Sir Peter MacCallum Department of Oncology - Research Publications

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    Targeting homologous recombination deficiency in uterine leiomyosarcoma
    Dall, G ; Vandenberg, CJJ ; Nesic, K ; Ratnayake, G ; Zhu, W ; Vissers, JHA ; Bedo, J ; Penington, J ; Wakefield, MJJ ; Kee, D ; Carmagnac, A ; Lim, R ; Shield-Artin, K ; Milesi, B ; Lobley, A ; Kyran, ELL ; O'Grady, E ; Tram, J ; Zhou, W ; Nugawela, D ; Stewart, KP ; Caldwell, R ; Papadopoulos, L ; Ng, APP ; Dobrovic, A ; Fox, SBB ; McNally, O ; Power, JDD ; Meniawy, T ; Tan, TH ; Collins, IMM ; Klein, O ; Barnett, S ; Olesen, I ; Hamilton, A ; Hofmann, O ; Grimmond, S ; Papenfuss, ATT ; Scott, CLL ; Barker, HEE (BMC, 2023-05-04)
    BACKGROUND: Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals with advanced uLMS having a five-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some individuals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened individuals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting. METHODS: A cohort of 58 individuals with uLMS were screened for HR Deficiency (HRD) using whole genome sequencing (WGS), whole exome sequencing (WES) or NGS panel testing. Individuals identified to have HRD uLMS were offered PARPi therapy and clinical outcome details collected. Patient-derived xenografts (PDX) were generated for therapeutic targeting. RESULTS: All 13 uLMS samples analysed by WGS had a dominant COSMIC mutational signature 3; 11 of these had high genome-wide loss of heterozygosity (LOH) (> 0.2) but only two samples had a CHORD score > 50%, one of which had a homozygous pathogenic alteration in an HR gene (deletion in BRCA2). A further three samples harboured homozygous HRD alterations (all deletions in BRCA2), detected by WES or panel sequencing, with 5/58 (9%) individuals having HRD uLMS. All five individuals gained access to PARPi therapy. Two of three individuals with mature clinical follow up achieved a complete response or durable partial response (PR) with the subsequent addition of platinum to PARPi upon minor progression during initial PR on PARPi. Corresponding PDX responses were most rapid, complete and sustained with the PARP1-specific PARPi, AZD5305, compared with either olaparib alone or olaparib plus cisplatin, even in a paired sample of a BRCA2-deleted PDX, derived following PARPi therapy in the patient, which had developed PARPi-resistance mutations in PRKDC, encoding DNA-PKcs. CONCLUSIONS: Our work demonstrates the value of identifying HRD for therapeutic targeting by PARPi and platinum in individuals with the aggressive rare malignancy, uLMS and suggests that individuals with HRD uLMS should be included in trials of PARP1-specific PARPi.
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    Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin
    Ho, GY ; Kyran, EL ; Bedo, J ; Wakefield, MJ ; Ennis, DP ; Mirza, HB ; Vandenberg, CJ ; Lieschke, E ; Farrell, A ; Hadla, A ; Lim, R ; Dall, G ; Vince, JE ; Chua, NK ; Kondrashova, O ; Upstill-Goddard, R ; Bailey, U-M ; Dowson, S ; Roxburgh, P ; Glasspool, RM ; Bryson, G ; Biankin, AV ; Cooke, SL ; Ratnayake, G ; McNally, O ; Traficante, N ; DeFazio, A ; Weroha, SJ ; Bowtell, DD ; McNeish, IA ; Papenfuss, AT ; Scott, CL ; Barker, HE (AMER ASSOC CANCER RESEARCH, 2022-12-01)
    UNLABELLED: Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. SIGNIFICANCE: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indicate that microtubule inhibitors could be used to suppress EMT and stimulate antitumor immunity.
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    Therapeutic options for mucinous ovarian carcinoma
    Gorringe, KL ; Cheasley, D ; Wakefield, MJ ; Ryland, GL ; Allan, PE ; Alsop, K ; Amarasinghe, KC ; Ananda, S ; Bowtell, DDL ; Christie, M ; Chiew, Y-E ; Churchman, M ; DeFazio, A ; Fereday, S ; Gilks, CB ; Gourley, C ; Hadley, AM ; Hendley, J ; Hunter, SM ; Kaufmann, SH ; Kennedy, CJ ; Kobel, M ; Le Page, C ; Li, J ; Lupat, R ; McNally, OM ; McAlpine, JN ; Pyman, J ; Rowley, SM ; Salazar, C ; Saunders, H ; Semple, T ; Stephens, AN ; Thio, N ; Torres, MC ; Traficante, N ; Zethoven, M ; Antill, YC ; Campbell, IG ; Scott, CL (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2020-03)
    OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.
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    Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
    Kondrashova, O ; Topp, M ; Nesic, K ; Lieschke, E ; Ho, G-Y ; Harrell, M ; Zapparoli, G ; Hadley, A ; Holian, R ; Boehm, E ; Heong, V ; Sanij, E ; Pearson, RB ; Krais, JJ ; Johnson, N ; McNally, O ; Ananda, S ; Alsop, K ; Hutt, KJ ; Kaufmann, SH ; Lin, KK ; Harding, TC ; Traficante, N ; deFazio, A ; McNeish, LA ; Bowtell, DD ; Swisher, EM ; Dobrovic, A ; Wakefield, MJ ; Scott, CL ; Chenevix-Trench, G ; Green, A ; Webb, P ; Gertig, D ; Fereday, S ; Moore, S ; Hung, J ; Harrap, K ; Sadkowsky, T ; Pandeya, N ; Malt, M ; Mellon, A ; Robertson, R ; Vanden Bergh, T ; Jones, M ; Mackenzie, P ; Maidens, J ; Nattress, K ; Chiew, YE ; Stenlake, A ; Sullivan, H ; Alexander, B ; Ashover, P ; Brown, S ; Corrish, T ; Green, L ; Jackman, L ; Ferguson, K ; Martin, K ; Martyn, A ; Ranieri, B ; White, J ; Jayde, V ; Mamers, P ; Bowes, L ; Galletta, L ; Giles, D ; Hendley, J ; Schmidt, T ; Shirley, H ; Ball, C ; Young, C ; Viduka, S ; Tran, H ; Bilic, S ; Glavinas, L ; Brooks, J ; Stuart-Harris, R ; Kirsten, F ; Rutovitz, J ; Clingan, P ; Glasgow, A ; Proietto, A ; Braye, S ; Otton, G ; Shannon, J ; Bonaventura, T ; Stewart, J ; Begbie, S ; Friedlander, M ; Bell, D ; Baron-Hay, S ; Ferrier, A ; Gard, G ; Nevell, D ; Pavlakis, N ; Valmadre, S ; Young, B ; Camaris, C ; Crouch, R ; Edwards, L ; Hacker, N ; Marsden, D ; Robertson, G ; Beale, P ; Beith, J ; Carter, J ; Dalrymple, C ; Houghton, R ; Russell, P ; Links, M ; Grygiel, J ; Hill, J ; Brand, A ; Byth, K ; Jaworski, R ; Harnett, P ; Sharma, R ; Wain, G ; Ward, B ; Papadimos, D ; Crandon, A ; Cummings, M ; Horwood, K ; Obermair, A ; Perrin, L ; Wyld, D ; Nicklin, J ; Davy, M ; Oehler, MK ; Hall, C ; Dodd, T ; Healy, T ; Pittman, K ; Henderson, D ; Miller, J ; Pierdes, J ; Blomfield, P ; Challis, D ; Mclntosh, R ; Parker, A ; Brown, B ; Rome, R ; Allen, D ; Grant, P ; Hyde, S ; Laurie, R ; Robbie, M ; Healy, D ; Jobling, T ; Manolitsas, T ; McNealage, J ; Rogers, P ; Susil, B ; Sumithran, E ; Simpson, I ; Phillips, K ; Rischin, D ; Fox, S ; Johnson, D ; Lade, S ; Loughrey, M ; O'Callaghan, N ; Murray, W ; Waring, P ; Billson, V ; Pyman, J ; Neesham, D ; Quinn, M ; Underhill, C ; Bell, R ; Ng, LF ; Blum, R ; Ganju, V ; Hammond, I ; Leung, Y ; McCartney, A ; Buck, M ; Haviv, I ; Purdie, D ; Whiteman, D ; Zeps, N (NATURE PUBLISHING GROUP, 2018-09-28)
    Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.