Review
Oncology
Javier Pozas, Sara Alvarez Rodriguez, Victor Albarran Fernandez, Javier Burgos, Matteo Santoni, Ray Manneh Kopp, Javier Molina-Cerrillo, Teresa Alonso-Gordoa
Summary: This review provides an overview of the current state of androgen inhibition in the treatment of advanced prostate cancer and discusses the mechanisms of resistance to approved antiandrogen drugs. It also summarizes the main research approaches in the field of androgen receptor inhibition to overcome resistance and explores potential new drugs under investigation.
Review
Oncology
Eva Estebanez-Perpina, Charlotte L. Bevan, Iain J. McEwan
Summary: Prostate cancer is the second most common cancer in men globally, with the major clinical problem being castration-resistant prostate cancer (CRPC), where the androgen receptor remains a key therapy target.
Article
Biochemistry & Molecular Biology
Chaima Cherif, Dang Tan Nguyen, Clement Paris, Thi Khanh Le, Thibaud Sefiane, Nadine Carbuccia, Pascal Finetti, Max Chaffanet, Abdessamad El Kaoutari, Julien Vernerey, Ladan Fazli, Martin Gleave, Mohamed Manai, Philippe Barthelemy, Daniel Birnbaum, Francois Bertucci, David Taieb, Palma Rocchi
Summary: Menin (MEN1) protein is highly regulated by HSP27, overexpressed in high-grade PC and CRPC, and high MEN1 mRNA expression is associated with decreased biochemical relapse-free and overall survival. Silencing Menin helps inhibit CRPC cell proliferation, tumor growth, and restore chemotherapeutic sensitivity.
Article
Cell Biology
Sadia Sarwar, Viacheslav M. Morozov, Hamsa Purayil, Yehia Daaka, Alexander M. Ishov
Summary: Androgen ablation therapy is the standard treatment for newly diagnosed prostate cancer patients. However, the relapse of castration-resistant prostate cancer (CRPC) often leads to metastasis and disease lethality. Current therapies for metastatic CRPC are limited due to resistance to Taxanes. In this study, we found that inhibition of the mitotic checkpoint kinase Mps1 enhances the efficacy of Taxanes treatment, providing a potential new therapeutic target for managing therapy-resistant metastatic CRPC.
CELL DEATH & DISEASE
(2022)
Article
Oncology
Yi Liang, Sujeeve Jeganathan, Stefano Marastoni, Adam Sharp, Ines Figueiredo, Richard Marcellus, Amanda Mawson, Zvi Shalev, Aleksandra Pesic, Joan Sweet, Haiyang Guo, David Uehling, Bora Gurel, Antje Neeb, Housheng Hansen He, Bruce Montgomery, Marianne Koritzinsky, Samantha Oakes, Johann S. de Bono, Martin Gleave, Amina Zoubeidi, Bradly G. Wouters, Anthony M. Joshua
Summary: This study identified BCL-2 and IKKB as dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo, with upregulation of IKKB having greater relevance to the progression of human castrate-resistant prostate cancer with ENZ/abiraterone resistance in patients.
CLINICAL CANCER RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Tae Jin Kim, Young Hwa Lee, Kyo Chul Koo
Summary: The androgen receptor (AR) plays a crucial role in the development and progression of prostate cancer (PCa), and treatment for hormone-sensitive prostate cancer (HSPC) relies heavily on androgen deprivation therapy (ADT). Despite most patients progressing to castration-resistant prostate cancer (CRPC), studies suggest that manipulating alternative molecular pathways can help improve current treatments and develop novel therapies for CRPC management.
Article
Multidisciplinary Sciences
Marita Zoma, Laura Curti, Dheeraj Shinde, Domenico Albino, Abhishek Mitra, Jacopo Sgrignani, Sarah N. Mapelli, Giada Sandrini, Gianluca Civenni, Jessica Merulla, Giovanna Chiorino, Paolo Kunderfranco, Alessia Cacciatore, Aleksandra Kokanovic, Andrea Rinaldi, Andrea Cavalli, Carlo V. Catapano, Giuseppina M. Carbone
Summary: ERG methylation by EZH2 enhances its transcriptional and oncogenic activity, promoting disease progression in ERG-positive prostate cancers.
NATURE COMMUNICATIONS
(2021)
Review
Oncology
Fabio Campodonico, Marco Ennas, Silvia Zanardi, Ekaterini Zigoura, Arnoldo Piccardo, Luca Foppiani, Concetta Schiavone, Lino Squillace, Andrea Benelli, Andrea De Censi, Filippo Grillo-Ruggieri, Carlo Introini
Summary: The systemic therapy for prostate cancer is evolving rapidly with the introduction of new drugs and treatment options. Research on new agents and imaging technologies to improve detection rates is ongoing. Several new drugs have shown effectiveness in metastatic prostate cancer, but further investigation is needed for optimal sequencing and consideration of tolerability and side effects. Understanding and discussing new medical therapies is crucial for uro-oncologic teams to engage in informed decision making in multidisciplinary discussions.
CURRENT CANCER DRUG TARGETS
(2021)
Review
Oncology
Samuel R. Denmeade, Laura A. Sena, Hao Wang, Emmanuel S. Antonarakis, Mark C. Markowski
Summary: Inhibition of androgen receptor signaling is the primary treatment for advanced prostate cancer, but eventually leads to resistance. Bipolar androgen therapy (BAT), which involves cycling of supraphysiologic and near-castrate levels of testosterone, disrupts adaptive AR regulation and targets the heterogeneous AR expression in castration-resistant prostate cancer (CRPC). Clinical studies have shown that BAT is safe, improves quality of life, and produces therapeutic responses in approximately 30% of patients. Resistance to BAT is associated with downregulation of AR expression, which interestingly restores sensitivity to subsequent AR inhibitor therapies.
Review
Oncology
Samuel R. Denmeade, Laura A. Sena, Hao Wang, Emmanuel S. Antonarakis, Mark C. Markowski
Summary: Inhibition of androgen receptor (AR) signaling has been the mainstay of treatment for prostate cancer, but resistance to primary and secondary AR-inhibiting therapies is a major challenge. Studies have shown that adaptive upregulation of AR activity and downregulation of AR expression are associated with resistance. Based on these findings, bipolar androgen therapy (BAT) has been developed as a treatment approach to disrupt adaptive AR regulation and target heterogeneous AR expression. Clinical studies have demonstrated that BAT can be safely given to patients with castration-resistant prostate cancer, improving their quality of life and producing therapeutic responses in a significant proportion of patients.
Article
Oncology
Elizabeth Thomas, Retheesh S. Thankan, Puranik Purushottamachar, David J. Weber, Vincent C. O. Njar
Summary: In this study, the researchers demonstrate the potential role of VNPP433-3 beta as a molecular glue that brings Androgen Receptor and MDM2 E3 ligase physically close in prostate cancer cells. This interaction promotes the degradation of AR through ubiquitination and inhibits the growth of prostate cancer cells.
Article
Oncology
Tuyen Thanh Tran, Keesook Lee
Summary: TR3 overexpression alters AR expression, splicing process, and activity, increasing the androgen independence of AR signaling in advanced prostate cancer. TR3 also enhances cell proliferation, mobility, and tumorigenesis of AR-positive and androgen-independent prostate cancer cells.
Article
Plant Sciences
Zhaolei Li, Xinxin Yang, Wenli Li, Zhiyan Wen, Jiangning Duan, Zhihao Jiang, Dingliang Zhang, Xialin Xie, Xueting Wang, Fangfang Li, Dawei Li, Yongliang Zhang
Summary: In this study, we found that SAMDC3 is involved in defense against BSMV infection by regulating the abundance of the γb protein. This finding contributes to our understanding of how a plant host deploys the ubiquitin-proteasome system to mount defenses against viral infections.
Article
Chemistry, Medicinal
Xiujin Chang, Di Zhang, Fangui Qu, Youquan Xie, Tian Chen, Yuqing Zhang, Qianming Du, Jinlei Bian, Zhiyu Li, Jubo Wang, Xi Xu
Summary: Prostate cancer (PC) is a common cancer in men, and androgen receptor (AR) is a validated drug target for PC treatment. However, PC often becomes resistant to AR antagonists, so there is a need for novel drugs. A new AR antagonist, molecule 26h, was discovered with improved antagonistic activity and potent degradation of AR. It also blocks AR nuclear translocation and inhibits AR/AR-V7 heterodimerization, leading to inhibition of gene transcription. In xenograft models, 26h showed potent efficacy against PC.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Oncology
Liling Jiang, Qingyan He, Xin Chen, Aochu Liu, Wa Ding, Haichuan Zhang, Xinmei Chen, Huan Zhou, Yi Meng, Bingyuan Liu, Guanjie Peng, Chunyan Wang, Jinbao Liu, Xianping Shi
Summary: This study found that the proteasomal deubiquitinases USP14 and UCHL5 were overexpressed in primary cancer cells from CML patients. The inhibitor of USP14 and UCHL5, b-AP15, displayed potent tumor-killing activity in BCR-ABL(WT) and BCR-ABL(T315I) CML cell lines, as well as in CML xenografts and primary CML cells. Inhibition of USP14 and UCHL5, either pharmacologically or genetically, induced cell apoptosis and decreased the protein level of BCR-ABL in CML cells expressing BCR-ABL(WT) and BCR-ABL(T315I). Moreover, b-AP15 synergistically enhanced the cytotoxic effect of TKI imatinib in BCR-ABL(WT) and BCR-ABL(T315I) CML cells.
CLINICAL AND TRANSLATIONAL MEDICINE
(2022)
Article
Oncology
Lan Yu, Mervi Toriseva, Syeda Afshan, Mario Cangiano, Vidal Fey, Andrew Erickson, Heikki Seikkula, Kalle Alanen, Pekka Taimen, Otto Ettala, Martti Nurmi, Peter J. Bostrom, Markku Kallajoki, Johanna Tuomela, Tuomas Mirtti, Ines J. Beumer, Matthias Nees, Pirkko Harkonen
Summary: This study found that FGFRL1 is significantly upregulated in prostate cancer. Different cellular localizations of FGFRL1 have different effects on clinical indicators. Knockdown of FGFRL1 suppresses xenograft tumor growth, while overexpression attenuates signal transduction. These results suggest that FGFRL1 is involved in prostate cancer progression, and nuclear FGFRL1 could serve as a prognostic marker.
Article
Multidisciplinary Sciences
Joona Pohjonen, Carolin Sturenberg, Antti Rannikko, Tuomas Mirtti, Esa Pitkanen
Summary: Neural networks for medical imaging often struggle to generalize to unseen data. Spectral decoupling, a recent technique, addresses this issue by encouraging networks to learn more features and improving their robustness to distribution shifts. The results show that networks trained with spectral decoupling outperform those without it, achieving up to 9.5% higher performance on external datasets.
Article
Multidisciplinary Sciences
Indu Kohaar, Xijun Zhang, Shyh-Han Tan, Darryl Nousome, Kevin Babcock, Lakshmi Ravindranath, Gauthaman Sukumar, Elisa Mcgrath-Martinez, John Rosenberger, Camille Alba, Amina Ali, Denise Young, Yongmei Chen, Jennifer Cullen, Inger L. Rosner, Isabell A. Sesterhenn, Albert Dobi, Gregory Chesnut, Clesson Turner, Clifton Dalgard, Matthew D. Wilkerson, Harvey B. Pollard, Shiv Srivastava, Gyorgy Petrovics
Summary: This study found higher mutation rates in specific DNA repair genes in African American prostate cancer patients compared to those with European ancestry. RAD family genes and PMS2, BRCA1 genes were among the most frequently mutated DNA repair genes in African American patients. This could have important implications for specific targeted therapies.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
William Gesztes, Cara Schafer, Denise Young, Jesse Fox, Jiji Jiang, Yongmei Chen, Huai-Ching Kuo, Kuwong B. Mwamukonda, Albert Dobi, Allen P. Burke, Judd W. Moul, David G. McLeod, Inger L. Rosner, Gyorgy Petrovics, Shyh-Han Tan, Jennifer Cullen, Shiv Srivastava, Isabell A. Sesterhenn
Summary: TP53 is frequently mutated in prostate cancer and its immunohistochemical assessment can improve prognosis. This study evaluated p53 protein expression and lymphovascular invasion (LVI) by immunohistochemistry in prostate cancer patients and found that both factors were associated with metastatic progression. The study also detected TP53 mutations in tumors with high p53 expression and suggested that high levels of p53 expression and the presence of LVI could enhance the early prediction of prostate cancer progression.
SCIENTIFIC REPORTS
(2022)
Article
Medicine, General & Internal
Kevin Sandeman, Sami Blom, Ville Koponen, Anniina Manninen, Juuso Juhila, Antti Rannikko, Tuomas Ropponen, Tuomas Mirtti
Summary: An AI algorithm for prostate cancer detection and grading was developed, which showed comparable performance with pathologists in detecting and grading prostate cancer on biopsies. The algorithm was also able to predict adverse staging and probability of recurrence after surgical treatment.
Review
Biochemistry & Molecular Biology
Hannu Koistinen, Ruusu-Maaria Kovanen, Morley D. Hollenberg, Antoine Dufour, Evette S. Radisky, Ulf-Hakan Stenman, Jyotsna Batra, Judith Clements, John D. Hooper, Eleftherios Diamandis, Oliver Schilling, Antti Rannikko, Tuomas Mirtti
Summary: Since the proposition of the pro-invasive activity of proteolytic enzymes over 70 years ago, several roles for proteases in cancer progression have been established. About half of the 473 active human proteases are expressed in the prostate and many of the most well-characterized members of this enzyme family are regulated by androgens, hormones essential for development of prostate cancer. Most notably, several kallikrein-related peptidases, including KLK3 (prostate-specific antigen, PSA), the most well-known prostate cancer marker, and type II transmembrane serine proteases, such as TMPRSS2 and matriptase, have been extensively studied and found to promote prostate cancer progression. Recent findings also suggest a critical role for proteases in the development of advanced and aggressive castration-resistant prostate cancer (CRPC). Perhaps the most intriguing evidence for this role comes from studies showing that the protease-activated transmembrane proteins, Notch and CDCP1, are associated with the development of CRPC.
Article
Oncology
Anna Aakula, Aleksi Isomursu, Christian Rupp, Andrew Erickson, Nikhil Gupta, Otto Kauko, Pragya Shah, Artur Padzik, Yuba Raj Pokharel, Amanpreet Kaur, Song-Ping Li, Lloyd Trotman, Pekka Taimen, Antti Rannikko, Jan Lammerding, Ilkka Paatero, Tuomas Mirtti, Johanna Ivaska, Jukka Westermarck
Summary: This study found that prostate cancer tumors with concomitant inhibition of PP2A and PTEN are particularly aggressive, with low patient survival rates. Overexpression of PME-1 inhibits anoikis in PTEN-deficient prostate cancer cells. The results suggest that PME-1 may be a candidate biomarker for particularly aggressive PTEN-deficient prostate cancer.
MOLECULAR ONCOLOGY
(2023)
Article
Oncology
Timo-Pekka K. Lehto, Ruusu-Maaria Kovanen, Susanna Lintula, Adrian Malen, Carolin Sturenberg, Andrew Erickson, Olli-Pekka Pulkka, Ulf-Hakan Stenman, Eleftherios P. Diamandis, Antti Rannikko, Tuomas Mirtti, Hannu Koistinen
Summary: This study aimed to investigate the mRNA levels and prognostic impact of all 15 human kallikrein-related peptidases (KLKs) and their targets, proteinase-activated receptors (PARs), in surgically treated prostate cancer (PCa). The results showed that the expression of KLK2, KLK3, KLK4, and KLK15 was closely associated with tumor aggressiveness and prognosis, suggesting their potential as prognostic biomarkers for PCa.
INTERNATIONAL JOURNAL OF CANCER
(2023)
Article
Biochemical Research Methods
Anni S. S. Halkola, Kaisa Joki, Tuomas Mirtti, Marko M. M. Maekelae, Tero Aittokallio, Teemu D. D. Laajala
Summary: This paper presents a novel methodology for feature subset selection based on the L-0 pseudonorm, which has advantages in clinical applicability, selection of grouped features, and analysis of high-dimensional transcriptomics data. The methodology is benchmarked against existing regularization methods and shows superior performance.
PLOS COMPUTATIONAL BIOLOGY
(2023)
Article
Cell Biology
Rim Bouslama, Vincent Dumont, Sonja Lindfors, Lassi Paavolainen, Jukka Tienari, Harry Nisen, Tuomas Mirtti, Moin A. Saleem, Daniel Gordin, Per-Henrik Groop, Shiro Suetsugu, Sanna Lehtonen
Summary: Changes in the podocytes, the glomerular epithelial cells, can lead to kidney dysfunction. The phosphorylation of PACSIN2 at serine 313 (S313) is increased in the glomeruli of rats with diabetic kidney disease, and this phosphorylation is associated with kidney dysfunction and increased free fatty acids. PACSIN2 phosphorylation is a dynamic process that regulates cell morphology and cytoskeletal arrangement in cooperation with N-WASP. The phosphorylation of PACSIN2 at S313 is important for regulating cytoskeletal reorganization.
Article
Oncology
Timo-Pekka K. Lehto, Juho Pylvalainen, Kevin Sandeman, Anu Kenttamies, Stig Nordling, Ian G. Mills, Jing Tang, Tuomas Mirtti, Antti Rannikko
Summary: Magnetic resonance imaging (MRI) is commonly used for prostate biopsy triage, but a significant number of prostate cancers are not visible using MRI. This study aimed to identify factors associated with MRI visibility and their impact on metastasis and prostate-specific death. The results showed that MRI-visible prostate cancers have more aggressive features and are associated with poor prognosis. Targeted biopsy of visible lesions may be sufficient for risk stratification in MRI-positive patients.
INTERNATIONAL JOURNAL OF CANCER
(2023)
Article
Biochemical Research Methods
Cara Schafer, Denise Young, Harpreet Singh, Rahul Jayakrishnan, Sreedatta Banerjee, Yingjie Song, Albert Dobi, Gyorgy Petrovics, Sudhir Srivastava, Shiv Srivastava, Isabell A. Sesterhenn, Gregory T. Chesnut, Shyh-Han Tan
Summary: A specific rabbit monoclonal antibody against ETV1 was developed and shown to have potential applications in the diagnosis, prognosis, and treatment stratification of prostate cancer and other malignancies.
JOURNAL OF IMMUNOLOGICAL METHODS
(2023)
Review
Urology & Nephrology
Rahul Jayakrishnan, Cara Schafer, Shyh-Han Tan
Summary: Although PSA testing is widely used, there is still a need for reliable biomarkers to monitor disease progression and treatment response in prostate cancer. Autoantibodies offer an attractive alternative, as they target prostate cancer specific antigens and can be collected non-invasively. High throughput approaches have improved the sensitivity and specificity of autoantibody detection, enhancing prostate cancer diagnosis and prognosis. Besides their diagnostic and predictive roles, autoantibodies can also be used as therapeutic agents for prostate cancer treatment.
AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL UROLOGY
(2023)
Article
Medicine, Research & Experimental
Tolou Shadbahr, Michael Roberts, Jan Stanczuk, Julian Gilbey, Philip Teare, Soeren Dittmer, Matthew Thorpe, Ramon Vinas Torne, Evis Sala, Pietro Lio, Mishal Patel, Jacobus Preller, James H. F. Rudd, Tuomas Mirtti, Antti Sakari Rannikko, John A. D. Aston, Jing Tang, Carola-Bibiane Schonlieb
Summary: This study demonstrates the importance of evaluating imputation quality when building classification models for incomplete data. The researchers developed a new method for assessing imputation quality and found that a classifier model trained on poorly imputed data can compromise its performance. They also discovered that commonly used measures for assessing imputation quality often result in imputed data that does not match the underlying data distribution.
COMMUNICATIONS MEDICINE
(2023)
Article
Oncology
Moon Hee Lee, Jason Theodoropoulos, Jani Huuhtanen, Dipabarna Bhattacharya, Petrus Jarvinen, Sara Tornberg, Harry Nisen, Tuomas Mirtti, Ilona Uski, Anita Kumari, Karita Peltonen, Arianna Draghi, Marco Donia, Anna Kreutzman, Satu Mustjoki
Summary: In this study, we investigated the expanded tumor-infiltrating lymphocytes (TILs) in patients with renal cell carcinoma (RCC) and explored their characteristics and ability to recognize the tumor using experimental and computational tools.
CANCER RESEARCH COMMUNICATIONS
(2023)