Article
Pharmacology & Pharmacy
Xia Xu, Hua Feng, Chaochao Dai, Weida Lu, Jun Zhang, Xiaosun Guo, Qihui Yin, Jianli Wang, Xiaopei Cui, Fan Jiang
Summary: The study showed that CX-5461 had good tolerance for in vivo treatments in rats with PAH, preventing pulmonary arterial remodelling, perivascular inflammation, and pulmonary hypertension, leading to improved survival. In vivo and in vitro experiments demonstrated that CX-5461 induced cell cycle arrest in human pulmonary arterial smooth muscle cells through increased activation of p53, suggesting that pharmacological inhibition of Pol I could be a novel therapeutic strategy for drug-resistant PAH.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ashwini Makhale, Devathri Nanayakkara, Prahlad Raninga, Kum Kum Khanna, Murugan Kalimutho
Summary: Combination therapy of APR-246 and CX-5461 shows significant inhibition of triple-negative breast cancer cell growth, inducing apoptosis and enhancing efficacy by inducing DNA damage and replication stress.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Oncology
Robert Cornelison, Kuntal Biswas, Danielle C. Llaneza, Alexandra R. Harris, Nisha G. Sosale, Matthew J. Lazzara, Charles N. Landen
Summary: Treatment with CX-5461 leads to the accumulation of cytosolic dsDNA, activating the cGAS-STING-TBK1-IRF3 innate immune pathway and inducing type I interferon production. This immune activation may be a powerful mechanism of action to exploit in novel drug combinations for increasing immunotherapy efficacy and potentially limiting deleterious toxicities with some cancer specificity.
Review
Oncology
Bayley G. Matthews, Nikola A. Bowden, Michelle W. Wong-Brown
Summary: High-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer, with a stagnant overall survival rate over the past three decades. Chemoresistance remains a major challenge in treating HGSOC, and may be driven by epigenetic modifications. Identifying epigenetic changes in chemoresistant HGSOC allows for the development of targeted therapies to improve outcomes.
Review
Oncology
Tibor A. Zwimpfer, Ori Tal, Franziska Geissler, Ricardo Coelho, Natalie Rimmer, Francis Jacob, Viola Heinzelmann-Schwarz
Summary: High-grade serous ovarian cancers (HGSOCs) arise from the fallopian tube and harbor TP53 gene mutations, while low-grade serous ovarian cancers (LGSOCs) have different features and are considered a distinct subtype. Treatment for LGSOCs is limited due to a lack of separate trial data, but current understanding suggests slow tumor growth and precursors from serous borderline ovarian tumors. Therapeutic decisions are guided by characteristics such as estrogen receptor positivity and specific mutations, leading to maintenance with endocrine treatment or targeted therapies. Ongoing trials are exploring the use of MEK inhibitors in combination with hormonal treatments for LGSOCs.
CANCER TREATMENT REVIEWS
(2023)
Article
Oncology
Gwo Yaw Ho, Cassandra J. Vandenberg, Ratana Lim, Elizabeth L. Christie, Dale W. Garsed, Elizabeth Lieschke, Ksenija Nesic, Olga Kondrashova, Gayanie Ratnayake, Marc Radke, Jocelyn S. Penington, Amandine Carmagnac, Valerie Heong, Elizabeth L. Kyran, Fan Zhang, Nadia Traficante, Ruby Huang, Alexander Dobrovic, Elizabeth M. Swisher, Orla McNally, Damien Kee, Matthew J. Wakefield, Anthony T. Papenfuss, David D. L. Bowtell, Holly E. Barker, Clare L. Scott
Summary: This study investigates the potential of anti-microtubule agent (AMA) therapy in platinum-resistant or refractory high-grade serous ovarian cancer (HGSC) using patient-derived xenograft (PDX) models. The results demonstrate that eribulin is effective in a subset of patients and shows a longer time to disease progression compared to cisplatin.
THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
(2023)
Article
Oncology
Puja Dey, Kentaro Nakayama, Sultana Razia, Masako Ishikawa, Tomoka Ishibashi, Hitomi Yamashita, Kosuke Kanno, Seiya Sato, Tohru Kiyono, Satoru Kyo
Summary: This study successfully developed an in vitro carcinogenic model of LGSOCs and found that the mutations of KRAS and PIK3CA play a causative role in LGSOC tumorigenesis. Simultaneous activation of the KRAS/ERK and PIK3CA/AKT signaling pathways is essential for LGSOC development.
Article
Oncology
Chang-Won Kang, Katherine M. Hannan, Anneke C. Blackburn, Amos H. P. Loh, Kuick Chik Hong, Goh Jian Yuan, Nadine Hein, Denis Drygin, Ross D. Hannan, Lucy A. Coupland
Summary: This study confirmed SK-UT-1 as a representative model for uterine leiomyosarcoma and demonstrated the significant potential of CX-5461 as a novel adjuvant for this rare cancer.
INVESTIGATIONAL NEW DRUGS
(2022)
Article
Cell Biology
Dongqing Huang, Shrabanti Chowdhury, Hong Wang, Sara R. Savage, Richard G. Ivey, Jacob J. Kennedy, Jeffrey R. Whiteaker, Chenwei Lin, Xiaonan Hou, Ann L. Oberg, Melissa C. Larson, Najmeh Eskandari, Davide A. Delisi, Saverio Gentile, Catherine J. Huntoon, Uliana J. Voytovich, Zahra J. Shire, Qing Yu, Steven P. Gygi, Andrew N. Hoofnagle, Zachary T. Herbert, Travis D. Lorentzen, Anna Calinawan, Larry M. Karnitz, S. John Weroha, Scott H. Kaufmann, Bing Zhang, Pei Wang, Michael J. Birrer, Amanda G. Paulovich
Summary: Resistance to platinum compounds is a major factor affecting patient survival in high-grade serous ovarian cancer. By analyzing multiomic data from HGSOC cells, this study identified that increased fatty acid oxidation pathway expression and inhibition of the key enzyme CPT1A can sensitize ovarian cancer cells to platinum. The results were further validated in patient-derived xenograft models, indicating CPT1A as a potential therapeutic target to overcome platinum resistance.
CELL REPORTS MEDICINE
(2021)
Article
Oncology
Mikhail S. Chesnokov, Imran Khan, Yeonjung Park, Jessica Ezell, Geeta Mehta, Abdelrahman Yousif, Linda J. Hong, Ronald J. Buckanovich, Akimasa Takahashi, Ilana Chefetz
Summary: High-grade serous ovarian carcinoma (HGSOC) has a poor prognosis due to high recurrence rate and acquired chemoresistance. Inhibition of MEK1/2 may suppress cancer growth but also promote stem-like properties in HGSOC cells, suggesting the need for combination therapy targeting cancer stem cells.
Review
Oncology
Amal A. Al-Dossary, Essam A. Tawfik, Adaugo C. Isichei, Xin Sun, Jiahe Li, Abdullah A. Alshehri, Munther Alomari, Fahad A. Almughem, Ahmad M. Aldossary, Hussein Sabit, Abdulaziz M. Almalik
Summary: This review discusses the role of natural extracellular vesicles (EVs) in high-grade serous ovarian cancer (HGSOC) and the advantages of using engineered EV-mimetic nanoparticles as a delivery vehicle. It also highlights the challenges and promising directions in the clinical translation of these systems.
Review
Biochemistry & Molecular Biology
Paula Punzon-Jimenez, Victor Lago, Santiago Domingo, Carlos Simon, Aymara Mas
Summary: High-grade serous ovarian carcinoma (HGSOC) is the most common form of epithelial ovarian carcinoma, and its early diagnosis still relies on traditional methods. Research on its etiopathogenesis provides new insights for finding early detection methods.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Inorganic & Nuclear
Zhen-Lei Zhang, Rui Rong, Xuan-Lin Ren, Ling-Wen Xu, Wen-Jing Lian, Xin Qiao, Jing-Yuan Xu
Summary: Unrestricted cell growth and proliferation of cancer cells correlate with accelerated RNA polymerase I transcription and upregulation of ribosome biogenesis. CX-5461, a Pol I selective inhibitor with multitargeting property and synthetic lethality in HR-deficient cancers, was used to modify cisplatin to obtain two monofunctional platinum Pol I selective inhibitors. The study demonstrated that P1-Q1 and P1-Q2 could specifically target Pol I transcription machinery and overcome platinum drug resistance in BRCA1-deficient A549 cells.
INORGANIC CHEMISTRY FRONTIERS
(2023)
Article
Oncology
Dane Cheasley, Abhimanyu Nigam, Magnus Zethoven, Sally Hunter, Dariush Etemadmoghadam, Timothy Semple, Prue Allan, Mark S. Carey, Marta L. Fernandez, Amy Dawson, Martin Kobel, David G. Huntsman, Cecile Le Page, Anne-Marie Mes-Masson, Diane Provencher, Neville Hacker, Yunkai Gao, David Bowtell, Anna deFazio, Kylie L. Gorringe, Ian G. Campbell
Summary: Low-grade serous ovarian carcinoma (LGSOC) is linked with poor response to chemotherapy, emphasizing the importance of genomic analysis to identify new therapeutic targets. A comprehensive study of LGSOC patients revealed potential driver aberrations and protein expressions that could impact disease outcomes and treatment responses.
(c) 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
JOURNAL OF PATHOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Kristie-Ann Dickson, Tao Xie, Christian Evenhuis, Yue Ma, Deborah J. Marsh
Summary: PARP inhibitors have shown efficacy in treating tumors with BRCA gene defects, improving survival outcomes. Variability exists between different PARP inhibitors in terms of chemical structure, toxicity, and cell survival, with acquired resistance being a concerning issue that needs further exploration.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Health Care Sciences & Services
Sabe Sabesan, Marie Malica, Chantal Gebbie, Clare Scott, David Thomas, John Zalcberg
Summary: This paper describes the steps and processes involved in the development and implementation of the Australasian Teletrial Model (ATM) by the Clinical Oncology Society of Australia. The implementation of ATM has improved access to clinical trials for patients in regional and rural areas, and enhanced collaboration between metropolitan and regional sites.
JOURNAL OF TELEMEDICINE AND TELECARE
(2023)
Article
Allergy
Gohar Shaghayegh, Clare Cooksley, George Spyro Bouras, Beula Subashini Panchatcharam, Rejhan Idrizi, Metta Jana, Sarah Ellis, Alkis James Psaltis, Peter -John Wormald, Sarah Vreugde
Summary: This study aimed to investigate the characteristics of Staphylococcus aureus biofilms in patients with chronic rhinosinusitis (CRS) and their correlation with inflammation and disease severity. The results showed that CRS patients with nasal polyps had thicker S aureus biofilms with higher bacterial counts and higher exoprotein production compared to the control group. The numbers of inflammatory cells and disease severity were positively correlated with S aureus biofilm properties.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Zilu Wang, Huimin Hu, Luuk Heitink, Kelly Rogers, Yue You, Tao Tan, Connie Li Wai Suen, Alex Garnham, Hao Chen, Elizabeth Lieschke, Sarah T. T. Diepstraten, Catherine Chang, Diane Moujalled, Kate Sutherland, Guillaume Lessene, Oliver M. M. Sieber, Jane Visvader, Gemma L. L. Kelly, Andreas Strasser
Summary: APR-246 can kill malignant cells irrespective of their TP53/TRP53 status. It induces various programmed cell death pathways, such as apoptosis, necroptosis, and ferroptosis. Therefore, the clinical testing of APR-246 should be expanded to cancers expressing wild-type TP53 or TP53-deficient.
CELL DEATH AND DIFFERENTIATION
(2023)
Article
Multidisciplinary Sciences
Mandy L. Ballinger, Swetansu Pattnaik, Piyushkumar A. Mundra, Milita Zaheed, Emma Rath, Peter Priestley, Jonathan Baber, Isabelle Ray-Coquard, Nicholas Isambert, Sylvain Causeret, Winette T. A. van der Graaf, Ajay Puri, Florence Duffaud, Axel Le Cesne, Beatrice Seddon, Coonoor Chandrasekar, Joshua D. Schiffman, Andrew S. Brohl, Paul A. James, Jean-Emmanuel Kurtz, Nicolas Penel, Ola Myklebost, Leonardo A. Meza-Zepeda, Hilda Pickett, Maya Kansara, Nicola Waddell, Olga Kondrashova, John Pearson, Andrew P. Barbour, Shuai Li, Tuong L. Nguyen, Diane Fatkin, Robert M. Graham, Eleni Giannoulatou, Melissa J. Green, Warren Kaplan, Shyamsundar Ravishankar, Joseph Copty, Joseph E. Powell, Edwin Cuppen, Kristel van Eijk, Jan Veldink, Jin-Hee Ahn, Jeong Eun Kim, R. Lor Randall, Kathy Tucker, Ian Judson, Rajiv Sarin, Thomas Ludwig, Emmanuelle Genin, Jean-Francois Deleuze, Michelle Haber, Glenn Marshall, Murray J. Cairns, Jean-Yves Blay, David M. Thomas
Summary: Cancer genetics has focused on epithelial malignancies, but this study explores specific pathways related to sarcomas, rare malignancies derived from embryonic mesoderm. Germline sequencing of sporadic cases and healthy controls reveals two sarcoma-specific pathways involved in mitotic and telomere functions. Centrosome gene variants are linked to specific tumors, while heritable defects in the shelterin complex increase susceptibility to sarcomas, melanomas, and thyroid cancers. These findings highlight the role of heritable defects in mitotic and telomere biology in sarcoma risk.
Correction
Biochemistry & Molecular Biology
Zilu Wang, Huimin Hu, Luuk Heitink, Kelly Rogers, Yue You, Tao Tan, Connie Li Wai Suen, Alex Garnham, Hao Chen, Elizabeth Lieschke, Sarah T. Diepstraten, Catherine Chang, Tianwei Chen, Diane Moujalled, Kate Sutherland, Guillaume Lessene, Oliver M. Sieber, Jane Visvader, Gemma L. Kelly, Andreas Strasser
CELL DEATH AND DIFFERENTIATION
(2023)
Article
Cell Biology
Heather Thorne, Lisa Devereux, Jason Li, Kathryn Alsop, Liz Christie, Courtney T. van Geelen, Nikki Burdett, Kathleen Pishas, Noel Woodford, Jodie Leditschke, Mohamed H. M. A. Izzath, Kate Strachan, Gregory Young, Rufaro D. Jaravaza, Mohammed S. Madadin, Melanie Archer, Joanna Glengarry, Linda Iles, Ajith Rathnaweera, Clare Hampson, Khamis Almazrooei, Michael Burke, Pradeep Bandara, David Ranson, Essa Saeedi, Orla McNally, Linda Mileshkin, Anne Hamilton, Sumitra Ananda, George Au-Yeung, Yoland Antill, Shahneen Sandhu, Peter Savas, Prudence A. Francis, Stephen Luen, Sherene Loi, Ross Jennens, Clare Scott, Kate Moodie, Margaret Cummings, Andrew Reid, Amy McCart Reed, David Bowtell, Sunil R. Lakhani, Stephen Fox
Summary: This study aims to examine the metastatic patterns of breast, ovarian, and prostate cancer in germline BRCA1/2 mutation carriers and non-carriers through a rapid autopsy program. It found significant differences in the patterns of metastases in breast and ovarian cancer between BRCA1/2 carriers and non-carriers, while no significant differences were observed in prostate cancer. The findings have implications for clinical diagnostic imaging in monitoring metastases.
Article
Genetics & Heredity
Nikki L. Burdett, Madelynne O. Willis, Kathryn Alsop, Allison L. Hunt, Ahwan Pandey, Phineas T. Hamilton, Tamara Abulez, Xuan Liu, Therese Hoang, Stuart Craig, Sian Fereday, Joy Hendley, Dale W. Garsed, Katy Milne, Shreena Kalaria, Ashley Marshall, Brian L. Hood, Katlin N. Wilson, Kelly A. Conrads, Kathleen Pishas, Sumitra Ananda, Clare L. Scott, Yoland Antill, Orla McNally, Linda Mileshkin, Anne Hamilton, George Au-Yeung, Lisa Devereux, Heather Thorne, Andrea Bild, Nicholas W. Bateman, G. Larry Maxwell, Jeffrey T. Chang, Thomas P. P. Conrads, Brad H. Nelson, David D. L. Bowtell, Elizabeth L. L. Christie
Summary: A multiomics approach was used to study molecular diversity in end-stage HR-deficient HGSC, revealing polyclonal disease, resistance mechanisms such as reversion mutations and HR restoration, whole-genome duplication, and global changes in immune composition with evidence of immune escape.
Article
Multidisciplinary Sciences
Shen Y. Y. Heazlewood, Tanveer Ahmad, Benjamin Cao, Huimin Cao, Melanie Domingues, Xuan Sun, Chad K. K. Heazlewood, Songhui Li, Brenda Williams, Madeline Fulton, Jacinta F. F. White, Tom Nebl, Christian M. M. Nefzger, Jose M. M. Polo, Benjamin T. T. Kile, Felix Kraus, Michael T. T. Ryan, Yu B. B. Sun, Peter F. M. Choong, Sarah L. L. Ellis, Minna-Liisa Anko, Susan K. K. Nilsson
Summary: Different sub-populations of megakaryocytes play important roles in generating platelets and regulating blood stem cells, and they are conserved in humans.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Samual MacDonald, Helena Foley, Melvyn Yap, Rebecca L. Johnston, Kaiah Steven, Lambros T. Koufariotis, Sowmya Sharma, Scott Wood, Venkateswar Addala, John V. Pearson, Fred Roosta, Nicola Waddell, Olga Kondrashova, Maciej Trzaskowski
Summary: Uncertainty estimation is crucial for understanding the reliability of deep learning predictions and deploying deep learning in clinical settings. In this study, the authors benchmarked several Bayesian deep learning models for predicting cancer of unknown primary using RNA-seq datasets. The results highlight the effectiveness of Bayesian deep learning in improving the generalization of uncertainty estimation and accuracy under data distributional shifts when using uncertainty thresholding.
SCIENTIFIC REPORTS
(2023)
Article
Multidisciplinary Sciences
Zoe R. C. Marks, Nicole Campbell, Niamh Mangan, Cassandra S. Vandenberg, Linden S. Gearing, Antony Matthews, Jodee L. Gould, Michelle N. Tate, Georgie Wray-McCann, Le J. Ying, Sarah Rosli, Natasha Brockwell, Belinda Parker, San Lim, Maree Bilandzic, Elizabeth Christie, Andrew Stephens, Eveline de Geus, Matthew Wakefield, Gwo-Yaw Ho, Orla A. McNally, David D. L. Australian Ovarian Cancer Study, Iain A. McNeish, David D. L. L. Bowtell, Nicole M. de Weerd, Clare J. Scott, Nollaig Bourke, Paul Hertzog
Summary: High-grade serous ovarian cancers have low survival rates due to late presentation and chemoresistance. In this study, we investigate the tumor-suppressive activities of interferon-e (IFNe) in ovarian cancer models. We find that IFNe is constitutively expressed in the fallopian tube and lost during tumor development. IFNe directly acts on tumor cells and activates anti-tumor immunity. It prevents the accumulation and activation of suppressor cells and regulatory T cells. Our findings suggest that IFNe could be a potential therapeutic target for ovarian cancer.
Article
Multidisciplinary Sciences
Khoa A. Tran, Venkateswar Addala, Rebecca L. Johnston, David Lovell, Andrew Bradley, Lambros T. Koufariotis, Scott Wood, Sunny Z. Wu, Daniel Roden, Ghamdan Al-Eryani, Alexander Swarbrick, Elizabeth D. Williams, John V. Pearson, Olga Kondrashova, Nicola Waddell
Summary: Cells in the tumour microenvironment (TME) can have a significant impact on tumour development and treatment response. Computational methods have been developed to analyze and separate TME from bulk RNA-seq data. In this study, the authors used single-cell RNA-seq data from breast cancer to generate simulated bulk data and compared the performance of nine different TME deconvolution methods. They found that some methods were more effective in deconvolving mixtures with high tumour purity levels, while most methods tended to misclassify normal epithelial cells as cancer epithelial cells as tumour purity increased. The authors also discovered that the molecular subtype of breast cancer played a role in this misclassification. BayesPrism and DWLS had the lowest number of false positives and false negatives, making them the most reliable methods for deconvolving specific immune lineages. These findings emphasize the importance of characterizing rare cell types using single-cell techniques and taking into account the tumour cell composition when deconvolving the TME.
NATURE COMMUNICATIONS
(2023)
Article
Biochemical Research Methods
Daffodil M. Canson, Aimee L. Davidson, Miguel de la Hoya, Michael T. Parsons, Dylan M. Glubb, Olga Kondrashova, Amanda B. Spurdle
Summary: SpliceAI is a widely used splicing prediction tool and we developed the SpliceAI-10k calculator (SAI-10k-calc) to extend its use for predicting various types of splicing aberrations with high accuracy. The SAI-10k-calc has 95% sensitivity and 96% specificity for predicting variants that impact splicing, and it performs well in predicting pseudoexon and partial intron retention. The automated amino acid sequence prediction feature allows for efficient identification of variants that may lead to mRNA nonsense-mediated decay or truncated proteins during translation.
Review
Oncology
Ana C. Veneziani, Clare Scott, Matthew J. Wakefield, Anna V. Tinker, Stephanie Lheureux
Summary: Poly (ADP-ribose) polymerase inhibitors (PARPis) have revolutionized the treatment of epithelial ovarian cancer, but resistance to PARPi has become a major concern. Ongoing studies aim to understand the mechanisms of resistance and explore potential therapeutic strategies to overcome this issue.
THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
(2023)
Review
Oncology
Mara N. Zeissig, Lauren M. Ashwood, Olga Kondrashova, Kate D. Sutherland
Summary: KRAS is the most frequently mutated oncogene in cancer, with G12D mutation having the highest prevalence across various cancers and adenocarcinomas. Understanding the biology of KRAS-G12D cancers and identifying biomarkers for therapeutic response prediction is crucial for developing effective treatment strategies.