المؤلفون: Abdelmogod, A, Papadopoulos, L, Riordan, S, Wong, M, Weltman, M, Lim, R, Mcevoy, C, Fellowes, A, Fox, S, Bedo, J, Penington, J, Pham, K, Hofmann, O, Vissers, JHA, Grimmond, S, Ratnayake, G, Christie, M, Mitchell, C, Murray, WK, Mcclymont, K, Luk, P, Papenfuss, AT, Kee, D, Scott, CL, Goldstein, D, Barker, HE

الوصف: BACKGROUND: Epithelioid haemangioendothelioma (EHE) is an ultra-rare malignant vascular tumour with a prevalence of 1 per 1,000,000. It is typically molecularly characterised by a WWTR1::CAMTA1 gene fusion in approximately 90% of cases, or a YAP1::TFE3 gene fusion in approximately 10% of cases. EHE cases are typically refractory to therapies, and no anticancer agents are reimbursed for EHE in Australia. METHODS: We report a cohort of nine EHE cases with comprehensive histologic and molecular profiling from the Walter and Eliza Hall Institute of Medical Research Stafford Fox Rare Cancer Program (WEHI-SFRCP) collated via nation-wide referral to the Australian Rare Cancer (ARC) Portal. The diagnoses of EHE were confirmed by histopathological and immunohistochemical (IHC) examination. Molecular profiling was performed using the TruSight Oncology 500 assay, the TruSight RNA fusion panel, whole genome sequencing (WGS), or whole exome sequencing (WES). RESULTS: Molecular analysis of RNA, DNA or both was possible in seven of nine cases. The WWTR1::CAMTA1 fusion was identified in five cases. The YAP1::TFE3 fusion was identified in one case, demonstrating unique morphology compared to cases with the more common WWTR1::CAMTA1 fusion. All tumours expressed typical endothelial markers CD31, ERG, and CD34 and were negative for pan-cytokeratin. Cases with a WWTR1::CAMTA1 fusion displayed high expression of CAMTA1 and the single case with a YAP1::TFE3 fusion displayed high expression of TFE3. Survival was highly variable and unrelated to molecular profile. CONCLUSIONS: This cohort of EHE cases provides molecular and histopathological characterisation and matching clinical information that emphasises the molecular patterns and variable clinical outcomes and adds to our knowledge of this ultra-rare cancer. Such information from multiple studies will advance our understanding, potentially improving treatment options.

العلاقة: NHMRC/1081178; NHMRC/1062702; pii: cancers15174378; Abdelmogod, A., Papadopoulos, L., Riordan, S., Wong, M., Weltman, M., Lim, R., Mcevoy, C., Fellowes, A., Fox, S., Bedo, J., Penington, J., Pham, K., Hofmann, O., Vissers, J. H. A., Grimmond, S., Ratnayake, G., Christie, M., Mitchell, C., Murray, W. K. ,. Barker, H. E. (2023). A Matched Molecular and Clinical Analysis of the Epithelioid Haemangioendothelioma Cohort in the Stafford Fox Rare Cancer Program and Contextual Literature Review. CANCERS, 15 (17), https://doi.org/10.3390/cancers15174378Test.; http://hdl.handle.net/11343/339230Test

الإتاحة: https://doi.org/10.3390/cancers15174378Test
http://hdl.handle.net/11343/339230Test

المؤلفون: Ho, GY, Vandenberg, CJ, Lim, R, Christie, EL, Garsed, DW, Lieschke, E, Nesic, K, Kondrashova, O, Ratnayake, G, Radke, M, Penington, JS, Carmagnac, A, Heong, V, Kyran, EL, Zhang, F, Traficante, N, Huang, R, Dobrovic, A, Swisher, EM, McNally, O, Kee, D, Wakefield, MJ, Papenfuss, AT, Bowtell, DDL, Barker, HE, Scott, CL

الوصف: BACKGROUND: Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire lethal drug resistance; indeed, ~15% of individuals have de novo platinum-refractory disease. OBJECTIVES: To determine the potential of anti-microtubule agent (AMA) therapy (paclitaxel, vinorelbine and eribulin) in platinum-resistant or refractory (PRR) HGSC by assessing response in patient-derived xenograft (PDX) models of HGSC. DESIGN AND METHODS: Of 13 PRR HGSC PDX, six were primary PRR, derived from chemotherapy-naïve samples (one was BRCA2 mutant) and seven were from samples obtained following chemotherapy treatment in the clinic (five were mutant for either BRCA1 or BRCA2 (BRCA1/2), four with prior PARPi exposure), recapitulating the population of individuals with aggressive treatment-resistant HGSC in the clinic. Molecular analyses and in vivo treatment studies were undertaken. RESULTS: Seven out of thirteen PRR PDX (54%) were sensitive to treatment with the AMA, eribulin (time to progressive disease (PD) ⩾100 days from the start of treatment) and 11 out of 13 PDX (85%) derived significant benefit from eribulin [time to harvest (TTH) for each PDX with p < 0.002]. In 5 out of 10 platinum-refractory HGSC PDX (50%) and one out of three platinum-resistant PDX (33%), eribulin was more efficacious than was cisplatin, with longer time to PD and significantly extended TTH (each PDX p < 0.02). Furthermore, four of these models were extremely sensitive to all three AMA tested, maintaining response until the end of the experiment (120d post-treatment start). Despite harbouring secondary BRCA2 mutations, two BRCA2-mutant PDX models derived from heavily pre-treated individuals were sensitive to AMA. PRR HGSC PDX models showing greater sensitivity to AMA had high proliferative indices and oncogene expression. Two PDX models, both with prior chemotherapy and/or PARPi exposure, were refractory to all AMA, one of which harboured the ...

العلاقة: NHMRC/400281; NHMRC/400413; NHMRC/1081178; pii: 10.1177_17588359231208674; Ho, G. Y., Vandenberg, C. J., Lim, R., Christie, E. L., Garsed, D. W., Lieschke, E., Nesic, K., Kondrashova, O., Ratnayake, G., Radke, M., Penington, J. S., Carmagnac, A., Heong, V., Kyran, E. L., Zhang, F., Traficante, N., Huang, R., Dobrovic, A., Swisher, E. M. ,. Scott, C. L. (2023). The microtubule inhibitor eribulin demonstrates efficacy in platinum-resistant and refractory high-grade serous ovarian cancer patient-derived xenograft models. THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY, 15, https://doi.org/10.1177/17588359231208674Test.; http://hdl.handle.net/11343/344499Test

الإتاحة: https://doi.org/10.1177/17588359231208674Test
http://hdl.handle.net/11343/344499Test

المؤلفون: Coleman, Robert L, Oza, Amit M, Lorusso, Domenica, Aghajanian, Carol, Oaknin, Ana, Dean, Andrew, Colombo, Nicoletta, Weberpals, Johanne I, Clamp, Andrew, Scambia, Giovanni, Leary, Alexandra, Holloway, Robert W, Gancedo, Margarita Amenedo, Fong, Peter C, Goh, Jeffrey C, O'Malley, David M, Armstrong, Deborah K, Garcia-Donas, Jesus, Swisher, Elizabeth M, Floquet, Anne, Konecny, Gottfried E, McNeish, Iain A, Scott, Clare L, Cameron, Terri, Maloney, Lara, Isaacson, Jeff, Goble, Sandra, Grace, Caroline, Harding, Thomas C, Raponi, Mitch, Sun, James, Lin, Kevin K, Giordano, Heidi, Ledermann, Jonathan A, investigators, ARIEL3, Buck, M, Dean, A, Friedlander, ML, Goh, JC, Harnett, P, Kichenadasse, G, Scott, CL, Denys, H, Dirix, L, Vergote, I, Elit, L, Ghatage, P, Oza, AM, Plante, M, Provencher, D, Weberpals, JI, Welch, S, Floquet, A, Gladieff, L, Joly, F, Leary, A, Lortholary, A, Lotz, J, Medioni, J, Tredan, O, You, B, El-Balat, A, Hänle, C, Krabisch, P, Neunhöffer, T, Pölcher, M, Wimberger, P, Amit, A, Kovel, S, Leviov, M, Safra, T, Shapira-Frommer, R, Stemmer, S, Bologna, A, Colombo, N, Lorusso, D, Pignata, S, Sabbatini, RF, Scambia, G, Tamberi, S, Zamagni, C, Fong, PC, O'Donnell, A, Gancedo, M Amenedo, Herraez, A Casado, Garcia-Donas, J, Guerra, EM, Oaknin, A, Palacio, I, Romero, I, Sanchez, A, Banerjee, SN, Clamp, A, Drew, Y, Gabra, HG, Jackson, D, Ledermann, JA, McNeish, IA, Parkinson, C, Powell, M

المصدر: The Lancet. 390(10106)

مصطلحات موضوعية: Reproductive Medicine, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Orphan Drug, Clinical Research, Cancer, Genetics, Clinical Trials and Supportive Activities, Ovarian Cancer, Rare Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, 6.2 Cellular and gene therapies, Aged, Disease-Free Survival, Double-Blind Method, Female, Follow-Up Studies, Humans, Indoles, Internationality, Maintenance Chemotherapy, Middle Aged, Molecular Targeted Therapy, Neoplasm Recurrence, Local, Ovarian Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Risk Assessment, Survival Rate, Treatment Outcome, ARIEL3 investigators, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences

الوصف: BackgroundRucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma.MethodsIn this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0-1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete.FindingsBetween April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4-22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4-6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16-0·34]; p

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9xn4w6v7Test

المؤلفون: Gao, J, Jung, M, Williams, RT, Hui, D, Russell, AJ, Naim, AJ, Kamili, A, Clifton, M, Bongers, A, Mayoh, C, Ho, G, Scott, CL, Jessup, W, Haber, M, Norris, MD, Henderson, MJ

المصدر: urn:ISSN:2072-6694 ; Cancers, 14, 8, 1878

مصطلحات موضوعية: Rare Diseases, Ovarian Cancer, Cancer, Orphan Drug, 5.1 Pharmaceuticals, 5 Development of treatments and therapeutic interventions, 2 Aetiology, 2.1 Biological and endogenous factors, ABCA1, cholesterol, epithelial ovarian cancer, anzsrc-for: 1112 Oncology and Carcinogenesis

الوصف: Background: Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy with over 80% of cases already disseminated at diagnosis and facing a dismal five-year survival rate of 35%. EOC cells often spread to the greater omentum where they take-up cholesterol. Excessive amounts of cholesterol can be cytocidal, suggesting that cholesterol efflux through transporters may be important to maintain homeostasis, and this may explain the observation that high expression of the ATP-binding cassette A1 (ABCA1) cholesterol transporter has been associated with poor outcome in EOC patients. Methods: ABCA1 expression was silenced in EOC cells to investigate the effect of inhibiting cholesterol efflux on EOC biology through growth and migration assays, three-dimensional spheroid culture and cholesterol quantification. Results: ABCA1 suppression significantly reduced the growth, motility and colony formation of EOC cell lines as well as the size of EOC spheroids, whilst stimulating expression of ABCA1 reversed these effects. In serous EOC cells, ABCA1 suppression induced accumulation of cholesterol. Lowering cholesterol levels using methyl-B-cyclodextrin rescued the effect of ABCA1 suppression, restoring EOC growth. Furthermore, we identified FDA-approved agents that induced cholesterol accumulation and elicited cytocidal effects in EOC cells. Conclusions: Our data demonstrate the importance of ABCA1 in maintaining cholesterol balance and malignant properties in EOC cells, highlighting its potential as a therapeutic target for this disease.

وصف الملف: application/pdf

العلاقة: http://hdl.handle.net/1959.4/unsworks_80925Test; https://unsworks.unsw.edu.au/bitstreams/24d7f4db-1710-4cb4-84df-bc8e9232d225/downloadTest; https://doi.org/10.3390/cancers14081878Test

الإتاحة: https://doi.org/10.3390/cancers14081878Test
http://hdl.handle.net/1959.4/unsworks_80925Test
https://unsworks.unsw.edu.au/bitstreams/24d7f4db-1710-4cb4-84df-bc8e9232d225/downloadTest

المؤلفون: Meagher, NS, Gorringe, KL, Wakefield, M, Bolithon, A, Pang, CNI, Chiu, DS, Anglesio, MS, Mallitt, K-A, Doherty, JA, Harris, HR, Schildkraut, JM, Berchuck, A, Cushing-Haugen, KL, Chezar, K, Chou, A, Tan, A, Alsop, J, Barlow, E, Beckmann, MW, Boros, J, Bowtell, DDL, Brand, AH, Brenton, JD, Campbell, I, Cheasley, D, Cohen, J, Cybulski, C, Elishaev, E, Erber, R, Farrell, R, Fischer, A, Fu, Z, Gilks, B, Gill, AJ, Gourley, C, Grube, M, Harnett, PR, Hartmann, A, Hettiaratchi, A, Hogdall, CK, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kim, B-G, Kim, J-W, Kim, J-H, Klett, K, Koziak, JM, Lai, T, Laslavic, A, Lester, J, Leung, Y, Li, N, Liauw, W, Lim, BWX, Linder, A, Lubinski, J, Mahale, S, Mateoiu, C, McInerny, S, Menkiszak, J, Minoo, P, Mittelstadt, S, Morris, D, Orsulic, S, Park, S-Y, Pearce, CL, Pearson, J, Pike, MC, Quinn, CM, Mohan, GR, Rao, J, Riggan, MJ, Ruebner, M, Salfinger, S, Scott, CL, Shah, M, Steed, H, Stewart, CJR, Subramanian, D, Sung, S, Tang, K, Timpson, P, Ward, RL, Wiedenhoefer, R, Thorne, H, Cohen, PA, Crowe, P, Fasching, PA, Gronwald, J, Hawkins, NJ, Hogdall, E, Huntsman, DG, James, PA, Karlan, BY, Kelemen, LE, Kommoss, S, Konecny, GE, Modugno, F, Park, SK, Staebler, A, Sundfeldt, K, Wu, AH, Talhouk, A, Pharoah, PDP, Anderson, L, DeFazio, A, Kobel, M, Friedlander, ML, Ramus, SJ

الوصف: PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

العلاقة: NHMRC/1092856; NHMRC/310670; NHMRC/400281; NHMRC/1023698; NHMRC/628903; NHMRC/400413; NHMRC/1117044; pii: 709665; Meagher, N. S., Gorringe, K. L., Wakefield, M., Bolithon, A., Pang, C. N. I., Chiu, D. S., Anglesio, M. S., Mallitt, K. -A., Doherty, J. A., Harris, H. R., Schildkraut, J. M., Berchuck, A., Cushing-Haugen, K. L., Chezar, K., Chou, A., Tan, A., Alsop, J., Barlow, E., Beckmann, M. W. ,. Ramus, S. J. (2022). Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes. CLINICAL CANCER RESEARCH, 28 (24), pp.5383-5395. https://doi.org/10.1158/1078-0432.CCR-22-1206Test.; http://hdl.handle.net/11343/320060Test

الإتاحة: https://doi.org/10.1158/1078-0432.CCR-22-1206Test
http://hdl.handle.net/11343/320060Test

المؤلفون: Cremona, M, Vandenberg, CJ, Farrelly, AM, Madden, SF, Morgan, C, Kalachand, R, McAlpine, JN, Toomey, S, Huntsman, DG, Grogan, L, Breathnach, O, Morris, P, Carey, MS, Scott, CL, Hennessy, BT

الوصف: BACKGROUND: We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered in BRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors. METHODS: The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vivo effects of treatments were evaluated in PDX mouse models. RESULTS: Expression of X-linked inhibitor of apoptosis (XIAP) is increased in BRCA1-mutated cancers and high levels are associated with improved patient outcomes after platinum chemotherapy. XIAP overexpression is mediated by NF-kB activation and is associated with an optimisation of PARP. BRCA1-mutated cell lines are particularly sensitive to IAP inhibitors due to an inhibitory effect on PARP. Both a BRCA1-mutated cell line with acquired resistance to PARP inhibitors and one with restored BRCA1 remain sensitive to IAP inhibitors. Treatment with IAP inhibitors restores the efficacy of PARP inhibition in these cell lines. The IAP inhibitor LCL161 alone and in combination with a PARP inhibitor, exhibited antitumour effects in PDX mouse models of resistant BRCA2 and 1-mutated ovarian cancer, respectively. CONCLUSION: A clinical trial may be justified to further investigate the utility of IAP inhibitors.

العلاقة: pii: 10.1038/s41416-022-01823-5; Cremona, M., Vandenberg, C. J., Farrelly, A. M., Madden, S. F., Morgan, C., Kalachand, R., McAlpine, J. N., Toomey, S., Huntsman, D. G., Grogan, L., Breathnach, O., Morris, P., Carey, M. S., Scott, C. L. & Hennessy, B. T. (2022). BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors. BRITISH JOURNAL OF CANCER, 127 (3), pp.488-499. https://doi.org/10.1038/s41416-022-01823-5Test.; http://hdl.handle.net/11343/309090Test

الإتاحة: https://doi.org/10.1038/s41416-022-01823-5Test
http://hdl.handle.net/11343/309090Test

المؤلفون: Bound, NT, Vandenberg, CJ, Kartikasari, AER, Plebanski, M, Scott, CL

الوصف: High-grade serous ovarian carcinoma (HGSOC) is a genomically unstable malignancy responsible for over 70% of all deaths due to ovarian cancer. With roughly 50% of all HGSOC harboring defects in the homologous recombination (HR) DNA repair pathway (e.g., BRCA1/2 mutations), the introduction of poly ADP-ribose polymerase inhibitors (PARPi) has dramatically improved outcomes for women with HR defective HGSOC. By blocking the repair of single-stranded DNA damage in cancer cells already lacking high-fidelity HR pathways, PARPi causes the accumulation of double-stranded DNA breaks, leading to cell death. Thus, this synthetic lethality results in PARPi selectively targeting cancer cells, resulting in impressive efficacy. Despite this, resistance to PARPi commonly develops through diverse mechanisms, such as the acquisition of secondary BRCA1/2 mutations. Perhaps less well documented is that PARPi can impact both the tumour microenvironment and the immune response, through upregulation of the stimulator of interferon genes (STING) pathway, upregulation of immune checkpoints such as PD-L1, and by stimulating the production of pro-inflammatory cytokines. Whilst targeted immunotherapies have not yet found their place in the clinic for HGSOC, the evidence above, as well as ongoing studies exploring the synergistic effects of PARPi with immune agents, including immune checkpoint inhibitors, suggests potential for targeting the immune response in HGSOC. Additionally, combining PARPi with epigenetic-modulating drugs may improve PARPi efficacy, by inducing a BRCA-defective phenotype to sensitise resistant cancer cells to PARPi. Finally, invigorating an immune response during PARPi therapy may engage anti-cancer immune responses that potentiate efficacy and mitigate the development of PARPi resistance. Here, we will review the emerging PARPi literature with a focus on PARPi effects on the immune response in HGSOC, as well as the potential of epigenetic combination therapies. We highlight the potential of transforming HGSOC from ...

العلاقة: pii: 886170; Bound, N. T., Vandenberg, C. J., Kartikasari, A. E. R., Plebanski, M. & Scott, C. L. (2022). Improving PARP inhibitor efficacy in high-grade serous ovarian carcinoma: A focus on the immune system. FRONTIERS IN GENETICS, 13, https://doi.org/10.3389/fgene.2022.886170Test.; http://hdl.handle.net/11343/322162Test

الإتاحة: https://doi.org/10.3389/fgene.2022.886170Test
http://hdl.handle.net/11343/322162Test

المؤلفون: 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

الوصف: 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 ...

العلاقة: NHMRC/1081178; NHMRC/1062702; NHMRC/400281; NHMRC/400413; pii: 709667; Ho, G. Y., Kyran, E. L., Bedo, J., Wakefield, M. J., Ennis, D. P., Mirza, H. B., Vandenberg, C. J., Lieschke, E., Farrell, A., Hadla, A., Lim, R., Dall, G., Vince, J. E., Chua, N. K., Kondrashova, O., Upstill-Goddard, R., Bailey, U. -M., Dowson, S., Roxburgh, P. ,. Barker, H. E. (2022). Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin. CANCER RESEARCH, 82 (23), pp.4457-4473. https://doi.org/10.1158/0008-5472.CAN-21-4012Test.; http://hdl.handle.net/11343/320081Test

الإتاحة: https://doi.org/10.1158/0008-5472.CAN-21-4012Test
http://hdl.handle.net/11343/320081Test

المؤلفون: Kok, P-S, Antill, YC, Scott, CL, Lee, CK

الوصف: BACKGROUND: Immune checkpoint inhibitor (ICI) therapy is an emerging option for advanced endometrial cancer (EC). Mismatch repair (MMR) status is widely regarded as a biomarker predictive of response to ICIs. The predictive value of MMR based on small, single-arm trials, however, is conflicting. In this meta-analysis, we aimed to assess the activity of single-agent ICI in advanced EC, and compared the magnitude of treatment benefit in MMR deficient (dMMR) and MMR proficient (pMMR) EC. METHODS: We carried out an electronic search to identify prospective trials of single-agent ICI in advanced EC. Data on objective response rate (ORR) and progression-free survival (PFS) were extracted and pooled. ORR was estimated using the inverse variance method and subgroup difference by MMR status was examined. PFS difference according to MMR status was summarized using the Kaplan-Meier approach. RESULTS: From eight trials with 492 women, the pooled ORR was 19% [95% confidence interval (CI) 16% to 22%]. ORR was significantly greater in dMMR (n = 281) than pMMR EC (n = 211) (dMMR: 46%, pMMR: 8%; risk ratio 5.74, 95% CI 3.58-9.21; interaction P < 0.001). Complete response was 11% and 0.05% and median PFS was 8.3 and 2.1 months in dMMR and pMMR EC, respectively (hazard ratio PFS 0.58, 95% CI 0.38-0.89; P = 0.01). The 12-month PFS rates were 42.0% and 20.7%, respectively. CONCLUSION: Single-agent ICI is associated with a 5.74 times greater objective response and 42% reduction in risk of disease progression or death in dMMR compared with pMMR EC. MMR status should be determined prospectively and be used as a stratification factor in future trials of advanced EC. Further translational analysis is urgently required to identify the cause of dMMR and allow subclassification of EC into different dMMR molecular subtypes.

العلاقة: pii: S2059-7029(22)00269-1; Kok, P. -S., Antill, Y. C., Scott, C. L. & Lee, C. K. (2022). The impact of single agent PD-1 or PD-L1 inhibition on advanced endometrial cancers: meta-analysis. ESMO OPEN, 7 (6), https://doi.org/10.1016/j.esmoop.2022.100635Test.; http://hdl.handle.net/11343/334541Test

الإتاحة: https://doi.org/10.1016/j.esmoop.2022.100635Test
http://hdl.handle.net/11343/334541Test

المؤلفون: Grohmann, C, Walker, F, Devlin, M, Luo, MX, Chüeh, AC, Doherty, J, Vaillant, F, Ho, GY, Wakefield, MJ, Weeden, CE, Kamili, A, Murray, J, Po’uha, ST, Weinstock, J, Kane, SR, Faux, MC, Broekhuizen, E, Zheng, Y, Shield-Artin, K, Kershaw, NJ, Tan, CW, Witchard, HM, Ebert, G, Charman, SA, Street, I, Kavallaris, M, Haber, M, Fletcher, JI, Asselin-Labat, ML, Scott, CL, Visvader, JE, Lindeman, GJ, Watson, KG, Burgess, AW, Lessene, G

المصدر: urn:ISSN:2041-4889 ; Cell Death and Disease, 12, 3, 268

مصطلحات موضوعية: Rare Diseases, Biotechnology, Orphan Drug, Lung Cancer, Neurosciences, Ovarian Cancer, Neuroblastoma, Cancer, Breast Cancer, Genetics, Lung, 5 Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Animals, Antimitotic Agents, Apoptosis, Cell Proliferation, Drug Resistance, Neoplasm, Female, G2 Phase Cell Cycle Checkpoints, Hep G2 Cells, Humans, Mice, Inbred BALB C, Inbred C57BL, Nude, Mitosis, Neoplasms, PC-3 Cells

الوصف: Targeting cell division by chemotherapy is a highly effective strategy to treat a wide range of cancers. However, there are limitations of many standard-of-care chemotherapies: undesirable drug toxicity, side-effects, resistance and high cost. New small molecules which kill a wide range of cancer subtypes, with good therapeutic window in vivo, have the potential to complement the current arsenal of anti-cancer agents and deliver improved safety profiles for cancer patients. We describe results with a new anti-cancer small molecule, WEHI-7326, which causes cell cycle arrest in G2/M, cell death in vitro, and displays efficacious anti-tumor activity in vivo. WEHI-7326 induces cell death in a broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts. Importantly, the compound elicits tumor responses as a single agent in patient-derived xenografts of clinically aggressive, treatment-refractory neuroblastoma, breast, lung and ovarian cancer. In combination with standard-of-care, WEHI-7326 induces a remarkable complete response in a mouse model of high-risk neuroblastoma. WEHI-7326 is mechanistically distinct from known microtubule-targeting agents and blocks cells early in mitosis to inhibit cell division, ultimately leading to apoptotic cell death. The compound is simple to produce and possesses favorable pharmacokinetic and toxicity profiles in rodents. It represents a novel class of anti-cancer therapeutics with excellent potential for further development due to the ease of synthesis, simple formulation, moderate side effects and potent in vivo activity. WEHI-7326 has the potential to complement current frontline anti-cancer drugs and to overcome drug resistance in a wide range of cancers.

وصف الملف: application/pdf

العلاقة: http://purl.org/au-research/grants/nhmrc/APP1119152Test; http://hdl.handle.net/1959.4/unsworks_76233Test; https://unsworks.unsw.edu.au/bitstreams/8e5191f0-886b-4b2d-984c-dbe15394dcd8/downloadTest; https://doi.org/10.1038/s41419-020-03269-0Test

الإتاحة: https://doi.org/10.1038/s41419-020-03269-0Test
http://hdl.handle.net/1959.4/unsworks_76233Test
https://unsworks.unsw.edu.au/bitstreams/8e5191f0-886b-4b2d-984c-dbe15394dcd8/downloadTest