Review
Cell Biology
Jiehan Li, Shuning Guo, Zhenqiang Sun, Yang Fu
Summary: In this review, the role of noncoding RNAs (ncRNAs) in drug resistance of gastrointestinal stromal tumor (GIST) was summarized. The study found that ncRNAs play important roles in the resistance of GIST, mainly through regulating mechanisms such as oxidative phosphorylation, autophagy, apoptosis, drug target changes, and signaling pathways.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Pharmacology & Pharmacy
Aldo Di Vito, Gloria Ravegnini, Francesca Gorini, Trond Aasen, Cesar Serrano, Eva Benuzzi, Emma Coschina, Sarah Monesmith, Fabiana Morroni, Sabrina Angelini, Patrizia Hrelia
Summary: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal sarcomas treated with tyrosine kinase inhibitors (TKIs). The first-line TKI, imatinib, usually only results in a partial response or stable disease, and resistance is common. Adaptive mechanisms and resistant subclones contribute to imatinib resistance in GISTs. Secondary mutations and alternative signaling pathways may play a role in resistance to novel multi-targeted TKIs, such as ripretinib. The review discusses the complex nature of imatinib resistance in GISTs and suggests potential mechanisms that contribute to the modest efficacy of ripretinib and other anti-GIST agents.
PHARMACOLOGY & THERAPEUTICS
(2023)
Review
Pharmacology & Pharmacy
Juan Jin, Yuhao Xie, Jin-Shi Zhang, Jing-Quan Wang, Shi-Jie Dai, Wen-fang He, Shou-Ye Li, Charles R. Ashby Jr, Zhe-Sheng Chen, Qiang He
Summary: Renal cell carcinoma (RCC) is the most prevalent type of kidney cancer, and targeted therapy with Sunitinib has become the main treatment option due to the lack of efficacy in radiation therapy and chemotherapy. However, many patients develop resistance to Sunitinib within months of therapy. In this review, we discuss the molecular mechanisms of Sunitinib resistance, strategies to overcome it, and potential predictive biomarkers.
DRUG RESISTANCE UPDATES
(2023)
Review
Pharmacology & Pharmacy
Yunxia Wang, Xiaolin Liu, Luyao Gong, Weihong Ding, Wenjing Hao, Yeheng Peng, Jun Zhang, Weimin Cai, Yuan Gao
Summary: This review summarizes the mechanisms of sunitinib resistance in renal cell carcinoma, including activation of bypass or alternative pathways, inadequate drug accumulation, tumor microenvironment, metabolic reprogramming, and epigenetic regulation. It also covers current and potential biomarkers as well as treatment strategies for overcoming sunitinib resistance.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Wangzhen He, Liangliang Xu, Jiongyan Ding, Li Song, Weili Yang, Isabella Klooster, Daniel F. Pilco-Janeta, Cesar Serrano, Hongming Fang, Guojun Jiang, Xiaoyan Wang, Jiren Yu, Wen-Bin Ou
Summary: Most GISTs have mutations in the receptor tyrosine kinase KIT/PDGFRA, which provides a potential target for therapy. However, these tumors often develop resistance to the KIT/PDGFRA inhibitor imatinib. This study found that the non-RTK activated kinase ACK1 is overexpressed in GISTs. Inhibition of ACK1 using a specific inhibitor or siRNA suppressed cell viability and migration, and also inhibited signaling pathways and epithelial-mesenchymal transition. Co-targeting ACK1 and KIT showed additive effects in suppressing proliferation and promoting apoptosis, as well as inhibiting invasiveness and migration in GIST cells.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Article
Oncology
Sara Renberg, Yifan Zhang, Fredrik Karlsson, Robert Branstrom, Jan Ahlen, Li Jalmsell, Christina Linder-Stragliotto, Felix Haglund de Flon, Andri Papakonstantinou
Summary: This retrospective study investigated the use of neoadjuvant imatinib in patients with gastrointestinal stromal tumors (GIST), showing that it can effectively reduce tumor size and minimize the extent of surgery, especially for tumors in the stomach or small intestine.
INTERNATIONAL JOURNAL OF CANCER
(2022)
Article
Oncology
You-Zhu Wei, Zhi-Bin Cai, Chen-Long Zhu, Yan-Ming Zhou, Xiao-Feng Zhang
Summary: The study evaluated the long-term survival outcomes of patients with duodenal GIST who underwent radical resection (RR) or limited resection (LR). Results showed that surgical modalities did not have a significant impact on long-term survival outcomes, which should mainly depend on tumor size and location.
ANNALS OF SURGICAL ONCOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Chiara Dalle Fratte, Jerry Polesel, Sara Gagno, Bianca Posocco, Elena De Mattia, Rossana Roncato, Marco Orleni, Fabio Puglisi, Michela Guardascione, Angela Buonadonna, Giuseppe Toffoli, Erika Cecchin
Summary: This study investigated the association between genetic polymorphisms in ABCB1 and ABCG2 and imatinib plasma trough concentration in GIST and CML patients. The results showed a borderline association between the ABCG2 c.421C>A genotype and imatinib plasma trough levels, which was further confirmed in a meta-analysis. However, no significant association was found between ABCB1 polymorphisms and imatinib C-trough.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Christos Vallilas, Panagiotis Sarantis, Anastasios Kyriazoglou, Evangelos Koustas, Stamatios Theocharis, Athanasios G. Papavassiliou, Michalis V. Karamouzis
Summary: Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with treatment options including drugs and immunotherapy, some patients have gene mutations, and drug resistance is becoming more common.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Agatha Lyczek, Benedict-Tilman Berger, Aziz M. Rangwala, YiTing Paung, Jessica Tom, Hannah Philipose, Jiaye Guo, Steven K. Albanese, Matthew B. Robers, Stefan Knapp, John D. Chodera, Markus A. Seeliger
Summary: Protein kinase inhibitors are potent anticancer drugs, but some patients develop resistance to these inhibitors, leading to suboptimal treatment outcomes. Mutations in the Bcr-Abl kinase domain contribute to resistance, with some altering drug-protein interactions and others located far from the drug-binding site still conferring resistance.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Chi Yan, Chengzhi Zhao, Ke Yang, Hongyan Zhou, Limin Jing, Weixing Zhao, Wenguang Dou, Qingxin Xia, Jie Ma, Bing Wei, Yongjun Guo
Summary: This study identified two rare c-KIT gene mutations in GIST and melanoma patients, which play a novel role in resistance to imatinib, expanding the clinical research field.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Multidisciplinary Sciences
Tahsin M. Khan, Emily A. Verbus, Alexander J. Rossi, Jonathan M. Hernandez, Jeremy L. Davis, Brian A. Coakley, Andrew M. Blakely
Summary: Wild-type KIT and PDGFRA gastrointestinal stromal tumors are rare and have limited treatment options. This study analyzed data from a large national database to identify factors influencing overall survival, finding that tumors in the small intestine and with high mitotic count were associated with decreased OS. Surgery remains the primary treatment modality for wild-type GIST.
SCIENTIFIC REPORTS
(2022)
Article
Oncology
Yunju Nam, Chan Kim, Junghee Han, SeongShick Ryu, Hanna Cho, Chiman Song, Nam Doo Kim, Namkyoung Kim, Taebo Sim
Summary: In this study, novel thiazolo[5,4-b]pyridine derivatives were designed and synthesized, and structure-activity relationship (SAR) studies were performed to overcome imatinib resistance. The derivative 6r was identified as a potent c-KIT inhibitor, capable of inhibiting c-KIT double mutant cells resistant to imatinib and attenuating proliferation of gastrointestinal stromal tumor cells.
Review
Oncology
William A. Clarke, Etienne Chatelut, Alan K. Fotoohi, Richard A. Larson, Jennifer H. Martin, Ron H. J. Mathijssen, Salvatore J. Salamone
Summary: Therapeutic drug monitoring (TDM) is not widely accepted in oncology but plays an important role in other medical fields. Imatinib and other oral chemotherapy drugs use a flat dosing approach, with numerous studies examining the correlation between blood concentrations and clinical effects. The International Association identified the need to develop consensus guidelines based on available data.
EUROPEAN JOURNAL OF CANCER
(2021)
Article
Chemistry, Multidisciplinary
Yan Zhao, Zhi-Xuan Li, Yan-Jing Zhu, Jing Fu, Xiao-Fang Zhao, Ya-Ni Zhang, Shan Wang, Jian-Min Wu, Kai-Ting Wang, Rui Wu, Cheng-Jun Sui, Si-Yun Shen, Xuan Wu, Hong-Yang Wang, Dong Gao, Lei Chen
Summary: This study investigates the molecular heterogeneity and evolution of hepatobiliary tumors using single-cell RNA sequencing, revealing that certain tumor subpopulations exhibit broad-spectrum drug resistance. The CD44-positive population may play a key role in drug resistance. Shared metabolism advantage clusters across organoids and the combination of GAPDH and NDRG1 are proposed as independent predictors for patient survival.
Article
Oncology
Susanne Grunewald, Lillian R. Klug, Thomas Muhlenberg, Jonas Lategahn, Johanna Falkenhorst, Ajia Town, Christiane Ehrt, Eva Wardelmann, Wolfgang Hartmann, Hans-Ulrich Schildhaus, Juergen Treckmann, Jonathan A. Fletcher, Sascha Jung, Paul Czodrowski, Stephen Miller, Oleg Schmidt-Kittler, Daniel Rauh, Michael C. Heinrich, Sebastian Bauer
Summary: Avapritinib shows substantial clinical activity in patients with PDGFRA D842V genotype, but secondary resistance has been observed. Some PDGFRA mutant patients develop secondary mutations that interfere with avapritinib binding, leading to resistance.
Article
Oncology
Suzanne George, Robin L. Jones, Sebastian Bauer, Yoon-Koo Kang, Patrick Schoffski, Ferry Eskens, Olivier Mir, Phillipe A. Cassier, Cesar Serrano, William D. Tap, Jonathan Trent, Piotr Rutkowski, Shreyaskumar Patel, Sant P. Chawla, Eval Meiri, Michael Gordon, Teresa Zhou, Maria Roche, Micahel C. Heinrich, Margaret von Mehren
Summary: The study showed that avapritinib, as a fourth-line or later treatment in patients with GIST harboring KIT or PDGFRA mutations, has manageable toxicity with meaningful clinical activity in some patients.
Review
Medicine, General & Internal
Antonio De Leo, Donatella Santini, Claudio Ceccarelli, Giacomo Santandrea, Andrea Palicelli, Giorgia Acquaviva, Federico Chiarucci, Francesca Rosini, Gloria Ravegnini, Annalisa Pession, Daniela Turchetti, Claudio Zamagni, Anna Myriam Perrone, Pierandrea De Iaco, Giovanni Tallini, Dario de Biase
Summary: Ovarian carcinomas are a heterogeneous group of neoplasms with different types and characteristics. The WHO classifies them into five distinct types, each with unique molecular features. Advances in molecular pathology have improved our understanding of ovarian carcinomas and can guide personalized clinical decisions.
Review
Endocrinology & Metabolism
Cecilia Catellani, Gloria Ravegnini, Chiara Sartori, Sabrina Angelini, Maria E. Street
Summary: Growth hormone and the insulin-like growth factor system play crucial roles in cell proliferation, differentiation, apoptosis, and angiogenesis, while miRNAs and lncRNAs regulate gene expression and have been linked to diseases such as cancer.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Article
Oncology
Federica D'Amico, Anna Myriam Perrone, Simone Rampelli, Sara Coluccelli, Monica Barone, Gloria Ravegnini, Marco Fabbrini, Patrizia Brigidi, Pierandrea De Iaco, Silvia Turroni
Summary: This pilot study on the trajectory of gut microbiota in patients with epithelial ovarian cancer undergoing chemotherapy found distinct changes in the microbiota of platinum-resistant patients, potentially linked to therapeutic failure. In contrast, platinum-sensitive patients showed more diverse and stable microbiota, which may be beneficial for treatment.
Review
Oncology
Gloria Ravegnini, Francesca Gorini, Eugenia De Crescenzo, Antonio De Leo, Dario De Biase, Marco Di Stanislao, Patrizia Hrelia, Sabrina Angelini, Pierandrea De Iaco, Anna Myriam Perrone
Summary: Endometrial cancer is the most common gynecological cancer with challenging diagnostic and prognostic features. miRNAs play an important role in EC but there is currently lack of consensus in studies. Future research needs to explore more diagnostic and prognostic biomarkers and address the challenges in the current classification schemes.
INTERNATIONAL JOURNAL OF CANCER
(2022)
Article
Oncology
Maria A. Pantaleo, Milena Urbini, Angela Schipani, Margherita Nannini, Valentina Indio, Antonio De Leo, Bruno Vincenzi, Antonella Brunello, Giovanni Grignani, Mariaelena Casagrande, Elena Fumagalli, Elena Conca, Maristella Saponara, Elisa Gruppioni, Annalisa Altimari, Dario De Biase, Giovanni Tallini, Gloria Ravegnini, Daniela Turchetti, Marco Seri, Andrea Ardizzoni, Paola Secchiero, Annalisa Astolfi
Summary: Germline SDHA variants are highly prevalent in SDHA-deficient GIST, and the disease may occur in older adults as well. Genetic testing and surveillance should be conducted for SDHA mutation carriers and their relatives.
FRONTIERS IN ONCOLOGY
(2022)
Article
Medicine, General & Internal
Camelia Alexandra Coada, Giulia Dondi, Gloria Ravegnini, Antonio De Leo, Donatella Santini, Eugenia De Crescenzo, Marco Tesei, Alessandro Bovicelli, Susanna Giunchi, Ada Dormi, Marco Di Stanislao, Alessio G. Morganti, Dario De Biase, Pierandrea De Iaco, Anna Myriam Perrone
Summary: Endometrial cancer is the most common gynecological malignancy. Risk stratification should be based on the integration of histologic, clinical, and molecular parameters.
Review
Oncology
Lillian R. Klug, Homma M. Khosroyani, Jason D. Kent, Michael C. Heinrich
Summary: When Gastrointestinal Stromal Tumour (GIST) was identified as a distinct pathological entity, effective medical therapies were lacking, leading to poor prognosis. However, the discovery of KIT mutations and the development of TKIs revolutionized GIST treatment. Although there are approved drugs for treating advanced-stage GIST, challenges still remain and new therapeutic approaches are needed.
NATURE REVIEWS CLINICAL ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Gloria Ravegnini, Margherita Nannini, Valentina Indio, Cesar Serrano, Francesca Gorini, Annalisa Astolfi, Aldo Di Vito, Fabiana Morroni, Maria Abbondanza Pantaleo, Patrizia Hrelia, Sabrina Angelini
Summary: GISTs with PDGFRA D842V mutation show differential miRNA expression compared to non-D842V mutated GISTs. Differentially expressed miRNAs mainly target genes involved in the immune response pathways. Additionally, the miRNA-mRNA network reveals the indolent behavior of D842V mutated GISTs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Pharmacology & Pharmacy
Homma M. Khosroyani, Lillian R. Klug, Michael C. Heinrich
Summary: Prior to the early 2000s, patients with advanced GIST had poor prognoses due to lack of effective therapies. Tyrosine kinase inhibitors significantly improved the overall survival for these patients. This review discusses the studies that led to the approval of specific targeted therapies for different molecular subtypes of GIST, as well as their impact on future therapeutic approaches.
Article
Health Care Sciences & Services
Martina Ruscelli, Thais Maloberti, Angelo Gianluca Corradini, Francesca Rosini, Giulia Querzoli, Marco Grillini, Annalisa Altimari, Elisa Gruppioni, Viviana Sanza, Alessia Costantino, Riccardo Ciudino, Matteo Errani, Alessia Papapietro, Sara Coluccelli, Daniela Turchetti, Martina Ferioli, Susanna Giunchi, Giulia Dondi, Marco Tesei, Gloria Ravegnini, Francesca Abbati, Daniela Rubino, Claudio Zamagni, Emanuela D'Angelo, Pierandrea De Iaco, Donatella Santini, Claudio Ceccarelli, Anna Myriam Perrone, Giovanni Tallini, Dario de Biase, Antonio De Leo
Summary: This study aims to evaluate the impact of integrated molecular and pathologic risk stratification in the clinical practice of endometrial carcinoma (EC). It found that molecular classes and risk groups were correlated with disease-free survival. The study supports the prognostic importance of EC molecular classification and the essential role of histopathologic assessment in patients' management.
JOURNAL OF PERSONALIZED MEDICINE
(2023)
Article
Oncology
Suzanne George, Michael C. Heinrich, Neeta Somaiah, Peter Oppelt, Robert McLeod, Satoshi Nishioka, Madan G. Kundu, Xiaozhong Qian, Prasanna Kumar, Abderrahmane Laadem, Yvonne Lau, Brittany P. Tran, Maura Fallon, Ololade Dosunmu, Julia Shi, Yoichi Naito
Summary: This study evaluated the safety and tolerability of DS-6157a in treating GIST. The results showed that DS-6157a was well-tolerated, but had lower efficacy outcomes than anticipated.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Camelia Alexandra Coada, Miriam Santoro, Vladislav Zybin, Marco Di Stanislao, Giulia Paolani, Cecilia Modolon, Stella Di Costanzo, Lucia Genovesi, Marco Tesei, Antonio De Leo, Gloria Ravegnini, Dario De Biase, Alessio Giuseppe Morganti, Luigi Lovato, Pierandrea De Iaco, Lidia Strigari, Anna Myriam Perrone
Summary: This study investigated the potential of radiomic features extracted from pre-surgical CT scans to predict disease-free survival (DFS) in endometrial cancer (EC) patients. Machine learning models achieved high sensitivities and specificities in both training and test sets, showing promise for predicting EC recurrence.
Review
Oncology
Federica Medici, Stefania Rizzo, Milly Buwenge, Alessandra Arcelli, Martina Ferioli, Gabriella Macchia, Francesco Deodato, Savino Cilla, Pierandrea De Iaco, Anna Myriam Perrone, Silvia Strolin, Lidia Strigari, Gloria Ravegnini, Alberto Bazzocchi, Alessio G. Morganti
Summary: Sarcopenia is a syndrome characterized by age-related loss of skeletal muscle mass and function, worsens radiation-induced toxicity and prognosis, and has a negative impact on the quality of life. Myosteatosis, a pathological infiltration of muscle tissue by adipose tissue, is correlated with prognosis in cancer patients. Sarcopenic obesity, characterized by large fat mass, is independently associated with higher mortality and worse complications compared to sarcopenia alone. Assessment of sarcopenia is commonly done using CT images. Several studies have shown the negative impact of sarcopenia on overall survival in patients undergoing radiation therapy for various tumors. Further research is needed to find ways to prevent and manage sarcopenia during and after radiation therapy in both adult and pediatric patients.