Article
Multidisciplinary Sciences
Michael DeBerardine, Gregory T. Booth, Philip P. Versluis, John T. Lis
Summary: Promoter-proximal pausing by RNA Pol II is a critical aspect of transcriptional regulation in higher eukaryotes. The study shows that only NELF-mediated pausing enforces a strict early checkpoint for Cdk9, shutting down gene transcription efficiently. NELF-depleted cells in Drosophila melanogaster recapitulate the NELF-independent pausing observed in fission yeast. Importantly, only NELF-mediated pausing requires Cdk9 kinase activity for the release of paused Pol II into productive elongation.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Ebtihal H. Mustafa, Geraldine Laven-Law, Zoya Kikhtyak, Van Nguyen, Simak Ali, Alex A. Pace, Richard Iggo, Alemwork Kebede, Ben Noll, Shudong Wang, Jean M. Winter, Amy R. Dwyer, Wayne D. Tilley, Theresa E. Hickey
Summary: Targeting transcription via CDK9 could be a potential therapeutic strategy for TNBC. Preclinical studies showed that a selective CDK9 inhibitor, CDDD11-8, effectively inhibited proliferation, induced cell cycle arrest, and increased apoptosis of TNBC cells in vitro and in vivo, without apparent toxicity to normal tissues.
Review
Oncology
Ranadip Mandal, Sven Becker, Klaus Strebhardt
Summary: CDK9, in combination with Cyclin T1, plays a crucial role in RNA Polymerase II mediated transcription. Enhanced CDK9 activity in various cancers is associated with poor prognosis, leading to the development of small-molecule inhibitors targeting CDK9. Research is ongoing to develop more specific inhibitors and explore combination therapies with other regulators to enhance anti-cancer effects.
Article
Pharmacology & Pharmacy
Chen Hua, Lijuan Shena, Fengming Zoua, Yun Wua, Beilei Wanga, Aoli Wanga, Chao Wud, Li Wanga, Jing Liua, Wenchao Wanga, Qingsong Liua
Summary: The study reveals a novel resistance mechanism for CDK9 inhibitors mediated by the L156F mutation, which disrupts the binding of inhibitors with CDK9 due to steric hindrance, and affects the thermal stability and catalytic activity of CDK9 protein. A new compound IHMT-CDK9-36 showed potent inhibition activity for both CDK9 WT and L156F mutant, providing a new chemical scaffold for the future development of CDK9 inhibitors.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Pathology
Xu Wang, Xiaolin Wei, Yu Cao, Peng Xing
Summary: Overexpression of ZNF33A in triple-negative breast cancer is associated with worse prognosis, promoting cell growth and resistance to BET inhibitors. ZNF33A also induces c-Myc, a key player in BET inhibitor resistance. Thus, inhibition of ZNF33A may enhance sensitivity of TNBC cells to BET inhibitors.
AMERICAN JOURNAL OF PATHOLOGY
(2022)
Review
Oncology
Abel Tesfaye Anshabo, Robert Milne, Shudong Wang, Hugo Albrecht
Summary: Cyclin-dependent kinases play a crucial role in cancer development, particularly in cell division and transcription. Dysregulation of the CDK9 pathway has been observed in various hematological and solid malignancies, making it a valuable anticancer target.
FRONTIERS IN ONCOLOGY
(2021)
Article
Chemistry, Medicinal
Dan Wei, Hanlin Wang, Qinghe Zeng, Wenjing Wang, Bingbing Hao, Xule Feng, Peipei Wang, Ning Song, Weijuan Kan, Guifang Huang, Xiaoyu Zhou, Minjia Tan, Yubo Zhou, Ruimin Huang, Jia Li, Xiao-Hua Chen
Summary: TNBC is highly aggressive and clinically challenging due to limited treatment options. Targeting transcription-associated CDK9 with a novel degrader compound shows great promise in inhibiting TNBC cell growth and inducing apoptosis by downregulating transcriptional targets like MYC. This study establishes compound 45 as a potent and efficacious CDK9 degrader for potential targeted therapy in TNBC.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Toshihiko Takeiwa, Kazuhiro Ikeda, Takashi Suzuki, Wataru Sato, Kaori Iino, Yuichi Mitobe, Hidetaka Kawabata, Kuniko Horie, Satoshi Inoue
Summary: Breast cancer is the most common cancer type among women worldwide. Endocrine therapy is the standard treatment for ER-positive breast cancer, but therapy resistance remains a challenge. This study found that the RNA-binding protein PSPC1 plays a crucial role in the growth of ER-positive breast cancer and is involved in post-transcriptional gene regulation. The interaction between PSPC1, PSF, and SCFD2 suggests that these genes could be potential targets for the clinical management of the disease.
SCIENTIFIC REPORTS
(2022)
Article
Materials Science, Biomaterials
Zhe Zhang, Xiaoyi Zhang, Zhaojun Ren, Xiaoliu Wu, Haishi Qiao, Xin Huang, Wei Zhao, Yuanying Zhang, Kexin Lou
Summary: In this study, CDK9 inhibitor (CI) and BRD4 inhibitor (BI) were co-delivered by macrophage membrane-encapsulated black phosphorus nanosheets (M@BP) for the treatment of gastric cancer with high expression of BRD4 and CDK9. The combination of CI and BI could efficiently inhibit tumor progression, and the antitumor activity could be further enhanced upon near-infrared irradiation. M@BP exhibited tumor-targeting capability and high drug loading efficiency, effectively blocking CDK9 and BRD4 activation without systemic toxicity in an orthotopic gastric cancer model.
JOURNAL OF MATERIALS CHEMISTRY B
(2023)
Article
Multidisciplinary Sciences
Rishi K. Vishwakarma, M. Zuhaib Qayyum, Paul Babitzke, Katsuhiko S. Murakami
Summary: NusG is a transcription elongation factor that induces transcription pausing in bacteria by interacting with a specific sequence in the non-template DNA strand. The interaction between NusG and the DNA rearranges the transcription bubble and affects the conformational changes of RNA polymerase, leading to the inhibition of RNA synthesis. This mechanism of pausing is widely conserved in bacteria.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Maria del Mar Noblejas-Lopez, Lucia Gandullo-Sanchez, Eva M. Galan-Moya, Raquel Lopez-Rosa, David Tebar-Garcia, Cristina Nieto-Jimenez, Monica Gomez-Juarez, Miguel Burgos, Atanasio Pandiella, Alberto Ocana
Summary: This article explores the antitumoral activity of a novel compound against CDK9 in breast cancer cells, showing significant inhibitory effects in certain subtypes and particular sensitivity in trastuzumab-resistant cell lines.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Multidisciplinary Sciences
Liliana Garcia-Martinez, Yusheng Zhang, Yuichiro Nakata, Ho Lam Chan, Lluis Morey
Summary: The majority of breast cancers express the estrogen receptor and endocrine therapy has been the mainstay for hormone-responsive breast cancer treatment. Recent studies have shown the importance of the epigenome in determining hormone therapy response and how targeting epigenetic factors can help overcome clinical resistance. Understanding epigenetic mechanisms regulating ER+ breast cancer and endocrine therapy resistance is crucial for improving targeted therapies for this type of cancer.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Chirangini Pukhrambam, Vadim Molodtsov, Mahdi Kooshkbaghi, Ammar Tareen, Hoa Vu, Kyle S. Skalenko, Min Su, Zhou Yin, Jared T. Winkelman, Justin B. Kinney, Richard H. Ebright, Bryce E. Nickels
Summary: In sigma-dependent transcriptional pausing, the presence or absence of GreB determines whether the paused state involves backtracking or scrunched by 2-4 base pairs or 2-3 base pairs respectively. The consensus sequence T(-3)N(-2)Y(-1)G(+1) is associated with pausing in both initial transcription and transcription elongation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Wen-Li Huang, Tuersunayi Abudureheman, Jing Xia, Lei Chu, Hang Zhou, Wei-Wei Zheng, Neng Zhou, Rong-Yi Shi, Ming-Hao Li, Jian-Min Zhu, Kai Qing, Chao Ji, Kai-Wei Liang, Sa Guo, Gang Yin, Cai-Wen Duan
Summary: The study demonstrates that CDK9 inhibitors induce apoptosis in B-ALL cells by inhibiting c-Myc-mediated glycolytic metabolism, providing a new therapeutic strategy for B-ALL treatment.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Chemistry, Medicinal
Tizhi Wu, Xiaowei Wu, Yifan Xu, Rui Chen, Jubo Wang, Zhiyu Li, Jinlei Bian
Summary: The dysregulation of CDK9 protein is closely associated with the proliferation and differentiation of various cancers, and targeting CDK9 is considered a promising strategy for antitumor drug development. The development of selective CDK9 inhibitors has gained increasing attention due to the potential side effects of pan-CDK9 inhibitors.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2023)
Editorial Material
Oncology
Michael Flood, Robert Ramsay, Alexander Heriot
ANNALS OF SURGICAL ONCOLOGY
(2022)
Article
Surgery
Michael P. Flood, Peadar S. Waters, Mikael Soucisse, Robert Ramsay, Michael Michael, Jacob J. McCormick, Satish Warrier, Alexander Heriot
Summary: Pelvic exenteration combined with CRS and HIPEC for PSM in a tertiary referral centre is feasible and safe, with no significant difference in perioperative major morbidity and mortality compared to PE alone. The majority of patients were female with colorectal cancer being the predominant pathology, and complete resection was achieved in all patients.
LANGENBECKS ARCHIVES OF SURGERY
(2021)
Article
Oncology
Michael P. Flood, Peadar S. Waters, Michael E. Kelly, Conor Shields, John Conneely, Robert Ramsay, Michael Michael, Benjamin Loveday, Satish K. Warrier, Jurgen Mulsow, Alexander G. Heriot
Summary: The study evaluated the perioperative and oncological outcomes of synchronous liver resection, cytoreductive surgery, and HIPEC for CRLM and CRPM patients. It found that performing these procedures in selected patients with low-volume CRPM and CRLM is feasible and associated with survival rates. Increased PCI is correlated with postoperative major morbidity, highlighting the importance of considering this factor during operative planning.
SURGICAL ONCOLOGY-OXFORD
(2021)
Article
Multidisciplinary Sciences
Emma Petley, Hui-Fern Koay, Melissa A. Henderson, Kevin Sek, Kirsten L. Todd, Simon P. Keam, Junyun Lai, Imran G. House, Jasmine Li, Magnus Zethoven, Amanda X. Y. Chen, Amanda J. Oliver, Jessica Michie, Andrew J. Freeman, Lauren Giuffrida, Jack D. Chan, Angela Pizzolla, Jeffrey Y. W. Mak, Timothy R. McCulloch, Fernando Souza-Fonseca-Guimaraes, Conor J. Kearney, Rosemary Millen, Robert G. Ramsay, Nicholas D. Huntington, James McCluskey, Jane Oliaro, David P. Fairlie, Paul J. Neeson, Dale Godfrey, Paul A. Beavis, Phillip K. Darcy
Summary: The study reveals that activated MAIT cells can induce an IFN-gamma transcriptome in NK cells and enhance NK-dependent anti-cancer immunity in mice, suggesting a new potential avenue for cancer therapy.
NATURE COMMUNICATIONS
(2021)
Editorial Material
Oncology
Michael Flood, Vignesh Narasimhan, Kasmira Wilson, Wei Mou Lim, Robert Ramsay, Michael Michael, Alexander Heriot
ANNALS OF SURGICAL ONCOLOGY
(2022)
Article
Oncology
Michael P. Flood, Joseph C. Kong, Toan Pham, Peadar S. Waters, Mikael Soucisse, Robert Ramsay, Hui-Li Wong, Catherine Mitchell, Michael Michael, Jacob J. McCormick, Satish K. Warrier, Tim Akhurst, Alexander G. Heriot
Summary: The study aimed to assess the ability of preoperative PET in predicting the histological grade of pseudomyxoma peritonei (PMP). The results showed that preoperative PET had a positive correlation with high-grade PMP and acceptable sensitivity and specificity as a diagnostic tool. Therefore, PET should be considered a useful adjunct to predict the histological grade in the staging of PMP patients.
Article
Multidisciplinary Sciences
Mahmoud A. Bassal, Saumya E. Samaraweera, Kelly Lim, Brooks A. Bernard, Sheree Bailey, Satinder Kaur, Paul Leo, John Toubia, Chloe Thompson-Peach, Tran Nguyen, Kyaw Ze Ya Maung, Debora A. Casolari, Diana G. Iarossi, Ilaria S. Pagani, Jason Powell, Stuart Pitson, Siria Natera, Ute Roessner, Ian D. Lewis, Anna L. Brown, Daniel G. Tenen, Nirmal Robinson, David M. Ross, Ravindra Majeti, Thomas J. Gonda, Daniel Thomas, Richard J. D'Andrea
Summary: This study reveals the mutual exclusivity between germline mutations in mitochondrial complex I and somatic mutations in the metabolic enzyme IDH1 in patients with acute myeloid leukemia (AML), and finds that IDH1 mutant cells have increased sensitivity to complex I inhibitors.
NATURE COMMUNICATIONS
(2022)
Article
Oncology
Shienny Sampurno, Timothy Chittleborough, Meara Dean, Michael Flood, Sandra Carpinteri, Sara Roth, Rosemary M. Millen, Helen Cain, Joseph C. H. Kong, John MacKay, Satish K. Warrier, Jacob McCormick, Jonathon G. Hiller, Alexander G. Heriot, Robert G. Ramsay, Andrew C. Lynch
Summary: This study compares the effects of different insufflation methods on patients undergoing colorectal cancer surgery and finds that dry-cold-carbon-dioxide insufflation leads to more peritoneal damage, inflammation, and hypothermia. The use of humidified-warm-CO2 insufflation can restore body temperature, reduce hospital stay, and protect peritoneal cells.
ANNALS OF SURGICAL ONCOLOGY
(2022)
Editorial Material
Oncology
Shienny Sampurno, Timothy Chittleborough, Meara Dean, Michael Flood, Sandra Carpinteri, Sara Roth, Rosemary M. Millen, Helen Cain, Joseph C. H. Kong, John MacKay, Satish K. Warrier, Jacob McCormick, Jonathon G. Hiller, Alexander G. Heriot, Robert G. Ramsay, Andrew C. Lynch
ANNALS OF SURGICAL ONCOLOGY
(2022)
Editorial Material
Oncology
Robert G. Ramsay, Michael Flood
Summary: Colorectal peritoneal metastases (CRPM) can develop resistance to oxaliplatin, a commonly used chemotherapy agent for hyperthermic intraperitoneal chemotherapy (HIPEC). However, genomic deletion or pharmacological inhibition of glutamate-cysteine ligase in CRPM tumors can effectively reduce the inactivation of oxaliplatin mediated by glutathione. These findings may reignite interest in combining HIPEC with cytoreductive surgery for the management of this previously considered incurable stage-IV disease.
BRITISH JOURNAL OF CANCER
(2022)
Article
Oncology
Michael P. Flood, Anshini Jain, Catherine Mitchell, Chelsee Hewitt, Robert Ramsay, Michael Michael, Alexander G. Heriot, Jeanne Tie
Summary: This study highlights the importance of molecular analysis in stratifying patients with colorectal peritoneal metastases. BRAF V600E mutation predicts poor outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy and may help refine patient selection. Preoperative molecular analysis should be performed to determine prognosis and guide perioperative therapeutic options.
Article
Oncology
Robert Ramsay, Shienny Sampurno, Michael P. Flood, Andrew C. Lynch
ANNALS OF SURGICAL ONCOLOGY
(2023)
Article
Oncology
Marija Dinevska, Samuel S. Widodo, Liam Furst, Lucero Cuzcano, Yitong Fang, Stefano Mangiola, Paul J. Neeson, Phillip K. Darcy, Robert G. Ramsay, Ryan Hutchinson, Fabienne MacKay, Michael Christie, Stanley S. Stylli, Theo Mantamadiotis
Summary: Tumor microenvironment in malignant astrocytoma undergoes changes in cell composition, cell signaling activation, and extracellular matrix deposition during disease progression. Targeting the extracellular matrix and cell signaling activation will be critical in designing personalized therapy.
Editorial Material
Hematology
Thomas J. Gonda
Summary: Clarke et al(1) demonstrate in this study that loss of 1 allele of Myb in mice leads to increased myeloproliferation and development of myeloid neoplasms, including AML, during aging. This is surprising given the established role of MYB in normal hematopoiesis and leukemogenesis. These findings suggest that even partial loss of MYB activity can predispose individuals to myeloid neoplasms.
Review
Cell Biology
Robert G. Ramsay, Vicki Whitehall, Michael P. Flood
Summary: Adoption of organoid/tumoroid propagation of normal and malignant intestinal epithelia has provided unprecedented opportunities to compare cell growth factor and signaling dependencies. These 3D structures mimic tumors in terms of gene expression and offer deeper insights into the tumor microenvironment (TME). Manipulation of TME elements and evaluation of different therapies can be done using patient-derived tumor models.