Recent Anti-KRASG12D Therapies: A “Possible Impossibility” for Pancreatic Ductal Adenocarcinoma

Cancers, Год журнала: 2025, Номер 17(4), С. 704 - 704

Опубликована: Фев. 19, 2025

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, able to thrive in a challenging tumor microenvironment. Current standard therapies, including surgery, radiation, chemotherapy, and chemoradiation, have shown dismal survival prognosis, resulting less than year of life the metastatic setting. Methods: The pressing need find better therapeutic methods brought about discovery new targeted therapies against infamous KRAS mutations, major oncological drivers PDAC. Results: most common mutation KRASG12D, which causes conformational change protein that constitutively activates downstream signaling pathways driving cancer hallmarks. Novel anti-KRASG12D been developed for solid-organ tumors, small compounds, pan-RAS inhibitors, protease chimeric T cell receptors, vaccines. Conclusions: This comprehensive review summarizes current knowledge on biology KRAS-driven PDAC, latest options experimentally validated, developments ongoing clinical trials.

Язык: Английский

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Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells

Cell Reports, Год журнала: 2024, Номер 43(9), С. 114710 - 114710

Опубликована: Сен. 1, 2024

Язык: Английский

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HSF1 at the crossroads of chemoresistance: from current insights to future horizons in cell death mechanisms

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 12

Опубликована: Янв. 9, 2025

Heat Shock Factor 1 (HSF1) is a major transcriptional factor regulating the heat shock response and has become potential target for overcoming cancer chemoresistance. This review comprehensively examines HSF1's role in chemoresistance its as therapeutic cancer. We explore complex, intricate mechanism that regulates activation of HSF1, function promoting resistance to chemotherapy, strategies used manipulate HSF1 benefit. In addition, we discuss emerging research implicating roles autophagy, apoptosis, DNA damage repair, drug efflux, thus article highlights significance enhancing treatment efficacy.

Язык: Английский

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Comprehensive Molecular Profiling of Metastatic Pancreatic Adenocarcinomas

Cancers, Год журнала: 2025, Номер 17(3), С. 335 - 335

Опубликована: Янв. 21, 2025

Background: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed late, with an extremely poor prognosis. Treatment options like surgery, radiation, and chemotherapy are rarely curative. Tumor progression from primary to metastatic PDAC remains poorly understood at the molecular level. Methods: In current study, we analyzed profiles of obtained via Oncomine Comprehensive Assay in comparison PDAC. Results: The study cohort consisted 115 cases, which 71 (62%) cases succeeded testing while remaining 44 (38%) contained insufficient tumor cells. Molecular profiling revealed a total 239 alterations, 3.4 alterations per case on average, predominantly form gene mutations. most common mutations included KRAS (86%) TP53 (83%) Gene copy number were also detected 19 (27%) involving genes such as CCNE1 ERBB2. Compared reported our prior TCGA database, there seemed be increased rates TP53, ARID1A, BRAF, PIK3CA diseases. Conclusions: These findings suggest that possesses unique genetic characteristics, offering potential therapeutic targets advanced-stage pancreatic cancer.

Язык: Английский

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Capturing the Heterogeneity of the PDAC Tumor Microenvironment: Novel Triple Co-Culture Spheroids for Drug Screening and Angiogenic Evaluation

Cells, Год журнала: 2025, Номер 14(6), С. 450 - 450

Опубликована: Март 18, 2025

Pancreatic ductal adenocarcinoma (PDAC) presents significant treatment challenges due to its desmoplastic reaction, which impedes therapeutic effectiveness, highlighting the need for advanced vitro models better mimic complex tumor environment. The current three-dimensional co-culture of fibroblasts and endothelial cells are lacking, a challenge performing more comprehensive in research. Our study developed triple spheroid using MiaPaCa-2 BxPC-3 cancer cell lines, with RLT-PSC hPSC21 pancreatic stellate lines line HMEC-1. These were assessed through growth assays, multicolor flow cytometry optimize ratios, viability assays evaluate drug responses, tube formation assay spheroid-conditioned medium examine angiogenesis. spheroids effectively replicate PDAC microenvironment, showing variations responses influenced by cellular composition, density, spatial arrangement. showcased potential our quantitatively assess treatment-induced angiogenic response. cost-effective triple-co-culture provide vital insights into significantly improving quality evaluation responses.

Язык: Английский

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Treatment Innovations in Pancreatic Cancer: Putting Patient Priorities First

American Society of Clinical Oncology Educational Book, Год журнала: 2025, Номер 45(3)

Опубликована: Апрель 2, 2025

Pancreatic adenocarcinoma remains one of the most aggressive and difficult-to-treat solid tumor malignancies, with a high mortality-to-incidence ratio. Globally, pancreatic cancer ranks 12th in terms incidence but sixth for mortality signifying its behavior limited treatment options. While rates many other tumors have substantially improved over past few decades, temporal trends are quite sobering. In United States, from 2000 to 2020, increased, whereas at same time, cancers, such as lung, colorectal, or kidney, fallen appreciably. Is this lack innovation? How do we improve survival patients cancer? chapter, discuss recent advances future directions targeted therapies immunotherapies cancer, provide reasons both optimism caution systemic cancer.

Язык: Английский

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Immune-Based Strategies for Pancreatic Cancer in the Adjuvant Setting

Cancers, Год журнала: 2025, Номер 17(7), С. 1246 - 1246

Опубликована: Апрель 7, 2025

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality in United States, with poor overall survival across all stages. Less than 20% patients are eligible for curative surgical resection at diagnosis, and despite adjuvant chemotherapy, most will experience disease recurrence within two years. The incorporation immune-based strategies setting remains an area intense investigation unrealized promise. It offers potential providing durable control micro-metastatic following intent surgery enabling personalized treatments based on mutational neoantigen profiles derived from resected specimens. However, these attempts have failed to demonstrate significant clinical success, likely due immunosuppressive tumor microenvironment (TME) individual genetic heterogeneity. Despite challenges, strategies, such as therapeutic vaccines targeted towards neoantigens, demonstrated promise via immune activation induction T-cell infiltration. In this review, we highlight foundational lessons learned previous trials immunotherapy, discussing knowledge gained analyses disappointing results. addition, discuss how data been incorporated design new agents study concepts that proving be exciting more recent trials, shared antigen combination therapy immune-checkpoint inhibitors chemotherapy. This review evaluate novel approaches ongoing future studies provide insight into might evolve address unique challenges treatment PDAC setting.

Язык: Английский

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Cancer genetic profile and risk of thrombosis

European Journal of Internal Medicine, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Cancer-associated thrombosis (CAT) remains a leading cause of morbidity and mortality among oncology patients, with an incidence influenced by tumor type, stage, treatment, molecular characteristics. This review explores the determinants venous thromboembolism (VTE) in cancer, emphasizing its pathophysiology association specific oncogenic alterations. Certain profiles exhibit heightened VTE risk. In lung due to hypercoagulability mechanisms linked tissue factor overexpression, increased has been reported populations ALK (30-40 %) ROS1 rearrangements (34.7-46.6 %). gastrointestinal cancers, while pancreatic adenocarcinoma highest rates (up 22 %), KRAS mutations seem be implicated but not conclusively validated. Similarly, colorectal cancer (KRAS/BRAFV600E) antiangiogenic therapies may elevate thrombotic risk, warranting further study. High-grade gliomas, particularly glioblastomas, present up 30 %, driven podoplanin-induced platelet aggregation. IDH1 inversely correlate thrombosis, highlighting protective role. Emerging evidence suggests that agnostic biomarkers such as STK11 influence risk across types, others like KRAS, MET BRCA show inconclusive results. Large-scale validation studies are imperative integrate into clinical practice. Until then, management decisions should individualized, balancing risks oncologic considerations.

Язык: Английский

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Prognostic Role of Specific KRAS Mutations Detected in Aspiration and Liquid Biopsies from Patients with Pancreatic Cancer

Genes, Год журнала: 2024, Номер 15(10), С. 1302 - 1302

Опубликована: Окт. 7, 2024

Although the overall survival prognosis of patients in advanced stages pancreatic ductal adenocarcinoma (PDAC) is poor, typically ranging from days to months diagnosis, there are rare cases remaining therapy for longer periods time. Early estimations would allow rational decisions on complex interventions, including radical surgery and robust systemic regimens. Understandably, great interest finding prognostic markers that can be used patient stratification. We determined role various

Язык: Английский

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Bringing Hope to Improve Treatment in Pancreatic Ductal Adenocarcinoma—A New Tool for Molecular Profiling of KRAS Mutations in Tumor and Plasma Samples

Cancers, Год журнала: 2024, Номер 16(20), С. 3544 - 3544

Опубликована: Окт. 21, 2024

Pancreatic ductal adenocarcinoma (PDAC) incidence is rising, and prognosis remains poor due to late diagnosis limited effective therapies. Currently, patients are treated based on TNM staging, without molecular tumor characterization. This study aimed validate a technique that combines the amplification refractory mutation system (ARMS) with high-resolution melting analysis (HRMA) for detecting mutations in codon 12 of KRAS plasma, assess its prognostic value.

Язык: Английский

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