Article
Biochemistry & Molecular Biology
Chengbin Yang, Menghui Wang, Yimin Gong, Mingli Deng, Yun Ling, Qingquan Li, Jianxin Wang, Yaming Zhou
Summary: A novel PI3K inhibitor, FD2056, was discovered using 7-azaindole-based fragment-oriented growth. FD2056 demonstrated potent inhibitory activity against PI3K and enhanced CDK2 inhibition, as well as moderate selectivity among 108 kinases. In cellular assays, FD2056 showed superior anti-proliferative profiles against TNBC cells and increased apoptosis of MDA-MB-231 cells in a dose-dependent manner. FD2056 also exhibited more efficacious anti-TNBC activity than the reference drugs BKM120 and CYC202 in the MDA-MB-231 xenograft model. These findings suggest that FD2056 has potential as a promising anticancer compound and co-targeting PI3K and CDK2 pathways may be a viable therapeutic strategy for TNBC.
BIOORGANIC CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Ava Safaroghli-Azar, Mohammad-Javad Sanaei, Atieh Pourbagheri-Sigaroodi, Davood Bashash
Summary: Lipid signaling refers to the biological process in which a lipid messenger binds to a protein target, converting its effects to specific cellular responses. The family of phosphoinositide 3-kinase (PI3K) plays a crucial role in this pathway, affecting various aspects of cellular biology such as cell survival, proliferation, migration, endocytosis, intracellular trafficking, metabolism, and autophagy. Different classes of PI3Ks have been identified in yeast and mammals, with class I PI3Ks being extensively studied in cancer biology. Abnormal activation of class I PI3Ks has been implicated in human tumors, particularly through activating mutations in the PIK3CA gene. Class II and III PI3Ks are involved in regulating vesicle trafficking and autophagy processes. This review aims to discuss the latest research findings on PI3Ks-mediated cell biological processes and explore the mechanisms by which different types of phosphoinositides derived from PI3Ks act.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Review
Toxicology
Miaomiao Yu, Jiajia Chen, Zhifei Xu, Bo Yang, Qiaojun He, Peihua Luo, Hao Yan, Xiaochun Yang
Summary: The PI3K signalling pathway regulates vital cellular processes and plays a crucial role in cancer development. However, the clinical application of PI3K inhibitors is limited due to severe adverse effects. The underlying mechanisms of these toxicities are unclear, and current management involves symptomatic treatment and discontinuation of the inhibitors. Therefore, it is necessary to understand these adverse events comprehensively and establish effective management guidelines for the safe use of PI3K inhibitors.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Biochemical Research Methods
Mohammad Al Hasan, Matthew Sabirianov, Grace Redwine, Kaitlin Goettsch, Stephen X. Yang, Haizhen A. Zhong
Summary: Overexpression of PI3K proteins is common in cancer cells and targeting the PI3K signaling pathway has proven to be effective in blocking cancer progression. Several PI3K inhibitors have been developed, seven of which have been approved by the US FDA. This study used docking tools to investigate the selective binding of ligands to different subtypes of PI3Ks and identified residues that could be targeted for subtype-specific inhibitor design.
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
(2023)
Article
Oncology
Evan K. Noch, Laura N. Palma, Isaiah Yim, Nayah Bullen, Yuqing Qiu, Hiranmayi Ravichandran, Junbum Kim, Andre Rendeiro, Melissa B. Davis, Olivier Elemento, David J. Pisapia, Kevin Zhai, Hongbiao Carl LeKaye, Jason A. Koutcher, Patrick Y. Wen, Keith L. Ligon, Lewis C. Cantley
Summary: This study investigated the critical role of insulin feedback in the poor clinical efficacy of phosphatidylinositol 3-kinase (PI3K) inhibition in cancer and the independent association between hyperglycemia and poor prognosis in glioblastoma (GBM). It was found that combining anti-hyperglycemic therapy with PI3K inhibition improved treatment efficacy in a GBM mouse model. Analysis of clinical trial data revealed that hyperglycemia was independently associated with poor progression-free survival in GBM patients.
Article
Multidisciplinary Sciences
Supharada Tessiri, Anchalee Techasen, Sarinya Kongpetch, Achira Namjan, Watcharin Loilome, Waraporn Chan-On, Raynoo Thanan, Apinya Jusakul
Summary: This study revealed the association between genetic alterations in ARID1A and the activation of the PI3K/AKT pathway in cholangiocarcinoma (CCA). It also found that CCA cells deficient in ARID1A were more sensitive to AKT inhibition.
Review
Biochemistry & Molecular Biology
Martin Ezeani, Sandeep Prabhu
Summary: This article reviews the signaling of PI3K in cancer and cardiovascular pathology, and discusses how to target PI3K for cancer treatment while maintaining cardiac safety. It proposes an intersection scheme of utilizing machine learning for safety and risk prediction, and defines new leads and targets for clinical translation.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Multidisciplinary Sciences
Qian Wang, Chenqi Tao, Abdul Hannan, Sungtae Yoon, Xuanyu Min, John Peregrin, Xiuxia Qu, Hongge Li, Honglian Yu, Jean Zhao, Xin Zhang
Summary: The patterning of epithelial buds in lacrimal gland development is determined by the interplay between PI3K, Ras, and ERK signaling pathways. PI3K is activated by both IGF and FGF signaling, and also promotes ERK signaling through direct interaction with Ras. Inhibition of EGF signaling is essential for induction of lacrimal gland buds, and the cross-talk among FGF, IGF, and EGF signaling is mediated by PI3K, MAPK, and mTOR.
Review
Biochemistry & Molecular Biology
Agnieszka Kaczmarska, Patrycja Sliwa, Monika Lejman, Joanna Zawitkowska
Summary: The fundamental pathophysiology of malignancies involves dysregulation of signaling pathways, with abnormal expression of protein tyrosine kinases playing a significant role in various cancers. The successful use of tyrosine kinase inhibitors has demonstrated the benefits of targeted therapy in oncology.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Yonglin Zhang, Zhenglu Shang, Aijun Liu
Summary: The study found that Angiotensin (Ang)-(3-7) could alleviate cardiac remodeling by inhibiting the cAMP/PKA and PI3K/Akt signaling pathways to reduce hypertrophy of NRCMs and fibrosis of NRCFs, respectively.
Article
Medicine, Research & Experimental
Hasibur Rehman, Darshan S. Chandrashekar, Chakravarthi Balabhadrapatruni, Saroj Nepal, Sai Akshaya Hodigere Balasubramanya, Abigail K. Shelton, Kasey R. Skinner, Ai-Hong Ma, Ting Rao, Sumit Agarwal, Marie-Lisa Eich, Alyncia D. Robinson, Gurudatta Naik, Upender Manne, George J. Netto, C. Ryan Miller, Chong-Xian Pan, Guru Sonpavde, Sooryanarayana Varambally, James E. Ferguson
Summary: The study reveals that bladder cancers with ARID1A mutations are more sensitive to EZH2 inhibitors and/or PI3K inhibitors. Mechanistic studies demonstrate that ARID1A deficiency leads to a dependency on PI3K signaling, and EZH2 inhibitor sensitivity is associated with upregulation of PIK3IP1. Moreover, combination therapy with EZH2 and PI3K inhibitors shows a synergistic effect on ARID1A-deficient bladder cancer.
Article
Biochemistry & Molecular Biology
Chengbin Yang, Mingzhu Lu, Yi Chen, Ruiqing Xiang, Tianze Qiu, Yu Jia, Yongtai Yang, Xiaofeng Liu, Mingli Deng, Yun Ling, Yaming Zhou
Summary: Breast cancer is the cancer with the highest incidence globally, and the newly designed 7-azaindole derivatives FD2054 and FD2078 are potent PI3K inhibitors with promising antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines, showing potential as candidates for anticancer drug development.
BIOORGANIC CHEMISTRY
(2021)
Article
Microbiology
Axel Dietschmann, Sebastian Schruefer, Stefanie Westermann, Fiona Henkel, Kirstin Castiglione, Ralf Willebrand, Jasmin Adam, Jurgen Ruland, Roland Lang, Donald C. Sheppard, Julia Esser-von-Bieren, Daniel Radtke, Sven Krappmann, David Voehringer
Summary: Eosinophilia is associated with various inflammatory diseases, such as allergic bronchopulmonary aspergillosis (ABPA). It has been shown that direct interaction between eosinophils and Aspergillus fumigatus is essential for the activation of eosinophils, which then secrete multiple proinflammatory mediators. The PI3K-AKT-mTOR pathway plays a crucial role in A. fumigatus-induced eosinophil activation.
Article
Biochemistry & Molecular Biology
Qing Liu, Hao Zeng, Yuhao Yuan, Zhiwei Wang, Ziyi Wu, Wei Luo
Summary: Chondrocyte degeneration and extracellular matrix component loss are the primary causes of osteoarthritis. Osteopontin (OPN) has potential therapeutic value for treating osteoarthritis by activating PI3K signaling molecules to delay chondrocyte degeneration and reduce cartilage matrix component loss.
Article
Multidisciplinary Sciences
Alessandro Poli, Shidqiyyah Abdul-Hamid, Antonio Enrico Zaurito, Francesca Campagnoli, Valeria Bevilacqua, Bhavwanti Sheth, Roberta Fiume, Massimiliano Pagani, Sergio Abrignani, Nullin Divecha
Summary: Regulatory T cells (Tregs) are crucial in maintaining peripheral tolerance and preventing autoimmunity, but their recruitment in tumor microenvironments can suppress immune surveillance. Pharmacological inhibition of PIP4K can reprogram human Treg identity without significantly impacting T conventional cell signaling, potentially improving therapeutic outcomes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Oncology
Giuseppe Curigliano, Geoffrey Shapiro, Rebecca S. Kristeleit, Albiruni R. Abdul Razak, Stephen Leong, Maria Alsina, Antonio Giordano, Karen A. Gelmon, Erica Stringer-Reasor, Ulka N. Vaishampayan, Mark Middleton, Anthony J. Olszanski, Hope S. Rugo, Kenneth A. Kern, Nuzhat Pathan, Rachelle Perea, Kristen J. Pierce, Sarah C. Mutka, Zev A. Wainberg
Summary: This study evaluated the efficacy and safety of gedatolisib in combination with other anti-tumour agents in advanced solid tumours. The results showed that the combination therapy of gedatolisib and cisplatin had good clinical activity and acceptable tolerability profile in patients with triple-negative breast cancer, both in first-line and second/third-line settings.
BRITISH JOURNAL OF CANCER
(2023)
Correction
Oncology
Giuseppe Curigliano, Geoffrey I. I. Shapiro, Rebecca S. S. Kristeleit, Albiruni R. R. Abdul Razak, Stephen Leong, Maria Alsina, Antonio Giordano, Karen A. A. Gelmon, Erica Stringer-Reasor, Ulka N. N. Vaishampayan, Mark Middleton, Anthony J. J. Olszanski, Hope S. S. Rugo, Kenneth A. A. Kern, Nuzhat Pathan, Rachelle Perea, Kristen J. J. Pierce, Sarah C. C. Mutka, Zev A. A. Wainberg
BRITISH JOURNAL OF CANCER
(2023)
Article
Oncology
Karin Jordan, Evandro De Azambuja, Teresa Amaral, Michiel Strijbos, Giuseppe Curigliano, Florian Lordick
Summary: High-quality medical oncology education is crucial for medical oncologists to provide excellent care for cancer patients. The demand for such education is increasing due to the development of new therapies and the rising number of cancer patients. Access to medical oncology education varies across countries. The European Society for Medical Oncology and other associations have implemented initiatives, such as the ESMO/ASCO global curriculum, to promote access to high-quality education.
ONCOLOGY RESEARCH AND TREATMENT
(2023)
Review
Oncology
Carmen Belli, Matteo Repetto, Santosh Anand, Camillo Porta, Vivek Subbiah, Giuseppe Curigliano
Summary: Phosphoinositide 3-kinases (PI3Ks) play a crucial role in tumorigenesis, particularly the p110 alpha subunit (PIK3CA) with activating mutations found in various tumors. Current PI3K inhibitors have limited efficacy due to on-target toxicity, inhibiting both wild-type and mutant PI3Ks. However, the development of mutant and isoform selective PIK3CA inhibitors has surged interest in targeting PIK3CA in solid tumors. This review summarizes the understanding of PI3K alterations, treatment strategies, and emerging resistance mechanisms and the role of mutant selective PIK3CA inhibitors.
BRITISH JOURNAL OF CANCER
(2023)
Review
Oncology
Chiara Corti, Federica Giugliano, Eleonora Nicolo, Paolo Tarantino, Carmen Criscitiello, Giuseppe Curigliano
Summary: Breast cancer is divided into three main groups: hormone receptor-positive HER2-negative, HER2-positive, and triple-negative BC. Technological breakthroughs have allowed for the development of antibody-drug conjugates (ADCs) as a treatment option. Even with low HER2 receptor expression, the use of T-DXd may provide clinical benefit for HER2-positive breast cancer. In HR-negative HER2-low subtype, the use of T-DXd is justified despite limited evidence, considering the poor prognosis of TNBC.
CURRENT TREATMENT OPTIONS IN ONCOLOGY
(2023)
Article
Oncology
Pamela Trillo, Jose Sandoval, Dario Trapani, Eleonora Nicolo, Paola Zagami, Federica Giugliano, Paolo Tarantino, Grazia Vivanet, Liliana Ascione, Alex Friedlaender, Angela Esposito, Carmen Criscitiello, Giuseppe Curigliano
Summary: The study retrospectively analyzed data of patients with recurrent invasive lobular carcinoma (ILC) and found discordance in the expression of ER, PgR, and HER2 between primary tumors and metastases. These findings suggest that phenotypic switch during metastasis may have implications for treatment decisions and prognosis in patients with ILC.
EUROPEAN JOURNAL OF CANCER
(2023)
Article
Pharmacology & Pharmacy
Luca Boscolo Bielo, Dario Trapani, Giuseppe Curigliano
Summary: Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer with unfavorable outcomes, traditionally had limited systemic treatment options. However, novel drugs have been approved and are causing economic challenges due to their high prices.
EXPERT OPINION ON PHARMACOTHERAPY
(2023)
Review
Oncology
Hope S. Rugo, Adam Brufsky, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Rachel M. Layman, Massimo Cristofanilli, Mylin A. Torres, Giuseppe Curigliano, Richard S. Finn, Angela DeMichele
Summary: This is a summary of an article about a study called P-REALITY X, which found that patients with metastatic HR+/HER2- breast cancer treated with palbociclib plus an AI lived longer than those treated with an AI only in routine clinical practice. These results support the use of palbociclib plus an AI as the standard first-line treatment for this type of breast cancer.
Editorial Material
Oncology
Elena Geuna, Giuseppe Curigliano, Filippo Montemurro
Review
Oncology
Federica Giugliano, Ambra Carnevale Schianca, Chiara Corti, Mariia Ivanova, Nadia Bianco, Silvia Dellapasqua, Carmen Criscitiello, Nicola Fusco, Giuseppe Curigliano, Elisabetta Munzone
Summary: Breast cancer is common and approximately 15% are HER2-positive. HER2 protein expression can be heterogeneous, affecting treatment choices. Novel pharmacological agents, such as antibody-drug conjugates, may help overcome this issue.
Review
Cell Biology
Gabriele Antonarelli, Valentina Pieri, Francesca Maria Porta, Nicola Fusco, Gaetano Finocchiaro, Giuseppe Curigliano, Carmen Criscitiello
Summary: Various tumors rely on post-translational modifications to promote invasiveness, angiogenesis, and reprogram cellular energetics. Fucosylation, a type of glycosylation, has been linked to immune and hormonal functions as well as tumor development. In breast cancer, fucosylation of the glycan core is associated with poor prognosis and increased metastatic potential. Pre-clinical studies have investigated the molecular mechanisms of core-fucosylation in breast cancer models and its potential as a biomarker for predicting cancer outcomes.
Article
Oncology
Emma Zattarin, Daniele Presti, Luigi Mariani, Caterina Sposetti, Rita Leporati, Alice Menichetti, Chiara Corti, Chiara Benvenuti, Giovanni Fuca, Riccardo Lobefaro, Francesca Ligorio, Leonardo Provenzano, Andrea Vingiani, Marta Del Vecchio, Gaia Griguolo, Marianna Sirico, Ottavia Bernocchi, Antonio Marra, Paola Zagami, Elisa Agostinetto, Flavia Jacobs, Pierluigi Di Mauro, Andrea Esposito, Carlo Alberto Giorgi, Luca Lalli, Laura Boldrini, Pier Paolo Berton Giacchetti, Ambra Carnevale Schianca, Valentina Guarneri, Rebecca Pedersini, Agnese Losurdo, Alberto Zambelli, Daniele Generali, Carmen Criscitiello, Giuseppe Curigliano, Giancarlo Pruneri, Filippo de Braud, Maria Vittoria Dieci, Claudio Vernieri
Summary: In 428 patients with HR+/HER2- advanced breast cancer, HER2-low status was found to be independently associated with worse progression-free survival (PFS) and overall survival (OS) compared to HER2-0 status. These findings suggest that HER2-low status could serve as a new prognostic biomarker in this clinical setting.
Article
Oncology
Luca Licata, Giulia Viale, Mario Giuliano, Giuseppe Curigliano, Mariana Chavez-MacGregor, Julia Foldi, Oluchi Oke, Joseph Collins, Lucia Del Mastro, Fabio Puglisi, Filippo Montemurro, Claudio Vernieri, Lorenzo Gerratana, Sara Giordano, Alessia Rognone, Lorenzo Sica, Oreste Davide Gentilini, Stefano Cascinu, Lajos Pusztai, Antonio Giordano, Carmen Criscitiello, Giampaolo Bianchini
Summary: This study evaluates whether Oncotype DX improves confidence and agreement among oncologists in adjuvant chemotherapy recommendations for ER+/HER2- early-stage breast cancers. The study found that using Oncotype DX significantly reduces discordance and uncertainty among oncologists, and improves agreement in adjuvant chemotherapy recommendations for patients.
Article
Oncology
Giuseppe Curigliano, Fatima Cardoso, Michael Gnant, Nadia Harbeck, Judy King, Anne-Vibeke Laenkholm, Frederique Penault-Llorca, Aleix Prat
Summary: Breast cancer multigene signatures (BCMS) have changed the management of early-stage breast cancer (eBC) by providing prognostic information and helping select patients for adjuvant chemotherapy. However, there is limited knowledge on the current usage and perceived utility of BCMS in clinical practice. A two-round Delphi survey involving 133 breast cancer experts from 11 European countries revealed that BCMS are widely used to assess risk of recurrence and select patients for adjuvant chemotherapy, but consensus is lacking regarding their utility in selecting specific chemotherapy types. There are also discrepancies between recommended usage and actual usage, with some profiles lacking supporting evidence. The study suggests the need for physician education initiatives to ensure proper use and interpretation of BCMS, ultimately improving management of eBC patients.
Review
Biochemistry & Molecular Biology
Laura Gilardi, Lighea Simona Airo Farulla, Giuseppe Curigliano, Giovanni Corso, Maria Cristina Leonardi, Francesco Ceci
Summary: Invasive lobular cancer (ILC) is the second most common histological type of breast cancer, characterized by infiltrative growth and metastatic spread. FDG-PET/CT is widely used in oncology and breast cancer patient evaluation, but its efficacy in ILCs is considered suboptimal. This review aims to summarize the current literature on the use of FDG-PET/CT in ILC and discuss the potential of non-FDG radiotracers for precision medicine.