Targeting PI3K in cancer: mechanisms and advances in clinical trials

Yang, Jing; Nie, Ji; Ma, Xuelei; Wei, Yuquan; Peng, Yong; Wei, Xiawei

doi:10.1186/s12943-019-0954-x

Cited by 1,177 publications

(897 citation statements)

References 277 publications

(250 reference statements)

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“…Another key therapeutic target is PI3K. Drugs targeting either a single isoform of PI3K (isoform-specific inhibitors) or all four isoforms (pan-PI3K inhibitors) are available [94]. Pan-PI3K inhibitors were the first generation of PI3K inhibitors, comprising GDC-0941, BKM120, PX866, ZSTK474, and BAY80-6946 (copanlisib) [94].…”

Section: (2) Pi3k Inhibitorsmentioning

confidence: 99%

“…Drugs targeting either a single isoform of PI3K (isoform-specific inhibitors) or all four isoforms (pan-PI3K inhibitors) are available [94]. Pan-PI3K inhibitors were the first generation of PI3K inhibitors, comprising GDC-0941, BKM120, PX866, ZSTK474, and BAY80-6946 (copanlisib) [94]. The first phase I clinical trial of BKM120 in patients with solid tumors, including EC, demonstrated an encouraging clinical outcomes: preliminary antitumor activity, acceptable toxicity, and favorable pharmacokinetic profile (NCT01068483) [95].…”

Section: (2) Pi3k Inhibitorsmentioning

confidence: 99%

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Pathogenesis and Clinical Management of Uterine Serous Carcinoma

Zhang

Kwan

Wong

et al. 2020

Cancers

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Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer that has not been well characterized. It accounts for less than 10% of all endometrial cancers and 80% of endometrial cancer-related deaths. Currently, staging surgery together with chemotherapy or radiotherapy, especially vaginal cuff brachytherapy, is the main treatment strategy for USC. Whole-exome sequencing combined with preclinical and clinical studies are verifying a series of effective and clinically accessible inhibitors targeting frequently altered genes, such as HER2 and PI3K3CA, in varying USC patient populations. Some progress has also been made in the immunotherapy field. The PD-1/PD-L1 pathway has been found to be activated in many USC patients, and clinical trials of PD-1 inhibitors in USC are underway. This review updates the progress of research regarding the molecular pathogenesis and putative clinical management of USC. Keywords: endometrial cancer; uterine serous carcinomaPrecis: Uterine serous cancer, although rare, is the most lethal type of uterine cancer. It has distinct molecular features and pathogenic pathways compared with other uterine cancer types Cancers 2020, 12, 686 2 of 21 heterogeneity, grade 3 EEC displays dissimilar features. Although a large number of grade 3 EEC cases show a serous-like phenotype, others display unequivocally endometrioid morphology [6,7]. Type II tumors are typically detected in women 70 years or older and carry a poor prognosis, high recurrence frequency, and much lower 5-year survival rate compared with type I tumors. In addition, type II tumors usually lack estrogen/progesterone receptors and do not respond to hormonal fluctuations [5].Among the type II tumors, uterine serous carcinoma (USC) is the most common subtype. This highly aggressive variant accounts for only 10% of all ECs but 80% of all EC-associated deaths [8,9]. The 5-year tumor-specific survival rate is 74% and 33% for early-and late-stage USC patients, respectively (and 89% and 77% for low-and high-grade EEC) [10]. Unlike type I EC, the risk of metastasis and recurrence of USC does not rely on primary tumor size or grade; this trait contributes to a low overall survival rate of 18% to 27%. Complete surgical staging is performed, comprising total hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection, followed by carboplatin and paclitaxel. In light of poor patient survival and high recurrence rates, the development of targeted therapies specific to USC pathway aberrations would aid in its management. However, conducting studies that focus solely on this rare subtype has been a constant challenge, making it difficult to determine optimal treatment strategies [9].

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Section: (2) Pi3k Inhibitorsmentioning

confidence: 99%

Section: (2) Pi3k Inhibitorsmentioning

confidence: 99%

Pathogenesis and Clinical Management of Uterine Serous Carcinoma

Zhang

Kwan

Wong

et al. 2020

Cancers

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“…LY-294002 HL60 and MCF7 (1e-05) are potent inhibitors of Phosphatidylinositol 3-Kinases. PI3K inhibitors are effective in inhibiting tumor progression (Yang et al, 2019). LY294002 is also a BET inhibitor having both anti-inflammatories and anti-cancer properties.…”

Section: Application To Drug Designmentioning

confidence: 99%

“…By removing acetyl groups, HDACs reverse chromatin acetylation and alter transcription of oncogenes and tumor suppressor genes. 105,106 Therefore, the use of deep sampling approaches combined with Connectivity Map technologies (CMAP) allows fast finding of possible compounds and the design of new drugs that maximize the mechanisms of action needed to counteract the progression of the disease. The results obtained in this case study back the introduction of AI in Precision Medicine, since the drugs obtained are also currently being tested in TNBC.…”

Section: Trichostatin a (Tsa) Is A Potent And Specific Inhibitormentioning

confidence: 99%

<p>On the Role of Artificial Intelligence in Genomics to Enhance Precision Medicine</p>

Álvarez-Machancoses¹,

deAndrés-Galiana²,

Cernea³

et al. 2020

PGPM

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The complexity of orphan diseases, which are those that do not have an effective treatment, together with the high dimensionality of the genetic data used for their analysis and the high degree of uncertainty in the understanding of the mechanisms and genetic pathways which are involved in their development, motivate the use of advanced techniques of artificial intelligence and in-depth knowledge of molecular biology, which is crucial in order to find plausible solutions in drug design, including drug repositioning. Particularly, we show that the use of robust deep sampling methodologies of the altered genetics serves to obtain meaningful results and dramatically decreases the cost of research and development in drug design, influencing very positively the use of precision medicine and the outcomes in patients. The target-centric approach and the use of strong prior hypotheses that are not matched against reality (disease genetic data) are undoubtedly the cause of the high number of drug design failures and attrition rates. Sampling and prediction under uncertain conditions cannot be avoided in the development of precision medicine.

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“…Initially, metabolomic changes in plasma induced by different pathway inhibitors in preclinical studies from tumour and in non-tumour bearing mice were measured. These preclinical data sets were used to generate target and tumour specific metabolomic signatures which were assessed later with plasma samples from patients in a Phase I clinical trial (Ang et al 2017(Ang et al , 2016Sarker et al 2015;Yang et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Metabolomic changes of the multi (-AGC-) kinase inhibitor AT13148 in cells, mice and patients are associated with NOS regulation

et al. 2020

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Introduction To generate biomarkers of target engagement or predictive response for multi-target drugs is challenging. One such compound is the multi-AGC kinase inhibitor AT13148. Metabolic signatures of selective signal transduction inhibitors identified in preclinical models have previously been confirmed in early clinical studies. This study explores whether metabolic signatures could be used as biomarkers for the multi-AGC kinase inhibitor AT13148. Objectives To identify metabolomic changes of biomarkers of multi-AGC kinase inhibitor AT13148 in cells, xenograft / mouse models and in patients in a Phase I clinical study. Methods HILIC LC-MS/MS methods and Biocrates AbsoluteIDQ™ p180 kit were used for targeted metabolomics; followed by multivariate data analysis in SIMCA and statistical analysis in Graphpad. Metaboanalyst and String were used for network analysis. Results BT474 and PC3 cells treated with AT13148 affected metabolites which are in a gene protein metabolite network associated with Nitric oxide synthases (NOS). In mice bearing the human tumour xenografts BT474 and PC3, AT13148 treatment did not produce a common robust tumour specific metabolite change. However, AT13148 treatment of non-tumour bearing mice revealed 45 metabolites that were different from non-treated mice. These changes were also observed in patients at doses where biomarker modulation was observed. Further network analysis of these metabolites indicated enrichment for genes associated with the NOS pathway. The impact of AT13148 on the metabolite changes and the involvement of NOS-AT13148-Asymmetric dimethylarginine (ADMA) interaction were consistent with hypotension observed in patients in higher dose cohorts (160-300 mg). Conclusion AT13148 affects metabolites associated with NOS in cells, mice and patients which is consistent with the clinical dose-limiting hypotension.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Targeting PI3K in cancer: mechanisms and advances in clinical trials

Cited by 1,177 publications

References 277 publications

Pathogenesis and Clinical Management of Uterine Serous Carcinoma

Pathogenesis and Clinical Management of Uterine Serous Carcinoma

<p>On the Role of Artificial Intelligence in Genomics to Enhance Precision Medicine</p>

Metabolomic changes of the multi (-AGC-) kinase inhibitor AT13148 in cells, mice and patients are associated with NOS regulation

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