Article
Multidisciplinary Sciences
Maria E. Monberg, Heather Geiger, Jaewon J. Lee, Roshan Sharma, Alexander Semaan, Vincent Bernard, Justin Wong, Fang Wang, Shaoheng Liang, Daniel B. Swartzlander, Bret M. Stephens, Matthew H. G. Katz, Ken Chen, Nicolas Robine, Paola A. Guerrero, Anirban Maitra
Summary: The use of single-cell technologies has revealed the heterogeneity and polyclonality in pancreatic cancer cell lines and patient-derived organoids. The study also highlights the impact of laboratory variations and the transition from 2D to 3D models on transcriptomic profiles. These findings raise concerns about the validity of commonly used control lines and the predictive abilities of organoids over time.
NATURE COMMUNICATIONS
(2022)
Article
Oncology
Jian Zhang, Nicholas P. McAndrew, Xiaojia Wang, Yiqun Du, Brian DiCarlo, Mei Wang, Kan Chen, Wenlei Yu, Xichun Hu
Summary: The authors described the design and structure-activity relationship of DZD1516, which showed good selectivity against HER2 and potent antitumor activity. A preclinical study in patients with HER2+ MBC found that DZD1516 has good blood-brain barrier penetration and tolerability, and has potential for the treatment of HER2-positive metastatic breast cancer.
BREAST CANCER RESEARCH
(2023)
Article
Oncology
Melodie Davy, Laurie Genest, Christophe Legrand, Oceane Pelouin, Guillaume Froget, Vincent Castagne, Tristan Rupp
Summary: Grade 4 gliomas and glioblastomas are the most common and aggressive brain tumors. Temozolomide, the current standard treatment, has varying responses depending on the tumor type, while Fingolimod, an immunomodulatory drug, may need further evaluation for its potential activity. The study highlights the need for new therapies to improve survival and quality of life for glioblastoma patients.
Review
Oncology
Natalie J. Serkova, Kristine Glunde, Chad R. Haney, Mohammed Farhoud, Alexandra De Lille, Elizabeth F. Redente, Dmitri Simberg, David C. Westerly, Lynn Griffin, Ralph P. Mason
Summary: Technological advances in cancer imaging in animal models allow for sophisticated, noninvasive exploration of molecular and physiological events, providing new opportunities for research and drug development.
Review
Immunology
Abolfazl Maghrouni, Maryam Givari, Mohammad Jalili-Nik, Hamid Mollazadeh, Bahram Bibak, Mohammad Montazami Sadeghi, Amir R. Afshari, Thomas P. Johnston, Amirhossein Sahebkar
Summary: GBM, an immunosuppressive brain tumor, remains difficult to manage despite current treatments. Immunotherapy, particularly checkpoint inhibitors, has potential for GBM treatment but faces challenges due to the tumor's immunosuppressive microenvironment.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2021)
Article
Radiology, Nuclear Medicine & Medical Imaging
Baosheng Chen, Devi Prasan Ojha, Takuya Toyonaga, Jie Tong, Richard Pracitto, Monique A. Thomas, Michael Liu, Michael Kapinos, Li Zhang, Ming-Qiang Zheng, Daniel Holden, Krista Fowles, Jim Ropchan, Nabeel Nabulsi, Henk De Feyter, Richard E. Carson, Yiyun Huang, Zhengxin Cai
Summary: Currently, there are multiple clinical trials using PARP inhibitors in the treatment of glioblastoma. This study reports the synthesis of a brain-penetrant PARP PET tracer and its evaluations in a rat glioblastoma model and healthy nonhuman primates. The tracer demonstrated specific binding to PARP and showed potential for noninvasive quantification of PARP in the brain.
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
(2023)
Article
Oncology
Elizabeth R. Tucker, Irene Jimenez, Lindi Chen, Angela Bellini, Chiara Gorrini, Elizabeth Calton, Qiong Gao, Harvey Che, Evon Poon, Yann Jamin, Barbara Martins Da Costa, Karen Barker, Sumana Shrestha, J. Ciaran Hutchinson, Simran Dhariwal, Angharad Goodman, Elaine Del Nery, Pierre Gestraud, Jaydutt Bhalshankar, Yasmine Iddir, Elnaz Saberi-Ansari, Alexandra Saint-Charles, Birgit Geoerger, Maria Eugenia Marques Da Costa, Cecile Pierre-Eugene, Isabelle Janoueix-Lerosey, Didier Decaudin, Fariba Nemati, Angel M. Carcaboso, Didier Surdez, Olivier Delattre, Sally L. George, Louis Chesler, Deborah A. Tweddle, Gudrun Schleiermacher
Summary: ALK-activating mutations are present in approximately 10% of neuroblastomas and ALK amplifications in a further 1%-2% of cases. Lorlatinib, a third-generation ALK inhibitor, is being considered as a treatment for children with ALK-aberrant neuroblastoma. Resistance to single-agent treatment has been reported, and combination therapies with chemotherapy or MDM2 inhibitor are being explored to improve treatment efficacy.
CLINICAL CANCER RESEARCH
(2023)
Review
Oncology
Marco Proietto, Martina Crippa, Chiara Damiani, Valentina Pasquale, Elena Sacco, Marco Vanoni, Mara Gilardi
Summary: Heterogeneity in cancer cells, both within and between tumors, is a complex and challenging aspect of cancer ecosystems. It contributes to tumor resistance, metastasis, and recurrence, impairing the effectiveness of solid tumor therapy. Understanding tumor heterogeneity through various models and genomic technologies is crucial for designing personalized and efficient cancer therapies. Leveraging the dynamic interactions within the tumor immune microenvironment can unlock immune recognition and improve immunotherapy. A multidisciplinary approach with advanced computational tools is essential for gaining integrated knowledge of tumor heterogeneity and implementing effective treatments for cancer patients.
FRONTIERS IN ONCOLOGY
(2023)
Review
Biotechnology & Applied Microbiology
Alexander Honkala, Sanjay Malhotra, Shivaani Kummar, Melissa R. Junttila
Summary: Recent advances in understanding molecular basis, identifying therapeutic targets, and evolving regulatory landscape have made oncology drug development an exciting time, yet challenges like high costs and high attrition rates persist. Alignment of patient tumor biology with preclinical models is crucial for developing effective treatments, enhancing translational research in both forward and reverse directions.
NATURE REVIEWS DRUG DISCOVERY
(2022)
Article
Oncology
Joshua T. Eggold, Stephanie Chow, Stavros Melemenidis, Jinghui Wang, Suchitra Natarajan, Phoebe E. Loo, Rakesh Manjappa, Vignesh Viswanathan, Elizabeth A. Kidd, Edgar Engleman, Oliver Dorigo, Billy W. Loo, Erinn B. Rankin
Summary: Treatment of advanced ovarian cancer using PD-1/PD-L1 immune checkpoint blockade shows promise. Ultrahigh-dose rate (FLASH) irradiation has the potential to improve therapeutic efficacy and increase intratumoral CD8+ T-cell infiltration.
MOLECULAR CANCER THERAPEUTICS
(2022)
Article
Chemistry, Medicinal
Kosuke Hashimoto, Soichiro Ide, Mayumi Arata, Akiko Nakata, Akihiro Ito, Takashi K. Ito, Norio Kudo, Bangzhong Lin, Kazuto Nunomura, Keiko Tsuganezawa, Minoru Yoshida, Yasuo Nagaoka, Takaaki Sumiyoshi
Summary: In this study, a hybrid strategy combining HDAC6 inhibitors and brain-penetrant histamine H-1 receptor antagonists was used to design CNS-penetrant HDAC6 inhibitors. The identified compound KH-259 displayed selective inhibition and penetration into the brain, making it a potential therapeutic agent for neurodegenerative diseases.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Robin A. Fairhurst, Pascal Furet, Patricia Imbach-Weese, Frederic Stauffer, Heinrich Rueeger, Clive McCarthy, Sebastien Ripoche, Susanne Oswald, Bertrand Arnaud, Aline Jary, Michel Maira, Christian Schnell, Daniel A. Guthy, Markus Wartmann, Michael Kiffe, Sandrine Desrayaud, Francesca Blasco, Toni Widmer, Frank Seiler, Sascha Gutmann, Mark Knapp, Giorgio Caravatti
Summary: Balanced pan-class I phosphoinositide 3-kinase inhibition is a promising approach for cancer treatment, offering the potential to treat various tumor types and enhance efficacy with a single inhibitor. This study identified a best-in-class phosphoinositide 3-kinase inhibitor, 40 (NVP-CLR457), by optimizing its properties, including eliminating off-target activity and balancing the inhibition profile.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
S. Lindsey Davis, Sarah J. Hartman, Stacey M. Bagby, Marina Schlaepfer, Betelehem W. Yacob, Tonia Tse, Dennis M. Simmons, Jennifer R. Diamond, Christopher H. Lieu, Alexis D. Leal, Elaine B. Cadogan, Gareth D. Hughes, Stephen T. Durant, Wells A. Messersmith, Todd M. Pitts
Summary: The study demonstrated that the combination of AZD0156 and irinotecan enhanced the effects on cellular proliferation and regrowth in select models. Additionally, increased G2/M arrest was observed with combination treatment in these models. In some PDX models, increased tumor growth inhibition was observed with the combination of AZD0156 and irinotecan compared to single-agent therapy.
Article
Chemistry, Medicinal
Rui Liang, Daisuke Tomita, Yusuke Sasaki, John Ginn, Mayako Michino, David J. Huggins, Leigh Baxt, Stacia Kargman, Maaz Shahid, Kazuyoshi Aso, Mark Duggan, Andrew W. Stamford, Elisa DeStanchina, Nigel Liverton, Peter T. Meinke, Michael A. Foley, Richard E. Phillips
Summary: Aberrant gene-silencing through dysregulation of polycomb protein activity is an important oncogenic mechanism that can be targeted for cancer treatment. This study identified a chemical strategy to improve brain penetrance of EZH2 inhibitors and reported the first brain-penetrant EZH2 inhibitor, as well as a novel peripherally active EZH2 inhibitor.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Review
Oncology
Andrew J. H. Sedlack, Kimia Saleh-Anaraki, Suresh Kumar, Po Hien Ear, Kate E. Lines, Nitin Roper, Karel Pacak, Emily Bergsland, Dawn E. Quelle, James R. Howe, Yves Pommier, Jaydira del Rivero
Summary: Neuroendocrine neoplasia (NENs) are a complex and heterogeneous group of cancers, originating from neuroendocrine tissues throughout the body. Due to their low incidence and high diversity, NENs are often orphan conditions with limited clinical trials. Understanding the molecular and genetic nature of these diseases heavily relies on preclinical models, including in vitro and in vivo models. While these models do not fully mimic the nature of NENs in patients, they are valuable tools for investigating basic biology and evaluating treatment options. This review provides an overview of available preclinical models for different types of NENs and discusses their history, current use, and translation.
Article
Oncology
Lucy C. Riches, Antonio G. Trinidad, Gareth Hughes, Gemma N. Jones, Adina M. Hughes, Andrew G. Thomason, Paul Gavine, Andy Cui, Stephanie Ling, Jonathan Stott, Roger Clark, Samantha Peel, Pendeep Gill, Louise M. Goodwin, Aaron Smith, Kurt G. Pike, Bernard Barlaam, Martin Pass, Mark J. O'Connor, Graeme Smith, Elaine B. Cadogan
MOLECULAR CANCER THERAPEUTICS
(2020)
Article
Multidisciplinary Sciences
Jacqueline H. L. Fok, Antonio Ramos-Montoya, Mercedes Vazquez-Chantada, Paul W. G. Wijnhoven, Valeria Follia, Neil James, Paul M. Farrington, Ankur Karmokar, Sophie E. Willis, Jonathan Cairns, Jenni Nikkila, David Beattie, Gillian M. Lamont, M. Raymond Finlay, Joanne Wilson, Aaron Smith, Lenka Oplustil O'Connor, Stephanie Ling, Stephen E. Fawell, Mark J. O'Connor, Simon J. Hollingsworth, Emma Dean, Frederick W. Goldberg, Barry R. Davies, Elaine B. Cadogan
NATURE COMMUNICATIONS
(2019)
Article
Chemistry, Multidisciplinary
Jasmine Allen, Juan Wang, Olga Yu Zolotarskaya, Amrita Sule, Sajjad Mohammad, Shukaib Arslan, Kenneth J. Wynne, Hu Yang, Kristoffer Valerie
JOURNAL OF CONTROLLED RELEASE
(2020)
Article
Genetics & Heredity
Christopher S. Hong, Juan C. Vasquez, Adam J. Kundishora, Aladine A. Elsamadicy, Jason M. Beckta, Amrita Sule, Asher M. Marks, Nalin Leelatian, Anita Huttner, Ranjit S. Bindra, Michael L. DiLuna, Kristopher T. Kahle, E. Zeynep Erson-Omay
NPJ GENOMIC MEDICINE
(2020)
Article
Oncology
Sonja J. Gill, Paul W. G. Wijnhoven, Jacqueline H. L. Fok, Rebecca L. Lloyd, Jonathan Cairns, Joshua Armenia, Jenni Nikkila, Alan Lau, Christopher J. Bakkenist, Susan M. Galbraith, Conchita Vens, Mark J. O'Connor
Summary: Radiopotentiation profiling of DNA damage response inhibitors (DDRi) revealed lower effective concentrations in radiotherapy combinations, with preferential sensitization of p53-deficient cells. Olaparib, ceralasertib, and adavosertib showed moderate increases in radiotherapy dose enhancement with increasing inhibitor concentration, while small increases in AZD0156 and KU-60648 resulted in steep increases in dose enhancement. Multiple concentration testing demonstrated a relationship between drug concentration and radiotherapy effect, providing valuable insights for dose-escalation strategies in clinical trials.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Cell Biology
Balakrishna Koneru, Ahsan Farooqi, Thinh H. Nguyen, Wan Hsi Chen, Ashly Hindle, Cody Eslinger, Monish Ram Makena, Trevor A. Burrow, Joanne Wilson, Aaron Smith, Venkatesh Pilla Reddy, Elaine Cadogan, Stephen T. Durant, C. Patrick Reynolds
Summary: Cancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT neuroblastoma cells exhibit de novo resistance to temozolomide + irinotecan, which may be linked to constitutive ataxia-telangiectasia mutated (ATM) activation. ATM inhibition with AZD0156 shows promise in reversing chemotherapy resistance in ALT neuroblastoma.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Biology
Tudor Petreus, Elaine Cadogan, Gareth Hughes, Aaron Smith, Venkatesh Pilla Reddy, Alan Lau, Mark James O'Connor, Susan Critchlow, Marianne Ashford, Lenka Oplustil O'Connor
Summary: Petreus et al. introduce a novel tumour-on-chip microfluidic system that mimics pharmacokinetic profiles of compounds on 3D tumour spheroids to evaluate their response to treatments, successfully predicting efficacy from in vivo studies and guiding drug dose and schedules for optimal efficacy while reducing the need for animal studies.
COMMUNICATIONS BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Sachita Ganesa, Amrita Sule, Ranjini K. Sundaram, Ranjit S. Bindra
Summary: In this study, we demonstrate that MSH2, MSH6, MLH1, and PMS2 are specifically involved in the activation of the ATR axis after TMZ exposure in glioblastoma cells. This provides mechanistic insights into how the MMR system is involved in ATR activation by TMZ in MMR-mutated cancers.
SCIENTIFIC REPORTS
(2022)
Article
Chemistry, Organic
Filip Meger, Alexander C. W. Kwok, Franziska Gilch, Dominic R. Willcox, Alex J. Hendy, Kieran Nicholson, Andrew D. Bage, Thomas Langer, Thomas A. Hunt, Stephen P. Thomas
Summary: In this study, a borane-catalysed hydroboration of nitriles to give primary amines is reported, with good yields and chemoselectivity observed. DFT calculations and mechanistic studies support the proposal of a double B-N/B-H transborylation mechanism.
BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Amrita Sule, Sarah E. Golding, Syed F. Ahmad, James Watson, Mostafa H. Ahmed, Glen E. Kellogg, Tytus Bernas, Sean Koebley, Jason C. Reed, Lawrence F. Povirk, Kristoffer Valerie
Summary: Ataxia telangiectasia mutated (ATM) is a key regulator of the DNA damage response (DDR) and plays a crucial role in the phosphorylation of the structural subunit A (PR65-S401) of protein phosphatase 2A (PP2A). Phosphorylation of PR65-S401 by ATM controls diverse cellular processes such as mitosis and cell growth, as well as the recovery from DNA damage. The study showed that mutations in S401 of PR65 resulted in chromosomal aberrations, impaired DNA double-strand break repair, and increased mitotic catastrophe after radiation.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Meeting Abstract
Oncology
Daiki Ueno, Amrita Sule, Jiayu Liang, Jinny van Doorn, Ranjini Sundaram, Randy Caliliw, Huihui Ye, Rong Rong Huang, Jing Li, Karla Boyd, Ranjit S. Bindra, Juan C. Vasquez, Brian M. Shuch
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Biochemistry & Molecular Biology
Amrita Sule, Jinny Van Doorn, Ranjini K. Sundaram, Sachita Ganesa, Juan C. Vasquez, Ranjit S. Bindra
Summary: The study demonstrates the efficacy of ATR inhibitors against IDH1/2-mutant cells, particularly when combined with PARP inhibitors, showing potential anti-tumor activity in IDH1/2-mutant cancers.
Meeting Abstract
Oncology
Christopher Hong, Amrita Sule, Jason Beckta, Ranjini Sundaram, Ranjit Bindra
Article
Pharmacology & Pharmacy
Chiara Fornari, Lenka Oplustil O'Connor, Carmen Pin, Aaron Smith, James W. T. Yates, S. Y. Amy Cheung, Duncan Jodrell, Jerome T. Mettetal, Teresa A. Collins
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
(2019)