Targeting AKT for cancer therapy

Expert Opinion on Investigational Drugs, Journal Year: 2019, Volume and Issue: 28(11), P. 977 - 988

Published: Oct. 9, 2019

Introduction: Targeted therapies in cancer aim to inhibit specific molecular targets responsible for enhanced tumor growth. AKT/PKB (protein kinase B) is a serine threonine involved several critical cellular pathways, including survival, proliferation, invasion, apoptosis, and angiogenesis. Although phosphatidylinositol-3 (PI3K) the key regulator of AKT activation, numerous stimuli kinases initiate pro-proliferative signaling which results activation pathway drive growth survival. Activating mutations amplification components are implicated pathogenesis many cancers breast ovarian. Given its importance, AKT, it has been validated as promising therapeutic target.Areas covered: This article summarizes AKT's biological function different classes inhibitors anticancer agents. We also explore efficacy monotherapies combination with cytotoxic other targeted therapies.Expert opinion: The complex mechanism following inhibition requires addition prevent resistance improve clinical response. Further studies necessary determine additional rational combinations that can enhance inhibitors, potentially by targeting compensatory mechanisms, and/or enhancing apoptosis. identification biomarkers response essential development successful therapeutics.

Language: Английский

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Advances in Ovarian Cancer Care and Unmet Treatment Needs for Patients With Platinum Resistance

JAMA Oncology, Journal Year: 2023, Volume and Issue: 9(6), P. 851 - 851

Published: April 20, 2023

Platinum-based chemotherapy has been the standard of care for ovarian cancer past 3 decades. Although most patients respond to platinum-based treatment, emergence platinum resistance in recurrent is inevitable during disease course. Outcomes with platinum-resistant are poor, and options remain limited, highlighting a substantial unmet need new treatment options.

Language: Английский

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ACSL1-induced ferroptosis and platinum resistance in ovarian cancer by increasing FSP1 N-myristylation and stability

Cell Death Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: March 8, 2023

Reprogramming of lipid metabolism, which modulates energy utilization and cell signaling, maintains survival promotes cancer metastasis in cells. Ferroptosis is a type necrosis caused by an overload oxidation, has been demonstrated to be involved metastasis. However, the mechanism fatty acid metabolism regulates anti-ferroptosis signaling pathways not fully understood. The formation ovarian spheroids helps counteract hostile microenvironment peritoneal cavity with low oxygen, shortage nutrients, subjected platinum therapy. Previously, we that Acyl-CoA synthetase long-chain family member 1 (ACSL1) metastases cancer, but still well elucidated. In this study, demonstrate under exposure chemotherapy increased levels proteins as ACSL1. Inhibition ferroptosis can enhance spheroid vice versa. Genetic manipulation ACSL1 expression showed reduced level oxidation resistance ferroptosis. Mechanistically, N-myristoylation suppressor (FSP1), resulting inhibition its degradation translocation membrane. increase myristoylated FSP1 functionally counteracted oxidative stress-induced Clinical data also suggested protein was positively correlated negatively markers 4-HNE PTGS2. conclusion, study enhances antioxidant capacity increases modulating myristoylation FSP1.

Language: Английский

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Challenges for immunotherapy for the treatment of platinum resistant ovarian cancer

Seminars in Cancer Biology, Journal Year: 2020, Volume and Issue: 77, P. 127 - 143

Published: Sept. 12, 2020

Platinum resistant ovarian cancer, usually defined as progression occurring within 6 months after completing platinum-based therapy, is a heterogeneous disease with poor prognosis and short survival (less than 18 months). It typically considered "cold tumor", characterized by reduced infiltration immune cells, particularly CD8+ T cells. Response rate to anti-PD1/PD-L1 monotherapy low, not exceeding 8%. Multiple therapeutic strategies are currently investigated in order increase response rates through adding chemotherapy, anti-angiogenic agents, DNA damage (PARP inhibitors, cyclophosphamide and/or radiotherapy) or other checkpoint inhibitors (CTLA-4, etc.). Ovarian clear cell carcinoma, rare histotype primary platinum-resistance, recently showed anecdotal but promising blockade. Other immunotherapeutic approaches such adoptive vaccines targeting myeloid checkpoints like "don't eat me" signal CD47 investigated. Each approach faces distinct challenges that will be reviewed here. Robust immunogenomics studies conducted parallel of the ongoing trials help into refining optimal immunotherapy combination for this lethal identify predictive biomarkers.

Language: Английский

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Integrative Bioinformatics Approaches to Map Potential Novel Genes and Pathways Involved in Ovarian Cancer

Frontiers in Bioengineering and Biotechnology, Journal Year: 2019, Volume and Issue: 7

Published: Dec. 17, 2019

Background and aims: Ovarian cancer (OC) is the seventh most commonly detected among women. This study aimed to map hub core genes potential pathways that might be involved in molecular pathogenesis of OC. Methods: In present work, we analyzed a microarray dataset (GSE126519) from Gene Expression Omnibus (GEO) database used GEO2R tool screen OC cells ovarian SINE-resistant for differentially expressed (DEGs). For functional annotation DEGs, conducted gene ontology (GO) pathway enrichment analyses (KEGG) using DAVID v6.8 online server GenoGo Metacore™ Cortellis Solution software. Protein-protein interaction (PPI) networks were constructed STRING database, Cytoscape software was visualization. The survival analysis performed platform GEPIA2 determine prognostic value expression cell lines patients. Results: We identified total 809 upregulated 700 downregulated DEGs. GO revealed with statistically significant differences mainly associated biological processes cycle, mitotic nuclear division, organ morphogenesis, development, morphogenesis. By Analyze Networks (AN) algorithm GeneGo, relevant involving DEGs enriched cycle (in metaphase checkpoints) role APC regulation pathways. found ten four (FZD6, FZd8, CDK2, RBBP8) are strongly linked Conclusion: sheds light on expected provide biomarkers beneficial treatment clinical diagnosis

Language: Английский

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BTLA blockade enhances Cancer therapy by inhibiting IL-6/IL-10-induced CD19high B lymphocytes

Journal for ImmunoTherapy of Cancer, Journal Year: 2019, Volume and Issue: 7(1)

Published: Nov. 21, 2019

Background

The standard treatment for epithelial ovarian carcinoma (EOC) is surgery followed by platinum/paclitaxel-based chemotherapy, but the overall survival rate poor. purpose of this study was to investigate therapeutic potential chemotherapy combined with inhibition B and T lymphocyte attenuator (BTLA) clinical use treat EOC.

Methods

Initially, we evaluated application anti-BTLA antibody in an animal model. We then analyzed distribution regulation BTLA expression on immunocytes vitro. Finally, examined correlation between levels cancerous tissues prognosis 254 EOC cases.

Results

combination inhibiting significantly reduced peritoneal tumor volume extended tumor-bearing mice. In addition, could be identified mostly lymphocytes, especially CD19^hi cells, rather than lymphocytes natural killer cells. Under interleukins 6 10, more BTLA⁺CD19^hi induced through AKT STAT3 signaling pathways. Detectable associated worse disease-free survivals patients.

Conclusions

detected can predict poor outcome Inhibition elevate immune activation generate potent anti-tumor effects. Thus, may hold

Trial registration

Trial Registration Number NCT00854399.

Language: Английский

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Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer

Cancer Drug Resistance, Journal Year: 2021, Volume and Issue: unknown

Published: Jan. 1, 2021

The survival rates for women with ovarian cancer have shown scant improvement in recent years, a 5-year rate of less than 40% diagnosed advanced cancer. High-grade serous (HGSOC) is the most lethal subtype where majority develop recurrent disease and chemotherapy resistance, despite over 70%-80% patients initially responding to platinum-based chemotherapy. phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target rapamycin (mTOR) signaling pathway regulates many vital processes such as cell growth, metabolism. However, this frequently dysregulated cancers including different subtypes cancer, through amplification or somatic mutations phosphatidylinositol-4,5-bisphosphate catalytic subunit alpha (PIK3CA), AKT isoforms, deletion inactivation PTEN. Further evidence indicates role PI3K/AKT/mTOR development resistance Thus, targeting key nodes potential therapeutic prospect. In review, we outline dysregulation PI3K particular emphasis on HGSOC platinum-resistant disease. We review pre-clinical inhibitors main components highlight past, current upcoming trials pathway. Whilst no thus far clinic treatment several promising compounds which restore platinum sensitivity improve clinical outcomes are under evaluation various phases trials.

Language: Английский

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Ovarian Cancer in the Era of Immune Checkpoint Inhibitors: State of the Art and Future Perspectives

Cancers, Journal Year: 2021, Volume and Issue: 13(17), P. 4438 - 4438

Published: Sept. 3, 2021

Background: Ovarian cancer (OC) represents the eighth most common and fifth leading cause of cancer-related deaths among female population. In an advanced setting, chemotherapy first-choice treatment, despite a high recurrence rate. last ten years, immunotherapy based on immune checkpoint inhibitors (ICIs) has profoundly modified therapeutic scenario many solid tumors. We sought to summarize main findings regarding clinical use ICIs in OC. Methods: searched PubMed, Embase, Cochrane Databases, conference abstracts from international congresses (such as ASCO, ESMO, SGO) for trials, focusing both monotherapy combinations Results: 20 studies were identified, which 16 phase I or II 4 III trials. These trials used targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, aterolizumab, durvalumab), CTLA4 (ipilimumab, tremelimumab). There was no reported improvement survival, some terminated early due toxicity lack response. Combining with chemotherapy, anti-VEGF therapy, PARP improved response rates survival spite worse safety profile. Conclusions: The identification biomarkers predictive role ICIs’ efficacy is mandatory. Moreover, genomic profiling OC might lead better treatment options facilitate design tailored

Language: Английский

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The response and resistance to drugs in ovarian cancer cell lines in 2D monolayers and 3D spheroids

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 165, P. 115152 - 115152

Published: July 11, 2023

Ovarian cancer is the most common type of gynecologic cancer. One leading causes high mortality chemoresistance, developed primarily or during treatment. Different mechanisms drug resistance appear at cellular and tissue organization levels. We examined differences in response to cytotoxic drugs CIS, MTX, DOX, VIN, PAC, TOP using 2D (two-dimensional) 3D (three-dimensional) culture methods. tested drug-sensitive ovarian cell line W1 established resistant lines appropriate drugs. The following qualitative quantitative methods were used assess: 1) morphology - inverted microscope hematoxylin & eosin staining; 2) viability MTT assay; 3) gene expression – a polymerase chain reaction; 4) identification proteins immunohistochemistry, immunofluorescence. Our results indicate that drug-resistant cells cultured conditions exhibit stronger than conditions. A traditional model shows caused mainly by changes genes encoding ATP-binding cassette transporter proteins, components extracellular matrix, "new" related lines, universal marker stem cells. Whereas model, spheroids can be other such as structure spheroid (dense loose), (necrotic, quiescent, proliferating cells), concentrations diffusion into dense cellular/ECM structure.

Language: Английский

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Predicting Prognosis and Platinum Resistance in Ovarian Cancer: Role of Immunohistochemistry Biomarkers

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 1973 - 1973

Published: Jan. 19, 2023

Ovarian cancer is a lethal reproductive tumour affecting women worldwide. The advancement in presentation and occurrence of chemoresistance are the key factors for poor survival among ovarian women. Surgical debulking was mainstay systemic treatment cancer, which followed by successful start to platinum-based chemotherapy. However, most develop platinum resistance relapse within six months receiving first-line treatment. Thus, there great need identify biomarkers predict before enrolment into chemotherapy, would facilitate individualized targeted therapy these subgroups patients ensure better an improved quality life overall outcome. Harnessing immune response through immunotherapy approaches has changed way with cancer. outline emerged as beneficial tool recognizing predictive prognostic clinically. Studying microenvironment (TME) tissue may provide awareness actionable targets enhancing chemotherapy outcomes life. This review analyses relevance immunohistochemistry predicting improving

Language: Английский

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