Review
Pharmacology & Pharmacy
Xing Bian, Chuanbo Sun, Jin Cheng, Bo Hong
Summary: This review article discusses the functional role of the DNA repair system in cancer development and progression and explores strategies that target DNA damage repair proteins. Additionally, it highlights compounds currently being evaluated for their efficacy in endometrial cancer treatment and proposes immunotherapeutic approaches targeting immune checkpoint proteins.
Article
Biochemistry & Molecular Biology
Ke Cong, Sharon B. Cantor
Summary: Defects in DNA double-strand break repair, such as BRCA1 or BRCA2 mutations, make tumors selectively sensitive to PARP inhibitors. However, BRCA and PARP1 also share functions in DNA synthesis on the lagging strand, suggesting that BRCA deficiency may be due to an inherent problem in lagging strand synthesis.
Review
Cell Biology
Jinhua Zhang, Jing Si, Lu Gan, Rong Zhou, Menghuan Guo, Hong Zhang
Summary: Radiotherapy is a major modality for cancer treatment, with high LET charged-particle beams showing favorable depth-dose distributions and radiobiological enhancement. Tumor cells manage ionizing radiation-induced DNA lesions through DNA damage responses (DDRs) and double-strand break (DSB) repair mechanisms. Inhibitors of DNA repair pathways can sensitize tumor cells to radiation and enhance cell killing.
JOURNAL OF CELLULAR PHYSIOLOGY
(2021)
Review
Oncology
Liqin Wang, Lina Lankhorst, Rene Bernards
Summary: This review discusses how senescence can be induced in cancer cells and how the distinctive features of senescent cancer cells can be exploited for selective eradication. It also explores activation of the host immune system as an attractive way to clear senescent cancer cells, and the potential benefits of a sequential treatment approach with pro-senescence therapy followed by senolytic therapy.
NATURE REVIEWS CANCER
(2022)
Article
Chemistry, Medicinal
Shu-Ping Wang, Yu Li, Shi-Hui Huang, Shi-Qi Wu, Ling-Li Gao, Qin Sun, Qian-Wen Lin, Lei Huang, Liu-Qiong Meng, Yi Zou, Qi-Hua Zhu, Yun-Gen Xu
Summary: Targeting PARP1/2 and BRD4 with the novel dual inhibitor III-16 showed promising synergistic antitumor efficacy in pancreatic cancer, suggesting it as a potential treatment option for advanced pancreatic cancer.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Oncology
Liliana Raimundo, Juliana Calheiros, Lucilia Saraiva
Summary: Chemical inhibition of central DDR proteins, especially BRCA1, has become a promising approach in precision cancer therapy. PARPi, as a targeted therapy, exploits cancer cells' inability to repair DNA damage. However, drug resistance and the search for additional agents targeting DDR remain crucial for advancing precision cancer medicine.
Article
Oncology
Yen-Yun Wang, Amos C. Hung, Steven Lo, Ya-Ching Hsieh, Shyng-Shiou F. Yuan
Summary: MRE11 plays a crucial role in DNA damage response and its expression in cancer cells is linked to radioresistance, making it a potential marker for radiosensitization strategies. Elevated MRE11 in tumor tissues has been associated with poor survival in radiotherapy patients, although recent findings of ionizing radiation-induced truncation of MRE11 may explain some conflicting observations. Advancements in understanding the biological modulation of MRE11 expression and the potential application of inhibitors for enhancing radiosensitivity are discussed, highlighting the importance of distinguishing between nuclease and non-nuclease activities of MRE11 in cancer cells treated with ionizing radiation.
Article
Oncology
Zachary Quinn, Benjamin Leiby, Guru Sonpavde, Atish D. Choudhury, Christopher Sweeney, David Einstein, Russell Szmulewitz, Oliver Sartor, Karen Knudsen, Eddy Shih-Hsin Yang, Wm. Kevin Kelly
Summary: The purpose of this study was to evaluate the safety of combining Radium-223 with the PARP inhibitor niraparib for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) in patients without known BRCA mutations. The results showed that the combination of niraparib and Radium-223 was safe in patients.
CLINICAL CANCER RESEARCH
(2023)
Review
Oncology
Paulina Tokarz, Katarzyna Wozniak
Summary: SUMOylation is a reversible post-translational modification involving the covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. SENPs are cysteine proteases with isopeptidase activity that facilitate the de-conjugation of SUMO proteins. Aberrant expression of SENPs is associated with cancer development and progression. The design and development of SENP inhibitors, including synthetic, peptide-based, small molecular weight, and naturally occurring compounds, have shown promise in anticancer treatment.
Article
Oncology
Ling Li, Bao-jia Zou, Juan-zhi Zhao, Jia-bi Liang, Zi-yue She, Wen-ying Zhou, Si-xiao Lin, Lin Tian, Wen-ji Luo, Fa-zhong He
Summary: This study systematically analyzes the relationship between DDR alterations and NSCLC prognosis, establishes a six-DDR gene prognostic model, and finds that high-risk patients are more responsive to immunotherapy while low-risk patients are more sensitive to DNA-damaging chemotherapy drugs.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Dimitra T. Stefanou, Marousa Kouvela, Dimitris Stellas, Konstantinos Voutetakis, Olga Papadodima, Konstantinos Syrigos, Vassilis L. Souliotis
Summary: The deregulated DNA damage response network is associated with the onset and progression of lung cancer. This study found that lung cancer patients have higher levels of endogenous DNA damage, which may be caused by oxidative stress and defective DNA repair mechanisms. The findings suggest that oxidative stress and DDR-related aberrations contribute to the accumulation of endogenous DNA damage in lung cancer patients.
Review
Biochemistry & Molecular Biology
Alexandra Wagner, Helena Kosnacova, Miroslav Chovanec, Dana Jurkovicova
Summary: Mitochondria play a crucial role in cellular metabolism and bioenergetics, and are involved in cancer development and treatment response. Studying the genetic and epigenetic control of mitochondria can provide insights into cancer therapy response and aid in the development of new therapeutic strategies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Editorial Material
Oncology
Ramona Rudalska, Lars Zender, Daniel Dauch
Summary: Metabolic alterations are common in solid tumors, but therapeutic approaches are hindered by the complexity and adaptability of metabolic networks. A recent study demonstrated that targeting the liver X receptor alpha (LXRα) and inhibiting a Raf-1-SCD1 protein complex can induce lethal lipotoxicity in tumor cells, offering a promising treatment avenue for liver carcinomas.
BRITISH JOURNAL OF CANCER
(2021)
Article
Biochemistry & Molecular Biology
Luis R. Raposo, Ana Silva, Dario Silva, Catarina Roma-Rodrigues, Margarida Espadinha, Pedro Baptista, Maria M. M. Santos, Alexandra R. Fernandes
Summary: This study assessed the antiproliferative activity of five spiropyrazoline oxindoles in ovarian cancer cells and identified a compound with the highest effectiveness and selectivity. The compound induced cell death through mitochondria-mediated apoptosis and autophagy, with interaction with DNA by groove-binding without genotoxicity. Proteomic studies revealed the compound's role in promoting ER stress and triggering cell death in ovarian cancer cells.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Feifei Wang, Odjo G. Gouttia, Ling Wang, Aimin Peng
Summary: First-line treatments for oral cancer include surgery, radiation, and chemotherapy. However, tumor recurrence and acquired resistance remain major challenges. PARP1 upregulation in recurrent tumor cells was found, and PARP inhibitors were shown to partially reverse treatment resistance.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Bernhard Luscher, Ivan Ahel, Matthias Altmeyer, Alan Ashworth, Peter Bai, Paul Chang, Michael Cohen, Daniela Corda, Francoise Dantzer, Matthew D. Daugherty, Ted M. Dawson, Valina L. Dawson, Sebastian Deindl, Anthony R. Fehr, Karla L. H. Feijs, Dmitri V. Filippov, Jean-Philippe Gagne, Giovanna Grimaldi, Sebastian Guettler, Nicolas C. Hoch, Michael O. Hottiger, Patricia Korn, W. Lee Kraus, Andreas Ladurner, Lari Lehtio, Anthony K. L. Leung, Christopher J. Lord, Aswin Mangerich, Ivan Matic, Jason Matthews, George-Lucian Moldovan, Joel Moss, Gioacchino Natoli, Michael L. Nielsen, Mario Niepel, Friedrich Nolte, John Pascal, Bryce M. Paschal, Krzysztof Pawlowski, Guy G. Poirier, Susan Smith, Gyula Timinszky, Zhao-Qi Wang, Jose Yelamos, Xiaochun Yu, Roko Zaja, Mathias Ziegler
Summary: ADP-ribosylation, a post-translational modification of proteins, nucleic acids, and metabolites, plays diverse roles in cellular processes such as stress responses, signaling, and transcriptional regulation. Recent advances in research have identified a wide range of cellular pathways regulated by ADP-ribosylation, highlighting the importance of understanding this mechanism in cell biology.
Article
Cell Biology
Dragomir B. Krastev, Shudong Li, Yilun Sun, Andrew Wicks, Gwendoline Hoslett, Daniel Weekes, Luned M. Badder, Eleanor G. Knight, Rebecca Marlow, Mercedes Pardo Calvo, Lu Yu, Tanaji T. Talele, Jiri Bartek, Jyoti Choudhary, Yves Pommier, Stephen J. Pettitt, Andrew Tutt, Kristijan Ramadan, Christopher J. Lord
Summary: The study reveals the regulatory mechanism of trapped PARP1, which is undergoes SUMOylation and ubiquitylation, leading to the recruitment of p97 ATPase for the removal of trapped PARP1 from chromatin and prevention of PARP inhibitor-induced cytotoxicity. Inhibitors targeting p97-complex prolong the trapping of PARP1, enhancing the cytotoxicity of PARP inhibitors in certain types of tumor cells.
NATURE CELL BIOLOGY
(2022)
Review
Oncology
K. Van Baelen, T. Geukens, M. Maetens, V Tjan-Heijnen, C. J. Lord, S. Linn, F-C Bidard, F. Richard, W. W. Yang, R. E. Steele, S. J. Pettitt, C. Van Ongeval, M. De Schepper, E. Isnaldi, I Nevelsteen, A. Smeets, K. Punie, L. Voorwerk, H. Wildiers, G. Floris, A. Vincent-Salomon, P. W. B. Derksen, P. Neven, E. Senkus, E. Sawyer, M. Kok, C. Desmedt
Summary: ILC is a unique type of breast cancer with distinct pathological and biological features, leading to differences in diagnosis, treatment response, resistance, and targets compared to NST.
ANNALS OF ONCOLOGY
(2022)
Article
Oncology
I Vergote, A. Gonzalez-Martin, I Ray-Coquard, P. Harter, N. Colombo, P. Pujol, D. Lorusso, M. R. Mirza, B. Brasiuniene, R. Madry, J. D. Brenton, M. G. E. M. Ausems, R. Buettner, D. Lambrechts
Summary: This study aimed to establish a European-wide consensus on genetic testing and clinical management for patients with newly diagnosed advanced ovarian cancer, as well as biomarkers for predicting the effectiveness of PARPi in first-line treatment. The consensus recommendations, based on input from experts across Europe, provide clear guidance on BRCA and HRR deficiency testing for these patients.
ANNALS OF ONCOLOGY
(2022)
Review
Oncology
Joseph S. Baxter, Diana Zatreanu, Stephen J. Pettitt, Christopher J. Lord
Summary: The DNA damage response is a complex protein network that detects and repairs DNA damage, preventing cancer. PARP inhibitors are effective in treating cancer, and new DDR targets are being investigated. Drug resistance is a problem in cancer treatment, and there is some understanding of PARPi resistance.
MOLECULAR ONCOLOGY
(2022)
Article
Oncology
Violeta Serra, Anderson T. Wang, Marta Castroviejo-Bermejo, Urszula M. Polanska, Marta Palafox, Andrea Herencia-Ropero, Gemma N. Jones, Zhongwu Lai, Joshua Armenia, Filippos Michopoulos, Alba Llop-Guevara, Rachel Brough, Aditi Gulati, Stephen J. Pettitt, Krishna C. Bulusu, Jenni Nikkila, Zena Wilson, Adina Hughes, Paul W. G. Wijnhoven, Ambar Ahmed, Alejandra Bruna, Albert Gris-Oliver, Marta Guzman, Olga Rodriguez, Judit Grueso, Joaquin Arribas, Javier Cortes, Cristina Saura, Alan Lau, Susan Critchlow, Brian Dougherty, Carlos Caldas, Gordon B. Mills, J. Carl Barrett, Josep V. Forment, Elaine Cadogan, Christopher J. Lord, Cristina Cruz, Judith Balmana, Mark J. O'Connor
Summary: Targeting the replication stress response is a valid therapeutic option to overcome PARPi resistance, providing new strategies for treating tumors such as breast and ovarian cancer.
CLINICAL CANCER RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Elise Rouleau-Turcotte, Dragomir B. Krastev, Stephen J. Pettitt, Christopher J. Lord, John M. Pascal
Summary: PARP1 can rapidly detect DNA strand break damage and activate the production of poly(ADP-ribose) by signaling break detection to its catalytic domain. This study provides insights into the contributions of the regulatory helical domain (HD) to PARP1 allostery and the interaction with DNA damage, as well as the mechanisms of PARP1 catalytic activation and retention on DNA damage.
Article
Biochemistry & Molecular Biology
Dalia Tarantino, Callum Walker, Daniel Weekes, Helen Pemberton, Kathryn Davidson, Gonzalo Torga, Jessica Frankum, Ana M. Mendes-Pereira, Cynthia Prince, Riccardo Ferro, Rachel Brough, Stephen J. Pettitt, Christopher J. Lord, Anita Grigoriadis, Andrew N. J. Tutt
Summary: HORMAD1 expression is usually limited to germline cells, but it becomes mis-expressed in epithelial cells in triple-negative breast cancers, leading to increased genomic instability. Through cell line modeling and small interfering RNA screening, we identified candidate genes associated with cellular growth in HORMAD1-expressing cells. Our study reveals the dependency of replication stress tolerance pathways on HORMAD1 expression, providing potential new approaches for treating this disease group.
Review
Biochemistry & Molecular Biology
Andrew J. Wicks, Dragomir B. Krastev, Stephen J. Pettitt, Andrew N. J. Tutt, Christopher J. Lord
Summary: PARP inhibitors have shown significant anti-tumor activity in patients with defects in the DNA repair pathway. Improving patient stratification, early detection of drug resistance, and predicting toxicity are important for the use of PARP inhibitors. The discussion also focuses on potential treatments for PARP inhibitor resistance.
Article
Oncology
Marta J. Llorca-Cardenosa, Lauren I. Aronson, Dragomir B. Krastev, Jadwiga Nieminuszczy, John Alexander, Feifei Song, Malgorzata Dylewska, Ronan Broderick, Rachel Brough, Astrid Zimmermann, Frank T. Zenke, Bora Gurel, Ruth Riisnaes, Ana Ferreira, Theodoros Roumeliotis, Jyoti Choudhary, Stephen J. Pettitt, Johann de Bono, Andres Cervantes, Syed Haider, Wojciech Niedzwiedz, Christopher J. Lord, Irene Y. Chong
Summary: The study highlights the potential issue of drug resistance in using ATR inhibitors in gastric cancer, particularly with loss-of-function mutations in SMG8 and SMG9, and suggests that targeting these pathways may enhance the overall effectiveness of ATRi.
Correction
Oncology
K. Van Baelen, T. Geukens, M. Maetens, V. Tjan-Heijnen, C. J. Lord, S. Linn, F. -C. Bidard, F. Richard, W. W. Yang, R. E. Steele, S. J. Pettitt, C. Van Ongeval, M. De Schepper, E. Isnaldi, I. Nevelsteen, A. Smeets, K. Punie, L. Voorwerk, H. Wildiers, G. Floris, A. Vincent Salomon, P. W. B. Derksen, P. Neven, E. Senkus, E. Sawyer, M. Kok, C. Desmedt
ANNALS OF ONCOLOGY
(2023)
Meeting Abstract
Oncology
Diana Zatreanu, Helen Robinson, Omar Alkhatib, Marie Boursier, Harry Finch, Lerin Geo, Diego Grande, Vera Grinkevich, Robert Heald, Sophie Langdon, Jayesh Majithiya, Claire McWhirter, Niall Martin, Shaun Moore, Joana Neves, Eeson Rajendra, Marco Ranzani, Theresia Schaedler, Martin Stockley, Kimberley Wiggins, Rachel Brough, Sandhya Sridhar, Aditi Gulati, Nan Shao, Luted Badder, Daniela Novo, Eleanor Knight, Rebecca Marlow, Syed Haider, Elsa Callen, Graeme Hewitt, Joost Schimmel, Remko Prevo, Christina Alli, Amanda Ferdinand, Cameron Bell, Peter Blencowe, Chris Bot, Mathew Calder, Mark Charles, Jayne Curry, Tennyson Ekwuru, Andre Nussenzweig, Marcel Tijsterman, Andrew N. Tutt, Simon Boulton, Geoff Higgins, Stephen J. Pettitt, Graeme C. Smith, Christopher J. Lord
Meeting Abstract
Oncology
Diana Zatreanu, Helen Robinson, Omar Alkhatib, Marie Boursier, Harry Finch, Lerin Geo, Diego Grande, Vera Grinkevich, Robert Heald, Sophie Langdon, Jayesh Majithiya, Claire McWhirter, Niall Martin, Shaun Moore, Joana Neves, Eeson Rajendra, Marco Ranzani, Theresia Schaedler, Martin Stockley, Kimberley Wiggins, Rachel Brough, Sandhya Sridhar, Aditi Gulati, Nan Shao, Luted Badder, Daniela Novo, Eleanor Knight, Rebecca Marlow, Syed Haider, Elsa Callen, Graeme Hewitt, Joost Schimmel, Remko Prevo, Christina Alli, Amanda Ferdinand, Cameron Bell, Peter Blencowe, Chris Bot, Mathew Calder, Mark Charles, Jayne Curry, Tennyson Ekwuru, Andre Nussenzweig, Marcel Tijsterman, Andrew N. Tutt, Simon Boulton, Geoff Higgins, Stephen J. Pettitt, Graeme C. Smith, Christopher J. Lord
Meeting Abstract
Oncology
R. Ferro, A. Carroll, A. Mendes-Pereira, V. Reen, I. Roxanis, S. Annunziato, J. Jonkers, N. Liv, J. Alexander, J. Quist, M. Pardo, T. I. Roumeliotis, J. S. Choudhary, D. Weekes, P. Marra, R. Natrajan, A. Grigoriadis, S. Haider, C. J. Lord, A. J. Tutt
EUROPEAN JOURNAL OF CANCER
(2022)
Meeting Abstract
Oncology
Asuka Kawai-Kawachi, Madison Lenormand, Clemence Henon, Thomas Eychenne, Leo Colmet-Daage, Nicolas Dorvault, Marlene Garrido, Clemence Astier, Carine Ngo, Helen Pemberton, Aditi Gulati, Stephen Pettitt, Roman Chabanon, Christopher J. Lord, Sophie Postel-Vinay
