Review
Biochemistry & Molecular Biology
Lucia Haronikova, Ondrej Bonczek, Pavlina Zatloukalova, Filip Kokas-Zavadil, Martina Kucerikova, Philip J. Coates, Robin Fahraeus, Borivoj Vojtesek
Summary: This review discusses the mechanism of action, determinants of sensitivity, and resistance issues of MDM2 inhibitors, emphasizing the need for patient stratification based on these aspects to achieve better clinical responses.
CELLULAR & MOLECULAR BIOLOGY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Kester Mo Henningsen, Valentina Manzini, Anna Magerhans, Sabrina Gerber, Matthias Dobbelstein
Summary: MDM2 can remove p53 from promoters by rapidly terminating its interactions with chromatin in a ubiquitin-dependent manner, in addition to its antagonism through covering the transactivation domain and destabilization.
Review
Medicine, Research & Experimental
Charlie Marvalim, Arpita Datta, Soo Chin Lee
Summary: The transcription factor p53 plays a crucial role in regulating cellular processes and is activated in response to genotoxic stress. In breast cancer, p53's tumor suppressive activities are often compromised by the overexpression of MDM2 or mutation, with the latter being more common in hormone receptor-negative patients. Targeting both wild-type and mutant p53 in different subtypes of breast cancer has potential clinical relevance, and various therapeutic strategies including small molecule inhibitors, peptides, PROTACs, and genetic-based approaches are being developed. This review highlights the ongoing efforts to overcome p53 inactivation in breast tumors and discusses the efficacy and limitations of these therapeutic strategies.
Review
Biochemistry & Molecular Biology
Neha Bhatia, Rakesh Khator, Swanand Kulkarni, Yogesh Singh, Pradeep Kumar, Suresh Thareja
Summary: The discovery of MDM2 and MDM2-p53 interaction inhibitors has revolutionized anticancer research due to their involvement in about 50% of cancer cases globally. In addition to inhibiting MDM2, targeting the interaction between MDM2 and p53 has proven to be an effective strategy for anticancer drug development. Both natural and synthetic molecules have shown promising MDM2 inhibitory potential. This review focuses on the pathophysiology of the MDM2-p53 interaction loop, characteristics of the active site, and the efficacy of various inhibitors from recent patents.
CURRENT MEDICINAL CHEMISTRY
(2023)
Review
Oncology
Arianna Romani, Enrico Zauli, Giorgio Zauli, Saleh AlMesfer, Samar Al-Swailem, Rebecca Voltan
Summary: MDM2 is the main inhibitor of p53, and MDM2 inhibitors can disrupt the physical interaction between MDM2 and p53. The short half-life of p53 in normal cells and tissues may have potential harmful effects if its levels increase uncontrollably. While p53 mutations are rare in retinoblastoma, therapeutic strategies aimed at increasing the expression levels of wild-type p53 are attractive. This minireview discusses the potential use of nutlin-3, a prototype small molecule inhibitor that disrupts the MDM2-p53 interaction, for treating retinoblastoma. The review also explores the relative contribution of p53-mediated gene transcription and mitochondrial perturbation to retinoblastoma treatment.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Antoine Italiano, Wilson H. Miller, Jean-Yves Blay, Jourik A. Gietema, Yung-Jue Bang, Linda R. Mileshkin, Hal W. Hirte, Brian Higgins, Steven Blotner, Gwen L. Nichols, Lin Chi Chen, Claire Petry, Qi Joy Yang, Christophe Schmitt, Candice Jamois, Lillian L. Siu
Summary: Idasanutlin exhibited dose- and schedule-dependent p53 activation in patients with advanced malignancies, leading to durable disease stabilization in some cases. The QD x 5 schedule was chosen for further development based on these findings.
INVESTIGATIONAL NEW DRUGS
(2021)
Article
Chemistry, Multidisciplinary
Wen-fang Li, Leader Alfason, Can Huang, Yu Tang, Li Qiu, Makoto Miyagishi, Shou-rong Wu, Vivi Kasim
Summary: This study reveals that p52-ZER6 may be a potential biomarker for determining patients appropriate for MDM2-p53 binding inhibition-based antitumor therapy, and demonstrates the potential of combinatorial therapy using MDM2-p53 binding inhibitors and p52-ZER6 inhibition.
ACTA PHARMACOLOGICA SINICA
(2023)
Review
Oncology
Xanthene Miles, Charlot Vandevoorde, Alistair Hunter, Julie Bolcaen
Summary: Inhibition of the MDM2/X-p53 interaction as a potential anti-cancer strategy, especially in treating GB, by reactivating p53 plays a central role in cell survival and cancer therapy effectiveness. Suppression of MDM2 presents an opportunity for new therapeutic interventions for GB, with combination with radiation showing promise as a valuable treatment approach.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Konstantina Psatha, Laxmikanth Kollipara, Elias Drakos, Elena Deligianni, Konstantinos Brintakis, Eustratios Patsouris, Albert Sickmann, George Z. Rassidakis, Michalis Aivaliotis
Summary: The activation of wild-type p53 protein in human lymphoma is a promising therapeutic strategy. An in vitro integrative comparative multi-omics analysis of different lymphoma types before and after p53 activation can shed light on the molecular mechanisms involved. Our findings provide valuable insights into the role of specific proteins and pathways in lymphoma pathogenesis and the global effect of nutlin-3a, which can guide targeted studies on lymphoma progression and resistance.
Review
Oncology
Chiao-En Wu, Chiao-Ping Chen, Wen-Kuan Huang, Yi-Ru Pan, Erhan Aptullahoglu, Chun-Nan Yeh, John Lunec
Summary: This article reviews the role of p53 in GIST and proposes targeting the p53 pathway as a novel treatment strategy for GIST.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Tatyana Grigoreva, Aleksandra Sagaidak, Angelina Romanova, Daria Novikova, Aleksander Garabadzhiu, Viacheslav Tribulovich
Summary: The development of chemoresistance in colorectal cancer cells was replicated in vitro by gradually increasing the drug content in the medium, resulting in reduced sensitivity to drugs of different mechanisms of action in resistant cell lines. The cells were found to utilize a universal efflux defense mechanism, which could be partially neutralized by inhibitors of ABC transport proteins, such as P-glycoprotein, confirming its role in chemoresistance.
CHEMICO-BIOLOGICAL INTERACTIONS
(2021)
Review
Oncology
Yier Lu, Meng Wu, Yang Xu, Lili Yu
Summary: Dysfunction of p53 plays a significant role in tumor cell resistance to therapeutic agents. The major mechanisms causing p53 dysfunction are mediated by MDM2/MDMX destabilization and inactivation of wtp53, and somatic p53 mutations. Despite efforts to develop therapeutic strategies to induce wtp53-like activities, their clinical efficacy and safety remain uncertain.
Article
Pharmacology & Pharmacy
Giada Lodi, Valentina Gentili, Fabio Casciano, Arianna Romani, Giorgio Zauli, Paola Secchiero, Enrico Zauli, Carolina Simioni, Silvia Beltrami, Mercedes Fernandez, Roberta Rizzo, Rebecca Voltan
Summary: SARS-CoV viruses downregulate antiviral defenses by manipulating p53, a key molecule for cell homeostasis and immune control. Using MDM2 inhibitors to raise p53 levels can inhibit cell cycle and virus release, as well as reduce the expression of inflammatory cytokines. Therefore, p53 and MDM2 inhibitors may be potential therapies against SARS-CoV-2.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Oncology
Immacolata Maietta, Francesca Del Peschio, Preziosa Buonocore, Eleonora Viscusi, Stefano Laudati, Giuseppe Iannaci, Michele Minopoli, Maria Letizia Motti, Valentina De Falco
Summary: This study aimed to verify whether p90RSK can phosphorylate MDM2 at serine 166 and investigate its role in regulating the p53 pathway, especially in thyroid tumors. It has been demonstrated that p90RSK can bind and phosphorylate MDM2 at serine 166, increasing the stability of MDM2 and promoting its degradation of p53. A pharmacological inhibitor of p90RSK, BI-D1870, can decrease MDM2 phosphorylation, restore p53 function, and inhibit cell proliferation while promoting apoptosis.
Article
Oncology
Atif Zafar, Wei Wang, Gang Liu, Wa Xian, Frank McKeon, Jia Zhou, Ruiwen Zhang
Summary: Neuroblastoma poses a significant challenge in pediatric oncology, with p53 protein playing a key protective role against genome instability. Overexpression of MDM2 in neuroblastoma can lead to p53 inhibition, drug resistance, and other non-canonical p53 functions. Research is focused on restoring p53 function by targeting the p53-MDM2 axis for potential therapeutic strategies.
Article
Biochemistry & Molecular Biology
Shanna Dewaele, Louis Delhaye, Boel De Paepe, Eric James de Bony, Jilke De Wilde, Katrien Vanderheyden, Jasper Anckaert, Nurten Yigit, Justine Nuytens, Eveline Vanden Eynde, Joel Smet, Maxime Verschoore, Fariba Nemati, Didier Decaudin, Manuel Rodrigues, Peihua Zhao, Aart Jochemsen, Eleonora Leucci, Jo Vandesompele, Jo Van Dorpe, Jean-Christophe Marine, Rudy Van Coster, Sven Eyckerman, Pieter Mestdagh
Summary: The inhibition of SAMMSON in uveal melanoma cells has shown to impair cell growth and viability, induce apoptosis, and affect protein translation levels, highlighting its potential as a therapeutic target. This study demonstrates the essential role of SAMMSON expression in uveal melanoma cell survival, suggesting ASO-mediated silencing of SAMMSON as a promising treatment strategy for both primary and metastatic uveal melanoma patients.
Article
Biochemistry & Molecular Biology
Gaelle Houthaeve, Gerardo Garcia-Diaz Barriga, Stephan Stremersch, Herlinde De Keersmaecker, Juan Fraire, Jo Vandesompele, Pieter Mestdagh, Stefaan De Smedt, Kevin Braeckmans, Winnok H. De Vos
Summary: The study investigates the effects of VNB photoporation on cell homeostasis, finding that A-type lamins are upregulated after photoporation and contribute to the recovery of the nucleus. Selective depletion of A-type lamins reduces cell viability, while stimulation of LMNA transcription increases the survival rate of successfully transfected cells.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Multidisciplinary Sciences
Jasper Verwilt, Jan Hellemans, Tom Sante, Pieter Mestdagh, Jo Vandesompele
Summary: This study models and compares pooling methods and sizes using anonymous data, aiming to improve testing efficiency and sensitivity. It also provides an online tool for customized pooling strategy recommendations.
SCIENTIFIC REPORTS
(2022)
Article
Multidisciplinary Sciences
Kathleen Schoofs, Annouck Philippron, Francisco Avila Cobos, Jan Koster, Steve Lefever, Jasper Anckaert, Danny De Looze, Jo Vandesompele, Piet Pattyn, Katleen De Preter
Summary: This study conducted comprehensive RNA analysis of samples from esophageal adenocarcinoma patients, providing a unique resource for studying biomarkers and disease mechanisms. The dataset allows for comparison of tissue and liquid biopsy profiles, integration of coding and non-coding RNA patterns, and can serve as a validation dataset in other RNA landscaping studies.
Review
Medicine, General & Internal
Daniela Drandi, Philippe Decruyenaere, Martina Ferrante, Fritz Offner, Jo Vandesompele, Simone Ferrero
Summary: This review aims to provide a comprehensive overview of molecular biomarkers in Waldenstrom Macroglobulinemia (WM) and IgM gammopathies, and explore their potential applications in precision medicine.
Meeting Abstract
Oncology
K. Schoofs, F. Avila Cobos, A. Philippron, J. Anckaert, P. Pattyn, J. Vandesompele, K. De Preter
ANNALS OF ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Anneleen Decock, David Creytens, Steve Lefever, Joni Van der Meulen, Jasper Anckaert, Ariane De Ganck, Jill Deleu, Bram De Wilde, Carolina Fierro, Scott Kuersten, Manuel Luypaert, Isabelle Rottiers, Gary P. Schroth, Sandra Steyaert, Katrien Vanderheyden, Eveline Vanden Eynde, Kimberly Verniers, Joke Verreth, Jo Van Dorpe, Jo Vandesompele
Summary: This study demonstrates that mRNA capture sequencing improves the detection rate of pathognomonic fusions in sarcomas and enables the identification of novel and secondary fusion transcripts.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Medicine, Research & Experimental
Philippe Decruyenaere, Kimberly Verniers, Franco Poma-Soto, Jo Van Dorpe, Fritz Offner, Jo Vandesompele
Summary: This study compared the impact of three RNA extraction methods on yield, quality, and sequencing-based gene expression results in FFPE samples. The results showed that methods B and C outperformed method A, resulting in higher fractions of uniquely mapped reads, an increased number of detectable genes, a lower fraction of duplicated reads, and better representation of the B-cell receptor repertoire. Caution should be applied when comparing and interpreting results obtained using different methods.
LABORATORY INVESTIGATION
(2023)
Article
Biochemical Research Methods
Celine Everaert, Jasper Verwilt, Kimberly Verniers, Niels Vandamme, Alvaro Marcos Rubio, Jo Vandesompele, Pieter Mestdagh
Summary: RNA sequencing is widely used for transcriptome analysis, but quantification of low-abundant transcripts remains challenging. Researchers have developed a strategy using high-affinity RNA-binding oligonucleotides to reduce the abundance of specific RNA transcripts in sequencing libraries. This method is efficient, reproducible, and can be easily integrated into existing RNA sequencing protocols, improving transcriptome coverage and complexity.
BIOLOGICAL PROCEDURES ONLINE
(2023)
Review
Biochemistry & Molecular Biology
Jasper Verwilt, Pieter Mestdagh, Jo Vandesompele
Summary: RNA sequencing has become influential in various research fields. However, the reverse transcription reaction in most protocols often leads to biases and artifacts in the resulting cDNA pool, which are overlooked in the literature. This review discusses these issues and provides solutions and good practices for RNA sequencing experiments, aiming to contribute to scientifically sound RNA studies.
Review
Medical Laboratory Technology
Matthijs Vynck, Yao Chen, David Gleerup, Jo Vandesompele, Wim Trypsteen, Antoon Lievens, Olivier Thas, Ward De Spiegelaere
Summary: Background partition classification is essential in digital PCR data analysis. This review provides an overview of available methods and their challenges, serving as a guide for practitioners. Strengths, weaknesses, and application gaps are discussed, stimulating method development.
CLINICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Lei Zhai, Anushree Balachandran, Rebecca Larkin, Janith A. Seneviratne, Sylvia A. Chung, Amit Lalwani, Shoma Tsubota, Dominik Beck, Kenji Kadomatsu, Anneleen Beckers, Kaat Durink, Katleen De Preter, Frank Speleman, Michelle Haber, Murray D. Norris, Alexander Swarbrick, Belamy B. Cheung, Glenn M. Marshall, Daniel R. Carter
Summary: Mitotic dysregulation is identified as a hallmark of tumor initiation in neuroblastoma and can be targeted by a combination therapy of antimitotic and pro-apoptotic compounds, leading to selective cell death in MYCN-driven neuroblastoma cell lines.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Alan Van Goethem, Jill Deleu, Nurten Yigit, Celine Everaert, Myrthala Moreno-Smith, Sanjeev A. Vasudevan, Fjoralba Zeka, Fleur Demuynck, Eveline Barbieri, Frank Speleman, Pieter Mestdagh, Jason Shohet, Jo Vandesompele, Tom Van Maerken
Summary: In this study, we evaluated whether circulating miRNAs can be used to monitor neuroblastoma tumor burden and treatment-induced changes in the tumor. We performed small RNA sequencing on serum samples from mice with neuroblastoma xenografts treated with idasanutlin or temsirolimus. We identified serum miRNAs that correlated with tumor tissue expression and tumor volume, as well as miRNAs that responded to p53 activation following idasanutlin treatment.
Article
Biochemistry & Molecular Biology
Vanessa Vermeirssen, Jill Deleu, Annelien Morlion, Celine Everaert, Jilke De Wilde, Jasper Anckaert, Kaat Durinck, Justine Nuytens, Muhammad Rishfi, Frank Speleman, Hanne Van Droogenbroeck, Kimberly Verniers, Maria Francesca Baietti, Maarten Albersen, Eleonora Leucci, Edward Post, Myron G. Best, Tom Van Maerken, Bram De Wilde, Jo Vandesompele, Anneleen Decock
Summary: This study developed a deconvolution framework to distinguish tumor-derived extracellular RNA (exRNA) from host RNA. Analysis of liquid biopsy samples from mice revealed that tumor-derived exRNA concentrations were not determined by plasma platelet levels, while host exRNA concentrations increased with platelet content. Additionally, there was a large variability in exRNA abundance and transcript content across individual mice. The detectability of tumor genes in plasma was largely correlated with RNA expression levels in the tumor tissue or cell line.
Article
Genetics & Heredity
Jill Deleu, Kathleen Schoofs, Anneleen Decock, Kimberly Verniers, Sofie Roelandt, Angie Denolf, Joke Verreth, Bram De Wilde, Tom Van Maerken, Katleen De Preter, Jo Vandesompele
Summary: This study establishes a framework to evaluate the performance of cfDNA/cfRNA co-purification kits and tests different kits under different plasma input volumes. The results demonstrate the advantage of combined quantification of cfDNA and cfRNA over separate quantification, which is crucial for increasing mutation detection sensitivity and improving disease detection and monitoring.
Review
Oncology
Xinru Zhou, Yin Jia, Chuanbin Mao, Shanrong Liu
Summary: Small extracellular vesicles (sEVs), such as exosomes, have emerged as crucial targets for liquid biopsy and promising drug delivery vehicles in tumor progression. They can serve as biomarkers for tumor diagnosis and as drug carriers for cancer treatment.
Article
Oncology
Ruochan Chen, Ju Zhu, Xiao Zhong, Jie Li, Rui Kang, Daolin Tang
Summary: The interplay between autophagy and apoptosis plays a crucial role in tumorigenesis and cancer therapy, with HMGB1 serving as a key regulator in these processes.
Article
Oncology
Zongfu Pan, Xixuan Lu, Tong Xu, Jinming Chen, Lisha Bao, Ying Li, Yingying Gong, Yulu Che, Xiaozhou Zou, Zhuo Tan, Ping Huang, Minghua Ge
Summary: This study uncovered the emerging role of HN1 in promoting dedifferentiation of anaplastic thyroid cancer (ATC) cells. HN1 negatively regulated the thyroid differentiation markers and had an inhibitory effect on the transcriptional activation of CTCF, thereby influencing the chromatin accessibility of thyroid differentiation genes.
Article
Oncology
Yi Qin, Shengjun Xiong, Jun Ren, Gautam Sethi
Summary: Autophagy plays an important regulatory role in glioblastoma, and its dysregulation can lead to drug resistance and radioresistance. It also affects stem cell characteristics, overall growth, and metastasis. Therefore, autophagy is a promising target for glioblastoma therapy.
Article
Oncology
Katsuya Nagaoka, Xuewei Bai, Dan Liu, Kevin Cao, Joud Mulla, Chengcheng Ji, Hongze Chen, Muhammad Azhar Nisar, Amalia Bay, William Mueller, Grace Hildebrand, Jin-Song Gao, Shaolei Lu, Hiroko Setoyama, Yasuhito Tanaka, Jack R. Wands, Chiung-Kuei Huang
Summary: This study found that serum 2-OG levels in cholangiocarcinoma patients are associated with the effectiveness of chemotherapy. Patients with progressive disease showed significantly higher levels of serum 2-OG compared to stable disease and partial response patients. The study also revealed that overexpression of ASPH mimics the effects of 2-OG, and knockdown of ASPH improves chemotherapy. Targeting ASPH enhances the effects of chemotherapy by modulating ATM and ATR, two key regulators of DDRs.