Castration-Resistant Prostate Cancer: From Uncovered Resistance Mechanisms to Current Treatments

Cancers, Journal Year: 2023, Volume and Issue: 15(20), P. 5047 - 5047

Published: Oct. 19, 2023

Prostate cancer (PC) is the second most common in men worldwide. Despite recent advances diagnosis and treatment, castration-resistant prostate (CRPC) remains a significant medical challenge. cells can develop mechanisms to resist androgen deprivation therapy, such as AR overexpression, mutations, alterations coregulators, increased steroidogenic signaling pathways, outlaw bypass pathways. Various treatment options for CRPC exist, including chemotherapy, immunotherapy, localized or systemic therapeutic radiation, PARP inhibitors. However, more research needed combat effectively. Further investigation into underlying of disease development new strategies will be crucial improving patient outcomes. The present work summarizes current knowledge regarding that promote CRPC, both AR-dependent independent Additionally, we provide an overview currently approved with special emphasis on radiation inhibitors, potential combination strategies.

Language: Английский

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Inhibition of CDC20 potentiates anti-tumor immunity through facilitating GSDME-mediated pyroptosis in prostate cancer

Experimental Hematology and Oncology, Journal Year: 2023, Volume and Issue: 12(1)

Published: Aug. 1, 2023

Abstract Background Increasing evidence suggests that immunotherapy, especially immune checkpoint inhibitors (ICIs), has the potential to facilitate long-term survival in various cancer besides prostate cancer. Emerging indicated pyroptosis, an immunogenic form of cell death, could trigger anti-tumor microenvironment and enhance effectiveness immunotherapy. Nevertheless, mechanism underlying regulation pyroptosis signaling remains unclear. Methods The differential expression human E3 ligases was integratedly analyzed from five independent public datasets. Moreover, immunohistochemistry analysis a tissue microarray derived patients confirmed results bioinformatic analysis. Furthermore, lines were evaluated via next-generation RNA sequencing assess transcriptomic profile upon CDC20 depletion. Next, qRT-PCR, Western blotting, cycloheximide assay, immunoprecipitation, ubiquitination assay employed explore correlation interaction between GSDME. Both immune-deficient immune-competent murine models utilized examine efficacy inhibition with or without anti-PD1 antibodies, respectively. To analyze xenografts, tumor tissues examined by flow cytometry. Results multiple cohorts suggested most significantly over-expressed ligase. In addition, exerted negative regulatory effect on pathway targeting GSDME for ubiquitination-mediated proteolysis degron-dependent manner. Knockdown leads increased abundance transition apoptosis response death signals. our syngeneic models, we found depletion enhances immunity promoting infiltration CD8 + T lymphocytes dependent existence GSDME, as well reducing myeloid cells. More importantly, Apcin, small molecular inhibitor targets CDC20, exhibited synergistic effects anti-PD1-based immunotherapy Conclusions Overall, these findings provide new insights into upstream GSDME-mediated which specifically interacts facilitates its Importantly, data highlight novel pathways cellular enhancing

Language: Английский

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Components, Formulations, Deliveries, and Combinations of Tumor Vaccines

ACS Nano, Journal Year: 2024, Volume and Issue: 18(29), P. 18801 - 18833

Published: July 9, 2024

Tumor vaccines, an important part of immunotherapy, prevent cancer or kill existing tumor cells by activating restoring the body's own immune system. Currently, various formulations vaccines have been developed, including cell membrane DNA mRNA polypeptide virus-vectored and tumor-in-situ vaccines. There are also multiple delivery systems for such as liposomes, vesicles, viruses, exosomes, emulsions. In addition, to decrease risk escape tolerance that may exist with a single vaccine, combination therapy radiotherapy, chemotherapy, checkpoint inhibitors, cytokines, CAR-T therapy, photoimmunotherapy is effective strategy. Given critical role in here, we look back history discuss antigens, adjuvants, formulations, systems, mechanisms, future directions

Language: Английский

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Overcoming drug resistance in castrate-resistant prostate cancer: current mechanisms and emerging therapeutic approaches

Cancer Drug Resistance, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Metastatic castration-resistant prostate cancer (mCRPC) is driven by a complex network of resistance mechanisms against standard-of-care therapies, resulting in poor long-term outcomes. This review offers uniquely comprehensive and integrative perspective on these pathways, systematically examining both androgen receptor (AR)-dependent factors (including AR overexpression, point mutations, glucocorticoid signaling, splice variants, post-translational modifications, altered coregulators, intratumoral hormone biosynthesis) AR-independent pathways (such as neuroendocrine differentiation, lineage plasticity, alternative growth factor signaling). We also highlight influencing immunotherapy, chemotherapy, radiopharmaceutical therapy targeted therapy. By synthesizing emerging insights across domains, this not only clarifies the underlying biology mCRPC but identifies key leverage points for more effective interventions. Building foundation, we propose forward-looking framework overcoming drug resistance, emphasizing importance biomarker-guided patient selection, combination strategies that simultaneously target multiple mechanisms, novel therapies under investigation. These recommendations are intended to guide future clinical trial designs research priorities move beyond incremental improvements. Ultimately, synthesis aims serve resource clinicians researchers accelerate development durable, precision-based treatment mCRPC.

Language: Английский

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The SGLT2 inhibitor canagliflozin suppresses growth and enhances prostate cancer response to radiotherapy

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: Sept. 8, 2023

Abstract Radiotherapy is a non-invasive standard treatment for prostate cancer (PC). However, PC develops radio-resistance, highlighting need agents to improve radiotherapy response. Canagliflozin, an inhibitor of sodium-glucose co-transporter-2, approved use in diabetes and heart failure, but also shown inhibit growth. whether canagliflozin can response remains unknown. Here, we show that well-tolerated doses suppress proliferation survival androgen-sensitive insensitive human cells tumors sensitize them radiotherapy. Canagliflozin blocks mitochondrial respiration, promotes AMPK activity, inhibits the MAPK mTOR-p70 S6k /4EBP1 pathways, activates cell cycle checkpoints, part through HIF-1 α suppression. mediates transcriptional reprogramming several metabolic pathways known be regulated by ETS E2F family transcription factors. Genes downregulated are associated with poor prognosis. This study lays groundwork clinical investigation prevention combination

Language: Английский

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Aberrant Glycosylation as Immune Therapeutic Targets for Solid Tumors

Cancers, Journal Year: 2023, Volume and Issue: 15(14), P. 3536 - 3536

Published: July 8, 2023

Glycosylation occurs at all major types of biomolecules, including proteins, lipids, and RNAs to form glycoproteins, glycolipids, glycoRNAs in mammalian cells, respectively. The carbohydrate moiety, known as glycans on glycoproteins is diverse their compositions structures. Normal cells have unique array or glycome which play pivotal roles many biological processes. glycan structures cancer however, are often altered, some having termed tumor-associated antigens (TACAs). TACAs tumor biomarkers epitopes themselves, glycoconjugates. Some those serve glyco-biomarkers clinical practice, while others the immune therapeutic targets for treatment cancers. A monoclonal antibody (mAb) GD2, an intermediate sialic-acid containing glycosphingolipids, example FDA-approved therapy neuroblastoma indication young adults others. Strategies targeting aberrant currently under development, proceeded trials. In this review, we summarize established most promising glycosylation solid tumors.

Language: Английский

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Emerging Immunotherapy Approaches for Treating Prostate Cancer

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(18), P. 14347 - 14347

Published: Sept. 20, 2023

Immunotherapy has emerged as an important approach for cancer treatment, but its clinical efficacy been limited in prostate compared to other malignancies. This review summarizes key immunotherapy strategies under evaluation cancer, including immune checkpoint inhibitors, bispecific T cell-engaging antibodies, chimeric antigen receptor (CAR) cells, therapeutic vaccines, and cytokines. For each modality, the rationale stemming from preclinical studies is discussed along with outcomes completed trials improve that are being tested ongoing trials. Imperative endeavors include biomarker discovery patient selection, deciphering resistance mechanisms, refining cellular therapies such CAR early-stage intervention were reviewed. These efforts instill optimism may eventually deliver significant benefits expand treatment options patients advanced cancer.

Language: Английский

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Targeting a STING agonist to perivascular macrophages in prostate tumors delays resistance to androgen deprivation therapy

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(7), P. e009368 - e009368

Published: July 1, 2024

Background Androgen deprivation therapy (ADT) is a front-line treatment for prostate cancer. In some men, their tumors can become refractory leading to the development of castration-resistant cancer (CRPC). This causes regrow and metastasize, despite ongoing treatment, impacts negatively on patient survival. ADT known stimulate accumulation immunosuppressive cells like protumoral tumor-associated macrophages (TAMs), myeloid-derived suppressor regulatory T in tumors, as well hypofunctional cells. Protumoral TAMs have been shown accumulate around tumor blood vessels during chemotherapy radiotherapy other forms cancer, where they drive relapse. Our aim was see whether such perivascular (PV) also ADT-treated prior CRPC, and, if so, selectively inducing them express potent immunostimulant, interferon beta (IFNβ), would antitumor immunity delay CRPC. Methods We used multiplex immunofluorescence assess effects distribution activation status TAMs, CD8+T cells, CD4+T NK mouse and/or human tumors. then antibody-coated, lipid nanoparticles (LNPs) target STING agonist, 2′3′-cGAMP (cGAMP), PV ADT. Results accumulated at high density response expressed markers phenotype including folate receptor-beta (FR-β), MRC1 (CD206), CD169 VISTA. Additionally, higher numbers inactive (PD-1-) reduced active (CD69+) were present these areas. LNPs coated with an antibody FR-β delivered cGAMP activated upregulated expression IFNβ. resulted marked increase (along cells) areas, significantly delayed onset Antibody depletion LNP administration demonstrated essential role CRPC induced by LNPs. Conclusion Together, our data indicate that targeting agonist could be extend window

Language: Английский

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Clinical insights into nanomedicine and biosafety: advanced therapeutic approaches for common urological cancers

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Aug. 13, 2024

Urological cancers including those of the prostate, bladder, and kidney, are prevalent often lethal malignancies besides other less common ones like testicular penile cancers. Current treatments have major limitations side effects, recurrence, resistance, high costs, poor quality life. Nanotechnology offers promising solutions through enhanced diagnostic accuracy, targeted drug delivery, controlled release, multimodal imaging. This review reflects clinical challenges nanomedical advances across urological In prostate cancer, nanoparticles improve delineation radiosensitization in radiation therapy, enable fluorescent guidance surgery, enhance chemotherapy penetration metastatic disease. Nanoparticles also overcome bladder permeability barriers to increase residence time intravesical therapy agents. renal nanocarriers potentiate tyrosine kinase inhibitors immunotherapy while gene vectors zinc oxide demonstrate antiproliferative effects. Across modalities, applications nanomedicine include polymeric, liposomal, metal for prodrug photodynamic thermal ablation. Biosafety assessments reveal favorable profiles but translation remains limited, necessitating further trials. conclusion, nanotechnology holds significant potential earlier detection, precise intervention, tailored treatment malignancies, warranting expanded research transform patient outcomes.

Language: Английский

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Immunoliposome-based targeted delivery of the CRISPR/Cas9gRNA-IL30 complex inhibits prostate cancer and prolongs survival

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: 56(9), P. 2033 - 2051

Published: Sept. 4, 2024

Language: Английский

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