Therapeutic expression of RAS Degrader RRSP in Pancreatic Cancer via Nanocarrier-mediated mRNA delivery DOI Creative Commons
Taylor E. Escher, Simseok A. Yuk,

Qian Yuan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 14, 2024

ABSTRACT Therapeutic gene expression can address many of the challenges associated with controlled delivery intracellularly active biologics, such as enzymes that degrade RAS for treatment RAS-driven cancers. Here, we demonstrate an optimized synthetic nonviral platform composed poly(ethylene glycol)- b -poly(propylene sulfide) (PEG-PPS) block copolymers conjugated to a dendritic cationic peptide (PPDP2) nontoxic and therapeutic mRNA within human pancreatic cancer cells tumors. The naturally occurring bacterial enzyme RAS/RAP1-specific endopeptidase (RRSP) is potent degrader specifically targets all isoforms. Using PPDP2, rrsp -mRNA delivered resulting in RRSP protein expression, degradation RAS, loss cell proliferation. Further, tumors are reduced residual lacking detectable phosphorylated ERK. structural modeling, further noncatalytic RAS-binding domain provides high specificity RAS. These data support nanocarrier PPDP2 deliver tumor interrupt signaling system.

Language: Английский

Small molecules for Kirsten rat sarcoma viral oncogene homolog mutant cancers: Past, present, and future DOI

Peiliang Dong,

Jiating Ni,

Xinyue Zheng

et al.

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 177428 - 177428

Published: Feb. 1, 2025

Language: Английский

Citations

0
Farnesyl Transferase Inhibitors as a Novel Strategy for Targeting KRAS-Dependent Cancers DOI Creative Commons
Robert B. Kargbo

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: 16(4), P. 517 - 519

Published: March 11, 2025

KRAS mutations drive tumorigenesis in multiple cancers, yet direct inhibitors display limited efficacy due to adaptive resistance. Recent preclinical findings indicate farnesyl transferase (FTIs) can reduce compensatory mTOR and MAPK pathway activation. Evidence supports combining FTIs with enhance tumor suppression delayed

Language: Английский

Citations

0
Immunotherapy in advanced, KRAS G12C-mutant non-small-cell lung cancer: current strategies and future directions DOI Creative Commons
Nadia Ghazali,

Marina Chiara Garassino,

Natasha B. Leighl

et al.

Therapeutic Advances in Medical Oncology, Journal Year: 2025, Volume and Issue: 17

Published: Jan. 1, 2025

Kirsten rat sarcoma ( KRAS ) mutations are present in up to 25% of non-small-cell lung cancer (NSCLC). G12C is the most common type mutation, representing approximately half cases -mutant NSCLC. Mutations activate RAF-MEK-ERK pathway, leading increased cell proliferation and survival. Recent advances drug development have led approval inhibitors sotorasib adagrasib. This review explores emerging therapeutic strategies G12C-mutant NSCLC, including dual checkpoint blockade combinations with inhibitors, a focus on setting advanced disease.

Language: Английский

Citations

0
Pancreatic cancer: failures and hopes—a review of new promising treatment approaches DOI Creative Commons
Vittore Cereda, Mario D’Andrea

Exploration of Targeted Anti-tumor Therapy, Journal Year: 2025, Volume and Issue: 6

Published: March 18, 2025

Pancreatic cancer is a challenging disease with limited treatment options and high mortality rate. Just few therapy advances have been made in recent years. Tumor microenvironment, immunosuppressive features mutational status represent important obstacles the improvement of survival outcomes. Up to now, first-line did achieve median overall less than 12 months this discouraging data lead clinicians all over world focus their efforts on various fields investigation: 1) sequential cycling different systemic order overcome mechanisms resistance; 2) discovery new predictive bio-markers, target specific patient population; 3) combination treatment, modulate tumor microenvironment pancreatic cancer; 4) modalities delivery drugs pass physical barrier desmoplasia stroma. This review shows future directions strategies advanced through deep analysis these macro areas research.

Language: Английский

Citations

0
PRMT5 inhibitors: Therapeutic potential in pancreatic cancer DOI
Carolin Schneider,

Valentina Spielmann,

Christian Braun

et al.

Translational Oncology, Journal Year: 2025, Volume and Issue: 55, P. 102366 - 102366

Published: March 30, 2025

Language: Английский

Citations

0
Targeting the Yin and Yang of KRASG12C DOI
Christos Adamopoulos, Kostas A. Papavassiliou, Athanasios G. Papavassiliou

et al.

Trends in Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
Current status of KRAS G12C inhibitors in NSCLC and the potential for combination with anti-PD-(L)1 therapy: a systematic review DOI Creative Commons
Fan Zhang,

Banglu Wang,

Menghuan Wu

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 15, 2025

In recent years, precision medicine for non-small cell lung cancer (NSCLC) has made significant strides, particularly with advancements in diagnostic and therapeutic technologies. Targeted 7therapies Anti-PD-(L)1 Therapies have emerged as vital treatment options, yet KRAS mutations, especially G12C, been historically difficult to address. Due the unique activation mechanism of G12C led development specific inhibitors, such AMG 510 MRTX849, which show promising potential. However, results from CodeBreaK 200 Phase III trial indicated that did not significantly improve overall survival compared docetaxel. Resistance after prolonged use inhibitors continues pose a challenge, prompting interest new drugs combination strategies. mutations can impair tumor-infiltrating T function create an immunosuppressive tumor microenvironment, making anti-PD-(L)1 therapies appealing. Preliminary data suggest these combinations may enhance both quality life, though safety concerns remain barrier. Ongoing research is crucial refine regimens identify suitable patient populations. This review focuses on monotherapy NSCLC, discussing major clinical trials future directions.

Language: Английский

Citations

0
Engineered protein circuits for cancer therapy DOI Creative Commons
Andrew Lu, Lukas Moeller, Stephen T. Moore

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Summary Many targeted therapies indirectly suppress cancer cells by inhibiting oncogenic signaling pathways such as Ras 1–4 . This renders them susceptible to resistance and limits their long-term clinical efficacy 4–10 Engineered protein circuits 11–25 have been envisioned an alternative pharmacological inhibition that directly rewires activity cell death. However, it has remained unclear whether engineered can potently safely treat cancers. Here, we show Ras-targeting accurately discriminate between non-cancer cells, circumvent intrinsic acquired mechanisms limit inhibitors, in vivo These combine three modules: a protease-based sensor responds broad spectrum of clinically relevant mutations, optional protease amplifier, protease-triggered death effectors. effectors flexibly trigger either non-inflammatory apoptosis or immunogenic pyroptosis, which shown extend therapeutic effects beyond transfected 26,27 The resulting sense-kill be safely, efficiently, transiently delivered mRNA lipid nanoparticles (LNPs). exhibited potent against Ras-mutant human lines with minimal off-target killing wild-type cells. In immunocompetent mice bearing aggressive, multifocal Ras-driven liver tumors, systemically-delivered mRNA-LNP significantly reduced tumor burden. Further, provided more than the inhibitors Sotorasib RMC-7977 7,28–30 , increased sensitivity Sotorasib-resistant vitro results establish potent, specific, programmable mechanism for treating other diseases.

Language: Английский

Citations

0
KRAS G12C Inhibitors as Monotherapy or in Combination for Metastatic Colorectal Cancer: A Proportion and Comparative Meta-Analysis of Efficacy and Toxicity from Phase I-II-III Trials DOI
Erman Akkuş,

Nurten Öksüz,

Enes Erul

et al.

Critical Reviews in Oncology/Hematology, Journal Year: 2025, Volume and Issue: unknown, P. 104741 - 104741

Published: April 1, 2025

Language: Английский

Citations

0
Advanced organoid models for targeting Kras-driven lung adenocarcinoma in drug discovery and combination therapy DOI Creative Commons
İsa Taş, Reinhilde Jacobs, Juliane Albrecht

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: April 24, 2025

Abstract Background Lung cancer remains one of the most challenging diseases to treat due its heterogeneity. Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) mutations are genetic drivers in numerous types including lung adenocarcinoma (LUAD). Despite recent advances KRAS-targeted therapies, treatment resistance and limited therapeutic options necessitate advanced preclinical models, such as organoids, identify personalized therapies by screening novel strategies synergistic drug combinations. Results We established LUAD genetically engineered mouse (GEM) models Kras G12V & Trp53 Δex2−10 (KP) KP with Ctnnb1 Δex3 mutation (KPC). Tumor-derived organoids from these recapitulated genomic landscape histopathological characteristics their parental tumors. The displayed tumorigenic potential when implanted immunocompromised mice, forming tumors contrast unlike healthy lung-derived organoids. Drug identified effective kinase inhibitors DNA methyltransferase (DNMT) against Notably, combination drugs exhibited highest synergy KPC Conclusion successfully developed harboring multiple agents targeting cells. Furthermore, we demonstrated effectiveness a DNMT inhibitor-based therapy, presenting promising strategy for this subtype.

Language: Английский

Citations

0