Editorial Material
Chemistry, Medicinal
Mark Klein
Summary: Cyclin-dependent kinases (CDKs) have important roles in normal cells and can be targeted for cancer therapy. CDK4 inhibitors have been approved for advanced breast cancer treatment. However, the development of selective inhibitors for individual CDKs is challenging due to the highly conserved ATP-binding site.
Review
Biochemistry & Molecular Biology
Marika A. V. Reinius, Elizabeth Smyth
Summary: The introduction of CKI inhibitors has been a major development in the treatment of advanced breast cancer, with potential applications beyond metastatic breast cancer treatment. Evidence suggests that these agents have impacts on cancer immunology and metabolism, expanding our understanding of their therapeutic effects. Challenges and opportunities in the 2020s, including treatment resistance and biomarker development, are anticipated in the continued research and application of CKIs.
EXPERT REVIEWS IN MOLECULAR MEDICINE
(2021)
Article
Oncology
Elena Garralda, Alison M. Schram, Philippe L. Bedard, Gary K. Schwartz, Eunice Yuen, Samuel C. McNeely, Silvia Ribeiro, Jason Cunningham, Yi Wang, Arantxa Urunuela, Xiaojian Xu, Patricia LoRusso
Summary: LY3405105 is a promising CDK7 inhibitor with good bioavailability and selectivity. However, the clinical trial showed limited efficacy and no plans for further development. The MTD of LY3405105 monotherapy was determined to be 20 mg QD.
Article
Plant Sciences
Rui-Yi Yang, Jia-Yi Tan, Zhe Liu, Xiao-Ling Shen, Ying-Jie Hu
Summary: The natural lignan LAF from Arctium lappa Linne has been found to inhibit tumor cell growth in vitro and in vivo. However, its role in cell cycle regulation remains unknown.
PHARMACEUTICAL BIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Yanting Zhou, Xiandeng Li, Peifang Luo, Huiting Chen, Yan Zhou, Xueting Zheng, Yuan Yin, Haoche Wei, Hongji Liu, Wen Xia, Mingsong Shi, Xiaoan Li
Summary: CDK4/6 is a crucial player in various cancers and a potential target for anticancer drugs. The interaction between abemaciclib and human CDK6 was studied, and C2231-A was identified as a promising candidate compound with significant inhibitory effects on human breast cancer cell lines.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Lanlan Fu, Jiajia Mou, Yanru Deng, Xiaoliang Ren, Shuang Qiu
Summary: CDK1 plays an essential role in the cell cycle and has emerged as a new target for cancer therapy. A new series of flavone derivatives, including compound 2a, were discovered as potent CDK1 inhibitors. Compound 2a exhibited strong inhibitory activity against CDK1 and showed potential as a lead compound for CDK1 inhibitor development.
FRONTIERS IN CHEMISTRY
(2022)
Review
Chemistry, Medicinal
Marketa Kovalova, Joseph Peter Baraka, Vaclav Mik, Radek Jorda, Lei Luo, Hao Shao, Vladimir Krystof
Summary: CDK7 is a protein kinase that regulates the cell cycle and mRNA transcription, and it has emerged as a potential drug target in oncology. Six promising drug candidates have been evaluated in early clinical trials. This review analyzes patents published from 2018 to 2022 and provides an overview of CDK7 inhibitors as anticancer drugs, including their chemical structures, biochemical profiles, and developmental stages.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2023)
Review
Oncology
Jeffrey W. Fuchs, Brian C. Schulte, Joseph R. Fuchs, Mark Agulnik
Summary: Soft tissue sarcomas are rare malignant tumors derived from mesenchymal cells, and their high morbidity and mortality are often associated with advanced and metastatic disease. Significant progress has been made in the use of targeted therapies for the treatment of soft tissue sarcoma over the past two decades. The ability to study various cellular markers and pathways related to sarcomagenesis has led to the development and approval of multiple novel therapies.
FRONTIERS IN ONCOLOGY
(2023)
Review
Oncology
Alessandra Merlini, Valeria Pavese, Giulia Manessi, Martina Rabino, Francesco Tolomeo, Sandra Aliberti, Lorenzo D'Ambrosio, Giovanni Grignani
Summary: Effective treatment of advanced/metastatic bone and soft tissue sarcomas remains a medical challenge. CDK inhibitors have shown potential therapeutic effects in various cancer types, including sarcomas. This review explores the molecular basis and therapeutic implications of CDK inhibitors in sarcoma treatment and discusses the possibility of combination therapies with conventional treatments, targeted therapy, and immunotherapy to integrate CDK inhibition in sarcoma treatment.
FRONTIERS IN ONCOLOGY
(2023)
Article
Cell Biology
Brian J. McHugh, Jillian Stephen, Calum T. Robb, Sarah Fox, Tiina Kipari, Jennifer A. Cartwright, Christopher Haslett, Rodger Duffin, Christopher D. Lucas, Adriano G. Rossi
Summary: Cyclin-dependent kinase inhibitor drugs can induce neutrophil apoptosis and enhance inflammation resolution. In this study, CDKi showed significant effects on macrophage pro-inflammatory mediator production and viability. Targeting CDK9 inhibited an inflammatory phenotype in human MDMs, suggesting its importance in therapeutically targeting pro-inflammatory macrophage functions during chronic inflammation.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Cell Biology
Kanta Yamazoe, Yoshihiro H. Inoue
Summary: The Cdk1-CycB complex is crucial for cell-cycle regulation. Import and export processes are important for the localization and activation of Cdk1. Interaction between Cdc25C and Cdk-activating kinase with Cdk1 in the nucleus is necessary for centrosome separation.
Article
Biochemistry & Molecular Biology
Jiajia Mou, Shuang Qiu, Danghui Chen, Yanru Deng, Teka Tekleab
Summary: The study reported a series of baicalein derivatives that significantly inhibited the proliferation of MCF-7 tumor cells and the activity of CDK1/cyclin B kinase. Among them, compound 4a showed better inhibition against MCF-7 proliferation, while compound 3o exhibited the best activity against CDK1/cyclin B kinase. These findings demonstrate that baicalein derivatives can be used as CDK1 inhibitors fighting against cancer.
CHEMICAL BIOLOGY & DRUG DESIGN
(2021)
Review
Pharmacology & Pharmacy
Kailin Li, Jieqiong You, Qian Wu, Wen Meng, Qiaojun He, Bo Yang, Chengliang Zhu, Ji Cao
Summary: Synthetic lethality is an effective antitumor strategy that has attracted great attention, with CDKs potentially serving as synthetic lethal factors when combined with certain oncogenes. This provides numerous antitumor treatment options and highlights the prospect of CDK inhibitors as antitumor compounds.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Cell Biology
Esther Baranov, Katrina Winsnes, Matthew O'Brien, Stephan D. Voss, Alanna J. Church, Katherine A. Janeway, Steven G. DuBois, Jessica L. Davis, Alyaa Al-Ibraheemi
Summary: This study characterizes the histologic features of pediatric mesenchymal neoplasms with kinase alterations treated with targeted inhibitors. The researchers found that these tumors showed a pathological response with decreased cellularity and stromal hyalinization after treatment.
Article
Oncology
David Howard, David James, Jezabel Garcia-Parra, Belen Pan-Castillo, Jenny Worthington, Nicole Williams, Zoe Coombes, Sophie Colleen Rees, Kerryn Lutchman-Singh, Lewis W. Francis, Paul Rees, Lavinia Margarit, R. Steven Conlan, Deyarina Gonzalez
Summary: Ovarian cancer is a deadly disease that is often diagnosed late, resulting in poor prognosis. Platinum-based therapies are commonly used, but resistance to these treatments is common, making prognosis even worse. This study aimed to evaluate the effectiveness of CDK inhibitors in platinum-resistant ovarian cancer models and their potential clinical utility. The results showed that the CDK inhibitor, dinaciclib, was highly effective in both cell lines and primary cells of ovarian cancer, even more so than cisplatin. Furthermore, resistance to cisplatin did not affect the sensitivity to dinaciclib, and the two drugs had an additive effect when used together. This suggests a potential role for pan-CDK inhibitors in the treatment of advanced and platinum-resistant ovarian cancer.
FRONTIERS IN ONCOLOGY
(2022)
Article
Clinical Neurology
Michiel E. R. Bongers, Paul T. Ogink, Katrina F. Chu, Anuj Patel, Brett Rosenthal, John H. Shin, Sang-Gil Lee, Francis J. Hornicek, Joseph H. Schwab
Summary: The study describes the surgical technique for spine reconstruction using free vascularized fibular grafts following total en bloc spondylectomy and reports the outcomes of 39 patients. The results show that the free vascularized fibular graft is an effective reconstruction technique, particularly in the cervicothoracic spine, but has high implant failure rates in the lumbar spine.
JOURNAL OF NEUROSURGERY-SPINE
(2021)
Article
Oncology
Kun Wang, Theodoros Michelakos, Bing Wang, Zikun Shang, Albert B. DeLeo, Zhenfeng Duan, Francis J. Hornicek, Joseph H. Schwab, Xinhui Wang
Summary: This study demonstrates that DSF/Cu can increase the radiosensitivity of chondrosarcoma stem cells, potentially providing better treatment outcomes for chondrosarcoma patients requiring radiotherapy.
Review
Orthopedics
Takashi Higuchi, Kentaro Igarashi, Hiromichi Oshiro, Kentaro Miyake, Norihiko Sugisawa, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Shinji Miwa, Zhenfeng Duan, Francis J. Hornicek, Hiroyuki Tsuchiya, Robert M. Hoffman
Summary: The establishment of the osteosarcoma-PDOX model by the research team provides a better understanding for discovering effective therapies. The model more accurately replicates human tumors, offering opportunities to identify effective treatments.
Article
Multidisciplinary Sciences
Ahmad Al Shihabi, Ardalan Davarifar, Huyen Thi Lam Nguyen, Nasrin Tavanaie, Scott D. Nelson, Jane Yanagawa, Noah Federman, Nicholas Bernthal, Francis Hornicek, Alice Soragni
Summary: This study successfully established patient-derived organoids from chordoma tumor samples and identified potential therapeutic targets, providing new directions for chordoma treatment.
Article
Medicine, Research & Experimental
Xiaoyang Li, Dylan C. Dean, Jin Yuan, Thomas H. Temple, Jonathan C. Trent, E. Rosenberg Andrew, Yu Shengji, J. Hornicek Francis, Zhenfeng Duan
Summary: This study demonstrates that overexpression of CDK7 in synovial sarcoma is associated with advanced clinical stage and worse prognosis. Inhibition of CDK7 reduces cell growth and migration, and promotes apoptosis in synovial sarcoma. CDK7-specific cytotoxic agents show promise as novel treatment options for synovial sarcoma.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Oncology
Walter Banfield, Myrsini Ioakeim-Ioannidou, Saveli Goldberg, Soha Ahmed, Joseph H. Schwab, Gregory M. Cote, Edwin Choy, John H. Shin, Francis J. Hornicek, Norbert J. Liebsch, Yen -Lin E. Chen, Shannon M. MacDonald, Thomas F. DeLaney
Summary: This study retrospectively reviewed the outcomes of high-dose proton-based definitive radiotherapy for newly diagnosed, unresected spinal and sacral chordomas. The results showed that high-dose definitive radiotherapy is an effective treatment option for medically inoperable or otherwise unresected mobile spine or sacrococcygeal chordomas.
RADIOTHERAPY AND ONCOLOGY
(2022)
Article
Orthopedics
Juncheng Cui, Dylan Dean, Francis J. Hornicek, Guoliang Yi, Zhenfeng Duan
Summary: High expression of HMGA2 in osteosarcoma is associated with metastasis and shorter overall survival, serving as an independent predictor of poor prognosis. HMGA2 expression is predominantly nuclear and directly correlated with neoadjuvant chemoresistance.
ORTHOPAEDIC SURGERY
(2022)
Article
Oncology
Akash A. Shah, Santiago A. Lozano-Calderon, Emily A. Berner, William G. Austen, Jonathan M. Winograd, Howard Y. Park, Nicholas M. Bernthal, Brooke M. Crawford, Francis J. Hornicek
Summary: This retrospective cohort study analyzed 28 patients who underwent reconstruction employing a pedicled vastus lateralis flap after wide resection of primary sacropelvic malignancies. The study found that even in a cohort with high baseline risk for wound complications, the use of a pedicled vastus lateralis flap is a safe reconstructive option.
JOURNAL OF SURGICAL ONCOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Robert L. Walker, Francis J. Hornicek, Zhenfeng Duan
Summary: This review summarizes recent enhancements and improvements made to generate useful chordoma models and discusses their applications in drug discovery and precision medicine.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2022)
Article
Oncology
Yang Wen, Fan Tang, Chongqi Tu, Francis Hornicek, Zhenfeng Duan, Li Min
Summary: This review discusses the use of immune checkpoint inhibitors (ICIs) in the treatment of osteosarcoma and their related mechanisms. Osteosarcoma treatment has had limited progress over the years, but the advent of ICIs provides a new therapeutic strategy. The current mechanisms of resistance to ICIs therapy in osteosarcoma are summarized, along with strategies to improve their efficacy and potential predictive biomarkers.
Review
Biotechnology & Applied Microbiology
Huali Ye, Xin Hu, Yang Wen, Chongqi Tu, Francis Hornicek, Zhenfeng Duan, Li Min
Summary: Exosomes play an important role in the tumor microenvironment of sarcoma, promoting cancer progression and metastasis through mediating cellular communications. Due to their unique characteristics, exosomes are regarded as potential biomarkers and vehicles for diagnosis and treatment of sarcoma.
JOURNAL OF NANOBIOTECHNOLOGY
(2022)
Article
Cell Biology
Lucia Casadei, Patricia Sarchet, Fernanda Costas C. de Faria, Federica Calore, Giovanni Nigita, Sayumi Tahara, Luciano Cascione, Martin Wabitsch, Francis J. Hornicek, Valerie Grignol, Carlo M. Croce, Raphael E. Pollock
Summary: EVs have emerged as an important player in tumor initiation, progression, and metastasis. Detection of EV cargoes remains a challenge, and this study demonstrates the potential of using ultrasensitive ISH to examine embedded EVs as substrates for detecting DNA amplification, providing a more direct visualization of DNA targets.
JOURNAL OF EXTRACELLULAR VESICLES
(2022)
Review
Orthopedics
David S. Constantinescu, William Pavlis, Juan J. Lizardi, Jonathan Weinerman, Thomas M. Best, Francis J. Hornicek, Seth D. Dodds
Summary: The purpose of this review was to analyze the types of questions in the Orthopaedic In-Training Examination. The study found that musculoskeletal trauma had the highest number of questions, and residents should focus on clinical management topics and primary journal sources for studying.
JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS
(2023)
Article
Pathology
Stefan C. Halvorsen, Yair Benita, Megan Hopton, Brooke Hoppe, Hilmar O. Gunnlaugsson, Parimal Korgaonkar, Charles R. Vanderburg, G. Petur Nielsen, Nicole Trepanowski, Jaime H. Cheah, Matthew P. Frosch, Joseph H. Schwab, Andrew E. Rosenberg, Francis J. Hornicek, Slim Sassi
Summary: This study compared the gene expression profiles of chordoma and notochord, and found consistency between the two, identifying a 12-gene diagnostic signature for chordoma. The TBXT/TGF-B/SOX6/SOX9 pathway was hyperactivated in the tumor, suggesting that chondrogenesis-related pathways play a key role in chordoma development. This research provided the first molecular connection between notochord and chordoma and identified potential therapeutic targets.
AMERICAN JOURNAL OF PATHOLOGY
(2023)
Review
Cell Biology
Michael G. G. Rizzo, Thomas M. M. Best, Johnny Huard, Marc Philippon, Francis Hornicek, Zhenfeng Duan, Anthony J. J. Griswold, Lee D. D. Kaplan, Joshua M. M. Hare, Dimitrios Kouroupis
Summary: Osteoarthritis (OA) is the leading cause of disability among the elderly and is increasingly affecting younger individuals. Recent advancements in understanding the pathology of OA have led to the identification of potential therapeutic approaches targeting specific molecular pathways, such as inflammation and cellular senescence. Stem cell therapies and senolytics show promise in controlling patient symptoms and slowing disease progression.