Harnessing endoscopic ultrasound-guided radiofrequency ablation to reshape the pancreatic ductal adenocarcinoma microenvironment and elicit systemic immunomodulation DOI Creative Commons
Vishali Moond,

Bhumi Maniyar,

Prateek S. Harne

et al.

Exploration of Targeted Anti-tumor Therapy, Journal Year: 2024, Volume and Issue: 5(5), P. 1056 - 1073

Published: Aug. 15, 2024

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognostics and substantial therapeutic challenges, with dismal survival rates. Tumor resistance in PDAC primarily attributed to its fibrotic, hypoxic, immune-suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA), an Food Drug Administration (FDA)-approved minimally invasive technique for treating pancreatic cancer, disrupts tumors heat induces coagulative necrosis, releasing antigens that may trigger a systemic immune response—the abscopal effect. We aim elucidate the roles of EUS-RFA-mediated thermal mechanical stress enhancing anti-tumor immunity PDAC. A comprehensive literature review focused on immunomodulation immunotherapy understand pathophysiological mechanisms RFA effect TME, which could prevent recurrence resistance. reviewed clinical, preclinical, vitro studies adenocarcinoma, discussing unique immunomodulatory effects EUS-RFA. Recent findings suggest combining adjuvants enhances responses adenocarcinoma. EUS-RFA offers dual benefit against directly reducing viability indirectly immunity. Observations neutrophil-mediated programmed cell death ligand 1 (PD-L1) modulation support integrating targeted immunotherapies managing Integrating treatment promises direct cytoreduction synergistic molecular therapies. Prospective clinical trials are crucial assess efficacy this combined approach improving outcomes rates advanced cases.

Language: Английский

Cancer immune evasion, immunoediting and intratumour heterogeneity DOI
Malte Roerden, Stefani Spranger

Nature reviews. Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Language: Английский

Citations

7
Clinicogenomic landscape of pancreatic adenocarcinoma identifies KRAS mutant dosage as prognostic of overall survival DOI Creative Commons
Anna M. Varghese, Maria Perry, Joanne F. Chou

et al.

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Nearly all pancreatic adenocarcinomas (PDAC) are genomically characterized by KRAS exon 2 mutations. Most patients with PDAC present advanced disease and treated cytotoxic therapy. Genomic biomarkers prognostic of outcomes have been challenging to identify. Herein leveraging a cohort 2,336 spanning stages, we characterize the genomic clinical correlates in PDAC. We show that subtype wild-type tumors is associated early onset, distinct somatic germline features, significantly better overall survival. Allelic imbalances at locus widespread. mutant allele dosage gains, observed one five (20%) KRAS-mutated diploid tumors, correlated demonstrate potential across stages. With rapidly expanding landscape targeting, our findings implications for practice understanding de novo acquired resistance RAS therapeutics. Analyses data from adenocarcinoma find gains hallmark progression predictive poor different

Language: Английский

Citations

3
KRAS Mutation Status and Treatment Outcomes in Patients With Metastatic Pancreatic Adenocarcinoma DOI Creative Commons
Carter Norton, Matthew Shaw,

Zachary Rubnitz

et al.

JAMA Network Open, Journal Year: 2025, Volume and Issue: 8(1), P. e2453588 - e2453588

Published: Jan. 7, 2025

Importance Despite the high prevalence of KRAS alterations in pancreatic ductal adenocarcinoma (PDAC), clinical impact common mutations with different cytotoxic regimens is unknown. This evidence important to inform current treatment and provide a benchmark for emergent targeted therapies metastatic PDAC. Objective To assess implications G12 PDAC compare outcomes standard-of-care multiagent across these mutations. Design, Setting, Participants retrospective cohort study obtained deidentified data 5382 patients from nationwide (US-based) clinicogenomic database. The originated approximately 280 US cancer clinics (approximately 800 sites care). Patients diagnosed February 9, 2010, September 20, 2022, sufficient follow-up were included. Main Outcomes Measures Median overall survival (OS) time next (TTNT) calculated each mutation group. Hazard ratios (HRs) generated using multivariate Cox proportional hazards models mutation-treatment combinations. Results A total 2433 included analysis (mean age at first treatment, 67.0 [range, 66.0-68.0] years; 1340 male [55.1%]). Among 2023 mutations, those G12R had longest median TTNT (6.0 [95% CI, 5.2-6.6] months) OS (13.2 10.6-15.2] months). G12D G12V significantly higher risk disease progression (HRs, 1.15; 1.04-1.29; P = .009] 1.16 1.04-1.30; .01], respectively) death 1.29 1.15-1.45; < .001] 1.23 1.09-1.39; .001], compared wild type. FOLFIRINOX regimen (fluorouracil, irinotecan, oxaliplatin, leucovorin) lower than gemcitabine 1.19 [1.09-1.29; 1.18 1.07-1.29; or without 1.37 1.11-1.69; .003] 1.41 CI 1.13-1.75; .002], nab-paclitaxel all patients. Conclusions Relevance In this PDAC, associated worse patient was more favorable outcomes, better gemcitabine-based therapies. These findings highlight need effective systemic groups

Language: Английский

Citations

2
The Clinical Implications of KRAS Mutations and Variant Allele Frequencies in Pancreatic Ductal Adenocarcinoma DOI Open Access

Faria Nusrat,

Akshay Khanna, Aditi Jain

et al.

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(7), P. 2103 - 2103

Published: April 4, 2024

The KRAS proto-oncogene is a major driver of pancreatic tumorigenesis and nearly ubiquitously mutated in ductal adenocarcinoma (PDAC). point mutations are detected over 90% PDAC cases, these have been shown to be associated with worse therapy response overall survival. Pathogenic mostly limited codons 12, 13 61, G12D, G12V, G12R, Q61H, G13D accounting for approximately 95% the mutant cases. Emerging data importance specific subtypes, as well variant allele frequency on clinical prognosis. Furthermore, novel technologies therapies being developed target encouraging early results. In this paper, we aim review recent studies regarding relative impact subtypes oncologic outcomes, application next generation sequencing analyses, ongoing research into targeting subtypes.

Language: Английский

Citations

11
Combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (OPTIMIZE-1): a single-arm, multicentre phase 1b/2 study DOI

Jean–Luc Van Laethem,

Ivan Borbath, Hans Prenen

et al.

The Lancet Oncology, Journal Year: 2024, Volume and Issue: 25(7), P. 853 - 864

Published: June 1, 2024

Language: Английский

Citations

9
MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer DOI Creative Commons
Sílvia Casacuberta‐Serra, Íñigo González-Larreategui,

Daniel Capitán-Leo

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 21, 2024

Abstract RAS and MYC rank amongst the most commonly altered oncogenes in cancer, with being frequently mutated amplified. The cooperative interplay between constitutes a complex multifaceted phenomenon, profoundly influencing tumor development. Together individually, these two regulate most, if not all, hallmarks of including cell death escape, replicative immortality, tumor-associated angiogenesis, invasion metastasis, metabolic adaptation, immune evasion. Due to their frequent alteration role tumorigenesis, emerge as highly appealing targets cancer therapy. However, due nature, both have been long considered “undruggable” and, until recently, no drugs directly targeting them had reached clinic. This review aims shed light on partnership, special attention active collaboration fostering an immunosuppressive milieu driving immunotherapeutic resistance cancer. Within this review, we also present update different inhibitors currently undergoing clinical trials, along outcomes combination strategies explored overcome drug resistance. recent development suggests paradigm shift long-standing belief “undruggability”, hinting at new era therapeutic targeting.

Language: Английский

Citations

8
Decoding pancreatic cancer: key risk factors across genetics and lifestyle DOI Creative Commons
Rohit Sharma, Rashmi Ghosh, Sourabh Kumar

et al.

Expert Review of Molecular Diagnostics, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 5

Published: Feb. 7, 2025

Language: Английский

Citations

1
Recent Anti-KRASG12D Therapies: A “Possible Impossibility” for Pancreatic Ductal Adenocarcinoma DOI Open Access
Navid Sobhani, Matteo Pittacolo, Alberto D’Angelo

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(4), P. 704 - 704

Published: Feb. 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.

Language: Английский

Citations

1
In Silico Prediction of New Inhibitors for Kirsten Rat Sarcoma G12D Cancer Drug Target Using Machine Learning-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulation Approaches DOI Creative Commons

Amar Ajmal,

Muhammad Danial,

Maryam Zulfat

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(5), P. 551 - 551

Published: April 25, 2024

Single-point mutations in the Kirsten rat sarcoma (KRAS) viral proto-oncogene are most common cause of human cancer. In humans, oncogenic KRAS responsible for about 30% lung, pancreatic, and colon cancers. One predominant mutant G12D variants is pancreatic cancer an attractive drug target. At time writing, no

Language: Английский

Citations

7
KRAS Mutation Subtypes and Their Association with Other Driver Mutations in Oncogenic Pathways DOI Creative Commons
Koushik Mondal, Mahesh Kumar Posa, Revathi P Shenoy

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(14), P. 1221 - 1221

Published: July 19, 2024

The KRAS mutation stands out as one of the most influential oncogenic mutations, which directly regulates hallmark features cancer and interacts with other cancer-causing driver mutations. However, there remains a lack precise information on their cooccurrence mutated variants any correlations between To enquire about this issue, we delved into cBioPortal, TCGA, UALCAN, Uniport studies. We aimed to unravel complexity its relationships noticed that G12D G12V are prevalent coexist TP53 in PAAD CRAD, while G12C LUAD. also similar observations case PIK3CA APC mutations CRAD. At transcript level, positive correlation exists existence co-mutation could influence signaling pathway neoplastic transformation. Moreover, it has immense prognostic predictive implications, help better therapeutic management treat cancer.

Language: Английский

Citations

7