Combination immune checkpoint and targeted protein kinase inhibitors for the treatment of renal cell carcinomas

Pharmacological Research, Journal Year: 2024, Volume and Issue: 203, P. 107181 - 107181

Published: April 12, 2024

Kidney cancers comprise about 3% of all new malignancies in the United States. Renal cell carcinomas (RCCs) are most common type renal malignancy making up 85% kidney cancer cases. Signs and symptoms can result from local tumor growth, paraneoplastic syndromes, or distant metastases. The classic triad presentation with flank pain, hematuria, a palpable abdominal mass occurs fewer than 10% patients. Most diagnoses incidental imaging findings (ultrasonography CT imaging) performed for another reason. Localized disease is treated by partial nephrectomy, total ablation (tumor destruction heat cold). When tumors have metastasized, systemic therapy protein-tyrosine kinase antagonists including sorafenib, sunitinib, pazopanib, tivozanib that target vascular endothelial, platelet-derived, fibroblast, hepatocyte, stem factor growth receptors (VEGFR, PDGFR, FGFR, MET, Kit) were prescribed after 2005. monoclonal antibody immune checkpoint inhibitor nivolumab (targeting programed death protein 1, PD1) was approved treatment RCCs 2015. It usually used now combination ipilimumab CTLA-4) cabozantinib (a multikinase blocker). Other therapies include pembrolizumab axitinib VEGFR PDGFR blocker) lenvatinib inhibitor). Since KEYNOTE-426 clinical trial, use inhibitors standard care patients metastatic monotherapies only those individuals who cannot receive tolerate inhibitors.

Language: Английский

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Dietary Restrictions and Cancer Prevention: State of the Art

Nutrients, Journal Year: 2025, Volume and Issue: 17(3), P. 503 - 503

Published: Jan. 29, 2025

Worldwide, almost 10 million cancer deaths occurred in 2022, a number that is expected to rise 16.3 by 2040. Primary prevention has long been acknowledged as crucial approach reducing incidence. In fact, between 30 and 50 percent of all tumors are known be preventable eating healthy diet, staying active, avoiding alcohol, smoking, being overweight. Accordingly, many international organizations have created tumor guidelines, which underlie the importance following diet emphasizes plant-based foods while minimizing consumption red/processed meat, sugars, processed foods, alcohol. However, further research needed define relationship effect specific diets or nutritional components on prevention. Interestingly, reductions food intake dietetic restrictions can extend lifespan yeast, nematodes, flies, rodents. Despite controversial results humans, those approaches potential ameliorate health via direct indirect effects signaling pathways involved onset. Here, we describe latest knowledge cancer-preventive dietary biochemical processes involved. Molecular, preclinical, clinical studies evaluating different fasting strategies will also reviewed.

Language: Английский

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CD44-Targeted nanoparticles for remodeling the tumor microenvironment in a 3D Macrophage-Embedded ovarian cancer model with stem Cell-Like features

International Journal of Pharmaceutics, Journal Year: 2025, Volume and Issue: unknown, P. 125483 - 125483

Published: March 1, 2025

Language: Английский

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MAM kinases: physiological roles, related diseases, and therapeutic perspectives—a systematic review

Cellular & Molecular Biology Letters, Journal Year: 2025, Volume and Issue: 30(1)

Published: March 28, 2025

Abstract Mitochondria-associated membranes (MAMs) are tethering regions amid the of endoplasmic reticulum (ER) and mitochondria. They a lipid raft-like structure occupied by various proteins that facilitates signal transduction between two organelles. The MAM proteome participates in cellular functions such as calcium (Ca 2+ ) homeostasis, synthesis, ER stress, inflammation, autophagy, mitophagy, apoptosis. human kinome is superfamily homologous consisting 538 kinases. MAM-associated kinases participate aforementioned act cell fate executors. Studies have proved dysregulated kinase interactions an etiology for diseases including cancer, diabetes mellitus, neurodegenerative diseases, cardiovascular (CVDs), obesity. Several small inhibitory molecules been well explored promising drug candidates clinical trials with accelerating impact field precision medicine. This review narrates physiological actions, pathophysiology, therapeutic potential recent updates field. Graphical

Language: Английский

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Exploring Potential Therapeutic Applications of Tazarotene: Gene Regulation Mechanisms and Effects on Melanoma Cell Growth

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(4), P. 237 - 237

Published: March 28, 2025

Tazarotene, a retinoid derivative, is widely used in treating skin conditions such as psoriasis and acne. Recent studies have demonstrated its potential promising therapeutic agent for melanoma situ. Its primary mechanism of action involves the selective activation retinoic acid receptors (RAR-β RAR-γ), which play important roles regulating cell growth, differentiation, apoptosis. By activating these receptors, tazarotene influences expression several downstream inducible genes, tazarotene-induced gene-1 (TIG1), TIG2, TIG3. These genes crucial proliferation, invasiveness, immune responses tumor microenvironment. This review aims to provide comprehensive overview current status derivatives—particularly tazarotene—in treatment latest research regarding their molecular mechanisms. We will explore how suppresses growth through gene regulation mechanisms discuss role within Additionally, we assess advantages challenges using topical future clinical applications. contribute wider understanding tazarotene’s antitumor mechanisms, providing solid theoretical foundation option

Language: Английский

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Hydrogel‐Mediated Preservation of Live Tumor Explants for Drug Development in Peritoneal Metastases

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: May 20, 2025

Abstract Clinically effective treatments for peritoneal metastases (PM) remain a significant unmet need. To expedite drug development in PM, hyaluronan (HA) hydrogel‐supported PM patient‐derived tumor explants (PDTE) that better preserve histological features, composition, and biological pathways of the original tumor, as compared to conventional PDTE culture methods are developed. Hydrogel modulation shows stiffness, degradation, three‐dimensional embedding, HA itself key parameters enhance maintenance ex vivo. Further, hydrogels effectively viability by disrupting myosin II‐mediated tissue contraction, phenomenon occurs absence hydrogel embedding. Lastly, addition ascites into not only recapitulates changes microenvironment observed patients but also ascites‐dependent efficacy, highlighting importance incorporating vivo models accurate therapeutic evaluation. The bioengineered this study serve valuable platform treatment personalization.

Language: Английский

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Regulatory-Associated Protein of mTOR-Mediated Signaling: A Nexus Between Tumorigenesis and Disease

Targets, Journal Year: 2024, Volume and Issue: 2(4), P. 341 - 371

Published: Nov. 7, 2024

RAPTOR (regulatory-associated protein of mTOR) is a pivotal component the mammalian target rapamycin complex 1 (mTORC1), playing central role in regulating cell growth, metabolism and stress responses. As scaffold protein, recruits key substrates such as eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) ribosomal S6 kinase (S6K), facilitating their phosphorylation by mTORC1, which turn drives synthesis, lipid cellular proliferation. Its regulatory function becomes especially crucial under conditions nutrient deprivation or stress, where it enhances stability mTORC1 complex, allowing cells to adapt fluctuating environmental cues. The hyperactivation largely mediated RAPTOR, frequently observed various cancers, contributing uncontrolled proliferation tumorigenesis. Moreover, RAPTOR’s modulation immune responses metabolic pathways extends its influence beyond oncogenesis, impacting inflammatory diseases disorders. This review meticulously elucidates structure, post-translational modifications well indispensable within emphasizing functions adaptation, response disease pathology including oncogenesis. Furthermore, explores emergent therapeutic avenues targeting RAPTOR-mediated signaling, underscoring potential revolutionize cancer treatment management related pathophysiological conditions.

Language: Английский

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Tumor Biology Hides Novel Therapeutic Approaches to Diffuse Large B-Cell Lymphoma: A Narrative Review

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(21), P. 11384 - 11384

Published: Oct. 23, 2024

Diffuse large B-cell lymphoma (DLBCL) is a malignancy of immense biological and clinical heterogeneity. Based on the transcriptomic or genomic approach, several different classification schemes have evolved over years to subdivide DLBCL into clinically (prognostically) relevant subsets, but each leaves unclassified samples. Herein, we outline tumor biology behind actual potential drug targets address challenges drawbacks coupled with their (potential) use. Therapeutic modalities are discussed, including small-molecule inhibitors, naked antibodies, antibody-drug conjugates, chimeric antigen receptors, bispecific antibodies T-cell engagers, immune checkpoint inhibitors. Candidate drugs explored in ongoing trials diverse toxicity issues refractoriness drugs. According literature DLBCL, promise for new therapeutic lies epigenetic alterations, receptor NF-κB pathways. present putative hiding lipid pathways, ferroptosis, gut microbiome that could be used addition immuno-chemotherapy improve general health status patients, thus increasing chance being cured. It may time devote more effort exploring metabolism discover novel druggable targets. We also performed bibliometric knowledge-map analysis published from 2014-2023.

Language: Английский

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A nanoencapsulated oral formulation of fenretinide promotes local and metastatic breast cancer dormancy in HER2/neu transgenic mice

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: Nov. 5, 2024

Abstract Background Prevention and treatment of metastatic breast cancer (BC) is an unmet clinical need. The retinoic acid derivative fenretinide (FeR) was previously evaluated in Phase I-III trials but, despite its excellent tolerability antitumor activity preclinical models, showed limited therapeutic efficacy due to poor bioavailability. We recently generated a new micellar formulation FeR, Bionanofenretinide (Bio-nFeR) showing enhanced bioavailability, low toxicity, strong on human lung cancer, colorectal melanoma xenografts. In the present study, we tested effect Bio-nFeR model BC. Methods used BC cell lines for vitro analyses viability, cycle migratory capacity. For vivo studies, HER2/neu transgenic mice (neuT) as spontaneously Mice were treated orally with at sacrifice primary tumors analyzed by histology immunohistochemistry. Molecular pathways activated immunoblotting. Stem content assessed flow cytometry, immunoblotting functional assays such colony formation ex second transplantation assay immunocompromised mice. Results inhibited proliferation migration neuT cells significant against onset Importantly, highest effectiveness progression, counteracting both metastasis initiation expansion. main mechanism action consists promoting tumor dormancy through combined induction antiproliferative signals inhibition mTOR pathway. Conclusion high mammary carcinogenesis, coupled indicates this potential candidate adjuvant therapy patients risk developing metastasis.

Language: Английский

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Selection and validation of reference genes for RT-qPCR normalization in dormant cancer cells

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 13, 2024

Recent findings have indicated that pharmacological inhibition of the mTOR kinase can become a widely used experimental approach to generate dormant cancer cells in vitro. However, suppression mTOR, which is responsible for global translation, significantly rewire basic cellular functions influencing expression housekeeping genes. To prevent incorrect selection reference gene in tumor cells, we analyzed stability genes GAPDH, ACTB, TUBA1A, RPS23, RPS18, RPL13A, PGK1, EIF2B1, TBP, CYC1, B2M, and YWHAZ T98G, A549, PA-1 cell lines treated with dual inhibitor AZD8055. It has been revealed ACTB gene, encoding cytoskeleton, RPL13A genes, ribosomal proteins, undergoes dramatic changes, these are categorically inappropriate RT-qPCR normalization inhibitors. B2M were determined be bestl A549 TUBA1A GAPDH best T98G cells. The optimal among 12 candidate not line. Validation investigated demonstrated led significant distortion profile

Language: Английский

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