Therapeutic resistance to anti-oestrogen therapy in breast cancer

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(10), P. 673 - 685

Published: July 27, 2023

Language: Английский

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Current and future immunotherapeutic approaches in pancreatic cancer treatment

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: June 4, 2024

Abstract Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type tumor have remained grim long time. Currently, it extremely challenging to prevent or detect early enough effective treatment because patients rarely exhibit symptoms there are no reliable indicators detection. Most advanced spreading that difficult treat, treatments like chemotherapy radiotherapy can only slightly prolong their life by few months. Immunotherapy has revolutionized pancreatic cancer, yet its effectiveness limited tumor's immunosuppressive hard-to-reach microenvironment. First, article explains microenvironment highlights wide range immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered chimeric antigen [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced cells, immune checkpoint inhibitors, immunomodulators, vaccines, strategies targeting myeloid in context contemporary knowledge future trends. Lastly, discusses main challenges ahead immunotherapy.

Language: Английский

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Tumor immune microenvironment-based therapies in pancreatic ductal adenocarcinoma: time to update the concept

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

Published: Jan. 2, 2024

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. The tumor immune microenvironment (TIME) formed by interactions among cancer cells, cancer-associated fibroblasts (CAF), and extracellular matrix (ECM) components drives PDAC in a more immunosuppressive direction: this major cause therapy resistance poor prognosis. In recent years, research has advanced our understanding signaling mechanism which TIME interact with evolution immunophenotyping. Through revolutionary technologies such as single-cell sequencing, we have gone from simply classifying PDACs “cold” “hot” to comprehensive approach immunophenotyping that considers all cells components. This key improving clinical efficacy treatments. review, elaborate on various PDAC, mechanisms underlying their interactions, latest into A deep these network will contribute effective combination TIME-based therapeutic approaches, checkpoint inhibitors (ICI), adoptive cell therapy, therapies targeting myeloid CAF reprogramming, stromal normalization. By selecting appropriate integrated based precise immunophenotyping, significant advances future treatment are possible.

Language: Английский

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Consensus, debate, and prospective on pancreatic cancer treatments

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Oct. 10, 2024

Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite improvement multi-modality treatment strategies, prognosis pancreatic was not improved dramatically. For resectable or borderline patients, surgical strategy centered on improving R0 resection rate is consensus; however, role neoadjuvant therapy in patients and optimal chemotherapy with without radiotherapy were debated. Postoperative adjuvant gemcitabine/capecitabine mFOLFIRINOX recommended regardless margin status. Chemotherapy as first-line for advanced metastatic included FOLFIRINOX, gemcitabine/nab-paclitaxel, NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan only standard care second-line therapy. Immunotherapy an innovative although anti-PD-1 antibody currently agent approved by MSI-H, dMMR, TMB-high tumors, which represent very small subset cancers. Combination strategies to increase immunogenicity overcome immunosuppressive tumor microenvironment may sensitize immunotherapy. Targeted therapies represented PARP KRAS inhibitors are also under investigation, showing benefits progression-free survival objective response rate. This review discusses current modalities highlights cancer.

Language: Английский

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Epigenetic regulation in cancer

MedComm, Journal Year: 2024, Volume and Issue: 5(2)

Published: Feb. 1, 2024

Abstract Epigenetic modifications are defined as heritable changes in gene activity that do not involve the underlying DNA sequence. The oncogenic process is driven by accumulation of alterations impact genome's structure and function. Genetic mutations, which directly disrupt sequence, complemented epigenetic modulate expression, thereby facilitating acquisition malignant characteristics. Principals among these shifts methylation histone mark patterns, promote tumor development metastasis. Notably, reversible nature alterations, opposed to permanence genetic changes, positions machinery a prime target discovery novel therapeutics. Our review delves into complexities regulation, exploring its profound effects on initiation, metastatic behavior, metabolic pathways, microenvironment. We place particular emphasis dysregulation at each level modulation, including but limited to, aberrations enzymes responsible for modification, subunit loss or fusions chromatin remodeling complexes, disturbances higher‐order structure. Finally, we also evaluate therapeutic approaches leverage growing understanding dysregulation, offering new avenues cancer treatment.

Language: Английский

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Overcoming immunotherapy resistance in gastric cancer: insights into mechanisms and emerging strategies

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 7, 2025

Abstract Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options in advanced stages. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD1/PD-L1, has emerged as promising therapeutic approach. However, significant proportion patients exhibit primary or acquired resistance, limiting the overall efficacy immunotherapy. This review provides comprehensive analysis mechanisms underlying immunotherapy resistance GC, including role tumor microenvironment, dynamic PD-L1 expression, compensatory activation other checkpoints, and genomic instability. Furthermore, explores GC-specific factors such molecular subtypes, unique evasion mechanisms, impact Helicobacter pylori infection. We also discuss emerging strategies to overcome combination therapies, novel immunotherapeutic approaches, personalized based on genomics microenvironment. By highlighting these key areas, this aims inform future research directions clinical practice, ultimately improving outcomes for GC undergoing

Language: Английский

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Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: July 24, 2023

Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared the localized tumors, current standard-of-care therapies have failed improve survival patients with metastatic PDAC, that necessecitates exploration novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) vaccines emerged promising treatment modalities in certain cancers, limited responses been achieved PDAC. Therefore, specific mechanisms regulating response immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, microbiome persists throughout PDAC progression, allowing neoplastic cells grow locally metastasize distantly. escaping host surveillance are unique molecular, immunological, metabolic characteristics. Following chemokine exosomal guidance, these organ-specific pre-metastatic niches (PMNs) constituted local resident cells, stromal fibroblasts, suppressive metastasis-associated macrophages, neutrophils, myeloid-derived suppressor cells. differs from primary tumors cell composition, functionality, metabolism. Thus far, multiple molecular pathways, distinct identified dampen effector functions, confounding This review describes major immunoregulatory pathways contribute progression limit outcomes Overall, we highlight vulnerabilities attributable factors discuss whether targeting immunological "hot spots" could immunotherapies.

Language: Английский

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The Extracellular Niche and Tumor Microenvironment Enhance KRAS Inhibitor Efficacy in Pancreatic Cancer

Cancer Research, Journal Year: 2024, Volume and Issue: 84(7), P. 1115 - 1132

Published: Jan. 31, 2024

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that lacks effective treatment options, highlighting the need for developing new therapeutic interventions. Here, we assessed response to pharmacologic inhibition of KRAS, central oncogenic driver PDAC. In a panel PDAC cell lines, KRASG12D with MRTX1133 yielded variable efficacy in suppressing growth and downstream gene expression programs 2D cultures. On basis CRISPR-Cas9 loss-of-function screens, ITGB1 was identified as target enhance by regulating mechanotransduction signaling YAP/TAZ expression, which confirmed gene-specific knockdown combinatorial drug synergy. Interestingly, considerably more efficacious 3D Moreover, elicited pronounced cytostatic effect vivo controlled tumor patient-derived xenografts. syngeneic models, led regression did not occur immune-deficient hosts. Digital spatial profiling on tissues indicated MRTX1133-mediated KRAS enhanced IFNγ induced antigen presentation modulated microenvironment. Further investigation immunologic using single-cell sequencing multispectral imaging revealed associated suppression neutrophils influx effector CD8+ T cells. Together, these findings demonstrate both cell-intrinsic -extrinsic events contribute credential promising strategy large percentage patients Significance: Pharmacologic elicits varied responses pancreatic cancer organoid cultures, xenografts, underscoring importance microenvironment responses.

Language: Английский

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Antibody drug conjugates: hitting the mark in pancreatic cancer?

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: Oct. 25, 2023

Pancreatic cancer is one of the most common causes cancer-related death, and 5-year survival rate has only improved marginally over last decade. Late detection disease means that in cases advanced locally and/or metastasized, curative surgery not possible. Chemotherapy still first-line treatment however, this had a modest impact improving survival, with associated toxicities. Therefore, there an urgent need for targeted approaches to better treat pancreatic cancer, while minimizing treatment-induced side-effects. Antibody drug conjugates (ADCs) are option could fill gap. Here, monoclonal antibody used deliver extremely potent drugs directly tumor site improve on-target killing reducing off-target toxicity. In paper, we review current literature ADC targets have been examined vivo treating summarize on-going clinical trials using ADCs discuss potential strategies their therapeutic window.

Language: Английский

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The Role of Tumor Microenvironment in Pancreatic Cancer Immunotherapy: Current Status and Future Perspectives

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9555 - 9555

Published: Sept. 3, 2024

Pancreatic cancer comprises different subtypes, where most cases include ductal adenocarcinoma (PDAC). It is one of the deadliest tumor types, with a poor prognosis. In majority patients, disease has already spread by time diagnosis, making full recovery unlikely and increasing mortality risk. Despite developments in its detection management, including chemotherapy, radiotherapy, targeted therapies as well advances immunotherapy, only about 13% PDAC patients does overall survival exceed 5 years. This may be attributed, at least part, to highly desmoplastic microenvironment (TME) that acts barrier limiting perfusion, drug delivery, immune cell infiltration contributes establishment immunologically ‘cold’ conditions. Therefore, there an urgent need unravel complexity TME promotes progression decipher mechanisms pancreatic tumors’ resistance immunotherapy. this review, we provide overview major cellular non-cellular components TME, their biological interplays. We also discuss current state therapeutic treatments focus on ongoing future immunotherapy efforts multimodal aiming remodeling improve efficacy.

Language: Английский

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