes in Regions Commonly Amplified in High-Grade Serous and Endometrioid Ovarian Cancer
    Davis, SJ ; Sheppard, KE ; Pearson, RB ; Campbell, IG ; Gorringe, KL ; Simpson, KJ (AMER ASSOC CANCER RESEARCH, 2013-03-15)
    PURPOSE: Ovarian cancer has the highest mortality rate of all the gynecologic malignancies and is responsible for approximately 140,000 deaths annually worldwide. Copy number amplification is frequently associated with the activation of oncogenic drivers in this tumor type, but their cytogenetic complexity and heterogeneity has made it difficult to determine which gene(s) within an amplicon represent(s) the genuine oncogenic driver. We sought to identify amplicon targets by conducting a comprehensive functional analysis of genes located in the regions of amplification in high-grade serous and endometrioid ovarian tumors. EXPERIMENTAL DESIGN: High-throughput siRNA screening technology was used to systematically assess all genes within regions commonly amplified in high-grade serous and endometrioid cancer. We describe the results from a boutique siRNA screen of 272 genes in a panel of 18 ovarian cell lines. Hits identified by the functional viability screen were further interrogated in primary tumor cohorts to determine the clinical outcomes associated with amplification and gene overexpression. RESULTS: We identified a number of genes as critical for cellular viability when amplified, including URI1, PAK4, GAB2, and DYRK1B. Integration of primary tumor gene expression and outcome data provided further evidence for the therapeutic use of such genes, particularly URI1 and GAB2, which were significantly associated with survival in 2 independent tumor cohorts. CONCLUSION: By taking this integrative approach to target discovery, we have streamlined the translation of high-resolution genomic data into preclinical in vitro studies, resulting in the identification of a number of genes that may be specifically targeted for the treatment of advanced ovarian tumors.