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
Multidisciplinary Sciences
Luc Snyers, Sylvia Laffer, Renate Loehnert, Klara Weipoltshammer, Christian Schoefer
Summary: In this study, the researchers investigated the impact of the compound CX-5461 on nucleolar morphology and function. The results showed that exposure to CX-5461 caused significant changes in nucleolar shape, with nucleoli becoming compact and spherical. The researchers also observed increased amounts of DNA damage response indicators and DNA unwinding enzymes in the nucleoli. Furthermore, incubation with CX-5461 led to increased senescence and decreased cell replication.
SCIENTIFIC REPORTS
(2022)
Review
Genetics & Heredity
Jiachen Xuan, Kezia Gitareja, Natalie Brajanovski, Elaine Sanij
Summary: The nucleolus is a subdomain of the nucleus responsible for rRNA synthesis and ribosome assembly. The highly repetitive and transcribed nature of rDNA poses challenges for DNA repair and replication. Unique responses to rDNA damage have recently been recognized, with the nucleolus emerging as a central hub for coordinating stress responses.
Article
Dermatology
Xiao Wu, Qihui Yin, Jie Wang, Chaochao Dai, Jianli Wang, Xiaosun Guo, Fan Jiang
Summary: CX-5461, a selective inhibitor of RNA polymerase I, demonstrates therapeutic effects on experimental psoriasis in mice, possibly through multiple mechanisms including anti-proliferative, anti-inflammatory, and anti-angiogenic activities.
EXPERIMENTAL DERMATOLOGY
(2023)
Article
Oncology
Mitchell G. Lawrence, Laura H. Porter, Nicholas Choo, David Pook, Jeremy P. Grummet, Carmel J. Pezaro, Shahneen Sandhu, Susanne Ramm, Jennii Luu, Andrew Bakshi, David L. Goode, Elaine Sanij, Richard B. Pearson, Ross D. Hannan, Kaylene J. Simpson, Renea A. Taylor, Gail P. Risbridger, Luc Furic
Summary: Combination therapy with CX-5461 and talazoparib is effective for HR-proficient CRPC tumors that are not suitable for monotherapy with PARP inhibitors, significantly reducing tumor growth and increasing DNA damage levels in patient-derived xenografts.
MOLECULAR CANCER THERAPEUTICS
(2021)
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
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
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.
Article
Pharmacology & Pharmacy
Jie Wang, Zhijian Zheng, Xiaopei Cui, Chaochao Dai, Jiaxin Li, Qunye Zhang, Mei Cheng, Fan Jiang
Summary: The study found that CX-5461 primarily induced cell cycle inhibition in activated macrophages, without inducing a systemic anti-inflammatory transcriptional program, although some inflammatory genes were downregulated by CX-5461.
FRONTIERS IN PHARMACOLOGY
(2022)
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
Biochemistry & Molecular Biology
Emily C. Sutton, Victoria J. DeRose
Summary: Recent reports suggest that oxaliplatin causes early nucleolar disruption via inhibition of rRNA synthesis, while cisplatin kills cells primarily via DNA damage without significant effects on nucleolar organization.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Chang-Won Kang, Anneke C. Blackburn, Amos Hong Pheng Loh, Kuick Chick Hong, Jian Yuan Goh, Nadine Hein, Denis Drygin, Chris R. Parish, Ross D. Hannan, Katherine M. Hannan, Lucy A. Coupland
Summary: The survival rate of patients with osteosarcoma has not improved in the past 30 years. Mutations in TP53, RB1, and c-Myc genes enhance the activity of RNA Polymerase I (Pol I), leading to uncontrolled cancer cell proliferation. Pol I inhibition may be an effective therapeutic strategy for osteosarcoma.
Article
Biochemistry & Molecular Biology
Shiyan Wang, Chi Chun Wong, Yanquan Zhang, Junzhe Huang, Chuangen Li, Jianning Zhai, Guoping Wang, Hong Wei, Xueji Zhang, Housheng Hansen He, Jun Yu
Summary: ZNF545 suppresses colorectal cancer by repressing rRNA transcription and protein translation. Deletion of Znf545 promotes gene expression and cell growth, leading to accelerated CRC development. Experimental evidence demonstrates the tumor-suppressive role of ZNF545 in CRC.
Article
Multidisciplinary Sciences
Stacey L. Lehman, Kayla R. Schwartz, Shrankhla Maheshwari, Kevin Camphausen, Philip J. Tofilon
Summary: Inhibitors of ribosome biogenesis can increase the sensitivity of cancer cells to radiotherapy. This study tested the radiosensitizing potential of the small molecule RNA polymerase I inhibitor CX-5461 and found that it enhanced the effectiveness of radiation therapy in tumor cells through the mechanism of mitotic catastrophe.
SCIENTIFIC REPORTS
(2022)
Article
Medicine, Research & Experimental
Shanwei Shi, Huigen Luo, Lihong Wang, Hua Li, Yujie Liang, Juan Xia, Zhi Wang, Bin Cheng, Linfeng Huang, Guiqing Liao, Baoshan Xu
Summary: The study demonstrated that OSCC tumors with partial loss of 45S rDNA copy number were sensitive to CX5461 and the combination of CX5461 and INK128. The synergistic effects of the cotreatment induced apoptosis, inhibited cell growth, and prolonged the survival time of tumor-bearing mice. INK128 also enhanced the antitumor activity of CX5461 by compromising the NHEJ-DNA repair pathway.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Article
Medicine, General & Internal
Kim H. Tay, Monica A. Slavin, Karin A. Thursky, Julien Coussement, Leon J. Worth, Benjamin W. Teh, Amit Khot, Constantine S. Tam, Michelle K. Yong
Summary: This study evaluated the epidemiology and clinical characteristics of CMV infection in cancer patients, finding that CMV infection is common in patients with hematological malignancies, particularly in those with B-cell LPD, T-cell LPD, chronic lymphocytic leukemia, and multiple myeloma.
INTERNAL MEDICINE JOURNAL
(2022)
Article
Oncology
Lisa C. Wellinger, Simon J. Hogg, Dane M. Newman, Thomas Friess, Daniela Geiss, Jessica Michie, Kelly M. Ramsbottom, Marina Bacac, Tanja Fauti, Daniel Marbach, Laura Jarassier, Phillip Thienger, Axel Paehler, Leonie A. Cluse, Conor J. Kearney, Stephin J. Vervoort, Joseph A. Trapani, Jane Oliaro, Jake Shortt, Astrid Ruefli-Brasse, Daniel Rohle, Ricky W. Johnstone
Summary: Targeting chromatin binding proteins and modifying enzymes can enhance antitumor immunity and effectiveness of cancer immunotherapies by affecting tumor cell proliferation and survival. BET inhibitors sensitize tumor cells to TNF-induced cell death and suppress inflammatory gene expression, leading to enhanced tumor growth inhibition in combination with T-cell bispecific antibodies or immune-checkpoint blockade.
CANCER IMMUNOLOGY RESEARCH
(2022)
Article
Hematology
Lauren M. Brown, Soroor Hediyeh-Zadeh, Teresa Sadras, Hannah Huckstep, Jarrod J. Sandow, Ray C. Bartolo, Hansen J. Kosasih, Nadia M. Davidson, Breon Schmidt, Stefan Bjelosevic, Ricky Johnstone, Andrew Webb, Seong L. Khaw, Alicia Oshlack, Melissa J. Davis, Paul G. Ekert
Summary: This study identified a rare SFPQ-ABL1 fusion gene that plays a crucial role in cellular transformation in Ph-like ALL. Unlike other ABL1 fusion genes, SFPQ-ABL1 exhibits differences in subcellular localization, proliferative capacity, and activation of cellular pathways. These findings highlight the significance of fusion partners in mediating the function of ABL1 fusion genes.
Article
Medicine, Research & Experimental
Joan So, Alexander C. Lewis, Lorey K. Smith, Kym Stanley, Rheana Franich, David Yoannidis, Lizzy Pijpers, Pilar Dominguez, Simon J. Hogg, Stephin J. Vervoort, Fiona C. Brown, Ricky W. Johnstone, Gabrielle McDonald, Danielle B. Ulanet, Josh Murtie, Emily Gruber, Lev M. Kats
Summary: The study reveals that DHODH inhibitors have potent and selective activity against AML, and can reverse the differentiation block in AML cells. In addition, the elimination of the CDK5 gene increases the sensitivity of AML cells to DHODHi.
EMBO MOLECULAR MEDICINE
(2022)
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
Oncology
Jessica M. Salmon, Izabela Todorovski, Kym L. Stanley, Claudia Bruedigam, Conor J. Kearney, Luciano G. Martelotto, Fernando Rossello, Timothy Semple, Gisela Mir Arnau, Magnus Zethoven, Michael Bots, Stefan Bjelosevic, Leonie A. Cluse, Peter J. Fraser, Veronique Litalien, Eva Vidacs, Kate McArthur, Antony Y. Matthews, Elise Gressier, Nicole A. de Weerd, Jens Lichte, Madison J. Kelly, Simon J. Hogg, Paul J. Hertzog, Lev M. Kats, Stephin J. Vervoort, Daniel D. De Carvalho, Stefanie Scheu, Sammy Bedoui, Benjamin T. Kile, Steven W. Lane, Andrew C. Perkins, Andrew H. Wei, Pilar M. Dominguez, Ricky W. Johnstone
Summary: Inhibition of HDACs can induce differentiation and therapeutic effects in AML cells, and epigenetic rewiring of pDCs enhances antitumor immunity, offering a new therapeutic approach.
Letter
Oncology
Tamasine Stewart, Mark Dowling, Brett Janson, Jim Siderov, Jing Xie, Andrew Grigg, Amit Khot
LEUKEMIA & LYMPHOMA
(2023)
Article
Developmental Biology
Olga Zaytseva, Naomi C. Mitchell, Damien Muckle, Caroline Delandre, Zuqin Nie, Janis K. Werner, John T. Lis, Eduardo Eyras, Ross D. Hannan, David L. Levens, Owen J. Marshall, Leonie M. Quinn
Summary: FUBP1 and Psi, members of the FUSE Binding Protein family, regulate gene transcription by binding to single-stranded DNA and RNA, promoting cell growth and division. Psi activates Myc and stg to promote cell proliferation, while repressing the transcription of tok, a growth inhibitor.
Editorial Material
Hematology
Amit Khot
Summary: In this study, Schavgoulidze et al validate the importance of the cytogenetic abnormality del(1p32) in risk stratification for newly diagnosed multiple myeloma (NDMM) patients. The study also identifies an ultra high-risk group (UHR) with biallelic deletion, who show significantly adverse outcomes after current standard frontline treatment.
Editorial Material
Oncology
Melissa Ng Liet Hing, Amit Khot
LEUKEMIA & LYMPHOMA
(2023)
Article
Oncology
Thomas E. Lew, Edward R. Scheffer Cliff, Michael Dickinson, Constantine S. Tam, John F. Seymour, Piers Blombery, Ashish Bajel, David Ritchie, Amit Khot
Summary: Cytarabine-containing chemoimmunotherapy followed by autologous transplantation and rituximab maintenance achieves durable remissions for most patients with mantle cell lymphoma (MCL). However, patients with TP53-mutated disease have poor outcomes with standard approaches. Allogeneic stem cell transplantation (alloSCT) can be curative in MCL, including patients with TP53-mutated disease, and should be considered as an earlier treatment option for this subgroup.
LEUKEMIA & LYMPHOMA
(2023)
Article
Multidisciplinary Sciences
Donald P. Cameron, Jan Grosser, Swetlana Ladigan, Vladislav Kuzin, Evanthia Iliopoulou, Anika Wiegard, Hajar Benredjem, Kathryn Jackson, Sven T. Liffers, Smiths Lueong, Phyllis F. Cheung, Deepak Vangala, Michael Pohl, Richard Viebahn, Christian Teschendorf, Heiner Wolters, Selami Usta, Keyi Geng, Claudia Kutter, Marie Arsenian-Henriksson, Jens T. Siveke, Andrea Tannapfel, Wolff Schmiegel, Stephan A. Hahn, Laura Baranello
Summary: This study demonstrates that concurrent inhibition of TOP1 and BRD4 can synergistically induce tumor regression in pancreatic carcinoma, with a specific effect on cancer cells.
Review
Hematology
Thomas E. Lew, Adrian Minson, Michael Dickinson, Sasanka M. Handunnetti, Piers Blombery, Amit Khot, Mary Ann Anderson, David Ritchie, Constantine S. Tam, John F. Seymour
Summary: Mantle cell lymphoma is a rare and heterogeneous subtype of lymphoma. TP53 mutations have a strong association with early disease progression and death among patients receiving conventional chemoimmunotherapy, making it an important prognostic factor. Poor outcomes for TP53-mutated mantle cell lymphoma patients receiving chemoimmunotherapy and second-line Bruton tyrosine kinase inhibitors call for alternative approaches. This review synthesises available data and presents a treatment strategy prioritising clinical trials and early use of cellular therapies for this high-risk subset of patients.
LANCET HAEMATOLOGY
(2023)
Meeting Abstract
Oncology
Jessica Crowe, Lara Edbrooke, Amit Khot, Linda Denehy, Jill Francis
ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY
(2022)
Review
Oncology
Stephin J. Vervoort, Jennifer R. Devlin, Nicholas Kwiatkowski, Mingxing Teng, Nathanael S. Gray, Ricky W. Johnstone
Summary: Accurate control of gene expression is crucial for normal development and any dysregulation can lead to cancer initiation and progression. The transcription process can be viewed as a multistep cycle, with dysregulation potentially causing defective gene expression control in cancer. Targeting transcriptional cyclin-dependent kinases and associated proteins may hold promise for cancer treatment by disrupting global or selective transcription.
NATURE REVIEWS CANCER
(2022)