Focal adhesion kinase: from biological functions to therapeutic strategies

Experimental Hematology and Oncology, Год журнала: 2023, Номер 12(1)

Опубликована: Сен. 25, 2023

Focal adhesion kinase (FAK), a nonreceptor cytoplasmic tyrosine kinase, is vital participant in primary cellular functions, such as proliferation, survival, migration, and invasion. In addition, FAK regulates cancer stem cell activities contributes to the formation of tumor microenvironment (TME). Importantly, increased expression activity are strongly associated with unfavorable clinical outcomes metastatic characteristics numerous tumors. vitro vivo studies have demonstrated that modulating by application inhibitors alone or combination treatment regimens could be effective for therapy. Based on these findings, several agents targeting been exploited diverse preclinical models. This article briefly describes structure function FAK, well research progress therapies. We also discuss challenges future directions regarding anti-FAK

Язык: Английский

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The promise and challenges of combination therapies with antibody-drug conjugates in solid tumors

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Янв. 4, 2024

Antibody-drug conjugates (ADCs) represent an important class of cancer therapies that have revolutionized the treatment paradigm solid tumors. To date, many ongoing studies ADC combinations with a variety anticancer drugs, encompassing chemotherapy, molecularly targeted agents, and immunotherapy, are being rigorously conducted in both preclinical clinical trial settings. Nevertheless, combination therapy does not always guarantee synergistic or additive effect may entail overlapping toxicity risks. Therefore, understanding current status underlying mechanisms is urgently required. This comprehensive review analyzes existing evidence concerning ADCs other classes oncology medicines. Here, we discuss biological different strategies, provide prominent examples, assess their benefits challenges. Finally, future opportunities for practice.

Язык: Английский

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Progression from ductal carcinoma in situ to invasive breast cancer: molecular features and clinical significance

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Апрель 3, 2024

Abstract Ductal carcinoma in situ (DCIS) represents pre-invasive breast carcinoma. In untreated cases, 25–60% DCIS progress to invasive ductal (IDC). The challenge lies distinguishing between non-progressive and progressive DCIS, often resulting over- or under-treatment many cases. With increasing screen-detected these years, the nature of has aroused worldwide attention. A deeper understanding biological molecular journey DCIS-IDC transition is crucial for more effective clinical management. Here, we reviewed key signaling pathways cancer that may contribute initiation progression. We also explored features IDC, shedding light on progression through both inherent changes within tumor cells alterations microenvironment. addition, valuable research tools utilized studying including preclinical models newer advanced technologies such as single-cell sequencing, spatial transcriptomics artificial intelligence, have been systematically summarized. Further, thoroughly discussed advancements prognostic biomarkers managements, with aim facilitating personalized treatment strategies future. Research already yielded significant insights into carcinogenesis will continue pave way practical applications.

Язык: Английский

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Advancements and challenges in triple-negative breast cancer: a comprehensive review of therapeutic and diagnostic strategies

Frontiers in Oncology, Год журнала: 2024, Номер 14

Опубликована: Май 28, 2024

Triple-negative breast cancer (TNBC) poses significant challenges in oncology due to its aggressive nature, limited treatment options, and poorer prognosis compared other subtypes. This comprehensive review examines the therapeutic diagnostic landscape of TNBC, highlighting current strategies, emerging therapies, future directions. Targeted including PARP inhibitors, immune checkpoint EGFR hold promise for personalized approaches. Challenges identifying novel targets, exploring combination developing predictive biomarkers must be addressed optimize targeted therapy TNBC. Immunotherapy represents a transformative approach TNBC treatment, yet biomarker identification, overcoming resistance persist. Precision medicine approaches offer opportunities tailored based on tumor biology, but integration multi-omics data clinical implementation present requiring innovative solutions. Despite these challenges, ongoing research efforts collaborative initiatives hope improving outcomes advancing strategies By addressing complexities biology effective approaches, treatments can realized, ultimately enhancing lives patients. Continued research, trials, interdisciplinary collaborations are essential realizing this vision making meaningful progress management.

Язык: Английский

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Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions

Critical Reviews in Oncology/Hematology, Год журнала: 2024, Номер 196, С. 104324 - 104324

Опубликована: Март 8, 2024

Aberrant cyclin-dependent kinase 2 (CDK2) activation has been identified as a main resistance mechanism to CDK4/6 inhibition in hormone-receptor positive (HR+) breast cancer. Additionally, consistent preclinical evidence states its crucial role MYC and CCNE1 overexpressed cancer survival, such triple-negative cancers (TNBC), thus representing an appealing relatively unexplored target treatment opportunity. Despite emerging initial results of novel CDK2 inhibitors (CDK2i) activity, comprehensive outcomes collection is currently absent from the scientific literature. We aim provide overview ongoing clinical trials involving CDK2i context metastatic (mBC), either monotherapy or combination with other agents. The review extends beyond encompass CDK4 inhibitors, combined CDK2/4/6 well-known pan-CDK including those specifically directed at CDK2. Delving into results, we critically appraise observed efficacy offer valuable insights their potential impact future applications.

Язык: Английский

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Targeting triple negative breast cancer stem cells using nanocarriers

Discover Nano, Год журнала: 2024, Номер 19(1)

Опубликована: Март 7, 2024

Abstract Breast cancer is a complex and heterogeneous disease, encompassing various subtypes characterized by distinct molecular features, clinical behaviors, treatment responses. Categorization of based on the presence or absence estrogen receptor (ER), progesterone (PR), human epidermal growth factor 2 (HER2), leading to such as luminal A, B, HER2-positive, triple-negative breast (TNBC). TNBC, comprising around 20% all cancers, lacks expression ER, PR, HER2 receptors, rendering it unresponsive targeted therapies presenting significant challenges in treatment. TNBC associated with aggressive behavior, high rates recurrence, resistance chemotherapy. Tumor initiation, progression, are attributed stem cells (BCSCs), which possess self-renewal, differentiation, tumorigenic potential. Surface markers, self-renewal pathways (Notch, Wnt, Hedgehog signaling), apoptotic protein (Bcl-2), angiogenesis inhibition (VEGF inhibitors), immune modulation (cytokines, checkpoint inhibitors) among key targets discussed this review. However, targeting BCSC subpopulation presents challenges, including off-target effects, low solubility, bioavailability anti-BCSC agents. Nanoparticle-based offer promising approach target cellular processes implicated survival BSCS TNBC. In review, we explore nanocarrier-based approaches for BCSCs aiming overcome these improve outcomes patients. These nanoparticle-based therapeutic strategies hold promise addressing gap delivering while minimizing systemic toxicity enhancing efficacy. Graphical abstract

Язык: Английский

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Global status and attributable risk factors of breast, cervical, ovarian, and uterine cancers from 1990 to 2021

Journal of Hematology & Oncology, Год журнала: 2025, Номер 18(1)

Опубликована: Янв. 10, 2025

Female-specific cancers, particularly breast, cervical, ovarian, and uterine account for nearly 40% of all cancers in women. This study aimed to analyze the global epidemiological trends these from 1990 2021, offering insights into their evolving patterns providing valuable information health policymakers allocate healthcare resources more effectively. Data Global Burden Disease Study 2021 (GBD 2021) were used comprehensively assess incidence, mortality, disability-adjusted life years (DALYs) female-specific cancers. Age-standardized rates facilitated cross-regional comparisons, accounting differences population size demographics. The socio-demographic index (SDI) was employed categorize regions evaluate correlations between cancer burden economic level. In addition, risk factors attributable deaths DALYs assessed based on comparative assessment model GBD project. From increased at varying rates. breast accounted 2.08 million incident cases, 0.66 deaths, 20.25 globally. comparison, had lower burdens, with 0.67 million, 0.30 0.47 respectively. showed positive SDI, while cervical exhibited a negative correlation. Attributable cancer-associated included dietary risks, high body-mass (BMI), fasting plasma glucose, alcohol use, tobacco low physical activity. Additional unsafe sex use cancer, BMI occupational risks ovarian cancer. has recent decades, significant demographic regional discrepancies. These findings highlight urgent need targeted public interventions mitigate impact

Язык: Английский

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Platycodon grandiflorum-derived extracellular vesicles suppress triple-negative breast cancer growth by reversing the immunosuppressive tumor microenvironment and modulating the gut microbiota

Journal of Nanobiotechnology, Год журнала: 2025, Номер 23(1)

Опубликована: Фев. 7, 2025

Despite the approval of several artificial nanotherapeutics for treatment triple-negative breast cancer (TNBC), significant challenges, including unsatisfactory therapeutic outcomes, severe side effects, and high cost large-scale production, still restrict their long-term application. In contrast, plant-derived extracellular vesicles (PEVs) exhibit promising potential in therapy due to negligible systemic toxicity, bioavailability cost- effectiveness. this study, we developed an alternative strategy inhibit TNBC via Platycodon grandiflorum (PG)-derived (PGEVs). The PGEVs were isolated by ultracentrifugation sucrose gradient centrifugation method contained adequate functional components such as proteins, lipids, RNAs active molecules. exhibited remarkable stability, tolerating acidic digestion undergoing minimal changes simulated gastrointestinal fluid. They efficiently taken up tumor cells induced increased production reactive oxygen species (ROS), leading cell proliferation inhibition apoptosis, particularly line 4T1. Additionally, facilitated polarization tumor-associated macrophages (TAMs) toward M1 phenotype secretion pro-inflammatory cytokines. Further vivo investigations revealed that accumulated 4T1 tumors exerted effects through boosting anti-tumor immune responses modulating gut microbiota whether administered orally or intravenously (i.v.). conclusion, these findings highlight a natural, biocompatible efficient nanotherapeutic candidate treating TNBC.

Язык: Английский

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“Triple-Punch” Strategy Exosome-Mimetic Nanovesicles for Triple Negative Breast Cancer Therapy

ACS Nano, Год журнала: 2024, Номер unknown

Опубликована: Фев. 9, 2024

Triple-negative breast cancer (TNBC) is the most malignant cancer, with high rates of relapse and metastasis. Because nonspecific targeting chemotherapy insurmountable aggressiveness, TNBC therapy lacks an effective strategy. Exosomes have been reported as efficient drug delivery system (DDS). CD82 a tumor metastasis inhibitory molecule that enriched in exosomes. Aptamer AS1411 specifically targets cells due to its expression nucleolin. We generated "triple-punch" cell membrane-derived exosome-mimetic nanovesicle integrated overexpression, conjugation, doxorubicin (DOX) delivery. enrichment effectively inhibits migration cells. conjugation DOX loading proliferation induces apoptosis Our results demonstrate nanovesicles may facilitate therapeutics.

Язык: Английский

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The immune checkpoint TIGIT/CD155 promotes the exhaustion of CD8 + T cells in TNBC through glucose metabolic reprogramming mediated by PI3K/AKT/mTOR signaling

Cell Communication and Signaling, Год журнала: 2024, Номер 22(1)

Опубликована: Янв. 12, 2024

Abstract Objective The CD155/TIGIT axis has attracted considerable interest as an emerging immune checkpoint with potential applications in cancer immunotherapy. Our research focused on investigating the role of checkpoints progression triple-negative breast (TNBC). Methods We evaluated CD155 and TIGIT expression TNBC tissues using both immunohistochemistry (IHC) gene profiling. experiments, vivo vitro, provided evidence that inhibiting pathway reinstates ability CD8 + T cells to generate cytokines. To assess impact signaling blockade, we utilized Glucose Assay Kits Lactate measure alterations glucose lactate levels within cells. employed western blotting (WB) investigate glycolytic-related proteins PI3K/AKT/mTOR pathways following inhibition signaling. Results exhibits heightened a negative correlation extent infiltrating Furthermore, patients demonstrate elevated expression. findings indicate interaction between disrupts metabolism by suppressing activation pathway, ultimately leading reduced production cytokines Both vitro experiments have conclusively demonstrated capacity Moreover, administration blocking antibody against not only inhibits tumor growth but also augments functionality lymphocytes. Conclusions strongly suggest represents promising therapeutic target for treating TNBC.

Язык: Английский

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