A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade DOI Creative Commons

Olta Ibruli,

France Rose, Filippo Beleggia

et al.

Journal of Cancer Research and Clinical Oncology, Journal Year: 2024, Volume and Issue: 150(11)

Published: Nov. 14, 2024

Abstract Purpose Small cell lung cancer (SCLC) has an extremely poor prognosis. Despite high initial response rates to chemotherapy and modest survival improvements with the addition of immune checkpoint inhibitors (ICI), almost all patients experience relapse fatal outcomes. Recent genomic insights uncovered extensive molecular heterogeneity in uniform loss RB1 TRP53 . Additionally, defective DNA mismatch repair (MMR) recently been described some SCLC cases. Here, we generated a novel mouse model capturing MMR deficiency assessed immunotherapy responses. Methods We developed MMR-deficient genetically engineered (GEMM) by introducing conditional Msh2 gene, crucial for maintaining integrity, into standard Rb1 fl/fl ; Trp53 (RP) model. Genomic characteristics preclinical therapy responses were evaluated focusing on overall whole exome sequencing (WES) analyses. Results MMR-defective tumors ( (RPM)) later than MMR-proficient mice. However, time from tumor manifestation death affected animals was substantially shortened (median 55 days RP vs. 46.5 RPM), indicating increased aggressiveness tumors. RPM exhibited deficiency, mutational burden (TMB), elevated load candidate neoantigens, compared lesions p = 0.0106), suggesting immunogenicity. Importantly, significantly improved when exposed ICI. Conclusion propose as suitable system mimic TMB. provide vivo evidence that enhances ICI sensitivity. These findings could contribute stratifying immunotherapy, thereby improving treatment

Language: Английский

The emerging landscape and future perspective of SCLC transformation: from molecular mechanisms to therapeutic strategies DOI
Chenyue Zhang, Kai Wang, Haiyong Wang

et al.

Critical Reviews in Oncology/Hematology, Journal Year: 2025, Volume and Issue: 207, P. 104616 - 104616

Published: Jan. 11, 2025

Language: Английский

Citations

1
The Potential of Single-Transcription Factor Gene Expression by RT-qPCR for Subtyping Small Cell Lung Cancer DOI Open Access

A. Iñañez,

R. Del Rey-Vergara,

Fabricio Gerel Quimis

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1293 - 1293

Published: Feb. 3, 2025

Complex RNA-seq signatures involving the transcription factors ASCL1, NEUROD1, and POU2F3 classify Small Cell Lung Cancer (SCLC) into four subtypes: SCLC-A, SCLC-N, SCLC-P, SCLC-I (triple negative or inflamed). Preliminary studies suggest that identifying these subtypes can guide targeted therapies potentially improve outcomes. This study aims to evaluate whether expression levels of three key effectively SCLC subtypes, comparable use individual antibodies in immunohistochemical (IHC) analysis formalin-fixed, paraffin-embedded (FFPE) tumor samples. We analyzed preclinical models increasing complexity, including eleven human five mouse cell lines, six patient-derived xenografts (PDXs), two circulating (CTC)-derived (CDXs) generated our laboratory. RT-qPCR conditions were established detect POU2F3. Additionally, protein-level was performed using Western blot for lines IHC FFPE samples PDX CDX tumors, following experience with patient from CANTABRICO trial (NCT04712903). found line predominantly expressed POU2F3, showed no expression, as identified by RT-qPCR, consistently matching previously assigned each line. The classification demonstrated consistency between analyses factors. Our results show single-gene FFPE-extracted RNA simplifies subtype classification. approach provides a cost-effective alternative staining expensive multi-gene sequencing panels, making subtyping more accessible both research clinical applications.

Language: Английский

Citations

0
Small cell lung cancer with EML4-ALK fusion: report of a case responding to ALK TKI and literature review DOI Creative Commons
Mingyue Wang, Hongzhi Liu, Ruixin Zhang

et al.

Journal of Cancer Research and Clinical Oncology, Journal Year: 2025, Volume and Issue: 151(2)

Published: Feb. 6, 2025

With the continuous development and progress of next-generation gene sequencing technology, many types anaplastic lymphoma kinase (ALK) rearrangement have been discovered. However, in small cell lung cancer (SCLC), ALK is extremely rare there no standard treatment protocol. By reviewing literature, we summarized previously reported cases ALK-positive SCLC, discussed significance molecular detection. We report a patient with EML4-ALK fusion 41-year-old woman history smoking or drinking, who was admitted to hospital chest tightness, dyspnea, cough sputum. Extensive SCLC (cT4N0M1) diagnosed after relevant examination pathological examination. The relapsed again six months receiving first-line chemoradiotherapy. And still developed disease progression (PD) continued multi-line including chemotherapy, immunotherapy, anti-vascular therapy. inhibitor currently being taken orally, significant clinical response has achieved. Progression-free survival (PFS) more than 8 months. rare. stage IV benefit from inhibitors multiline For patients may be reliable option.

Language: Английский

Citations

0
Challenges of small cell lung cancer heterogeneity and phenotypic plasticity DOI
Kathryn Simpson, Dominic G. Rothwell, Fiona Blackhall

et al.

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

Published: April 10, 2025

Language: Английский

Citations

0
MST1/2 DKO abates salvianolic acid B’s therapeutic effect on CCl4-induced liver injury mice DOI
Yanyan Xu, Yu Zhang, Mengru Yang

et al.

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: April 12, 2025

Language: Английский

Citations

0
Applied models and molecular characteristics of small cell lung cancer DOI Creative Commons
Gabriella Fűr,

Kolos Nemes,

Éva Magó

et al.

Pathology & Oncology Research, Journal Year: 2024, Volume and Issue: 30

Published: April 22, 2024

Small cell lung cancer (SCLC) is a highly aggressive type of frequently diagnosed with metastatic spread, rendering it surgically unresectable for the majority patients. Although initial responses to platinum-based therapies are often observed, SCLC invariably relapses within months, developing drug-resistance ultimately contributing short overall survival rates. Recently, research aimed elucidate dynamic changes in genetic and epigenetic landscape. These have revealed distinct subtypes SCLC, each characterized by unique molecular signatures. The recent understanding heterogeneity has opened up potential avenues precision medicine, enabling development targeted therapeutic strategies. In this review, we delve into applied models computational approaches that been instrumental identification promising drug candidates. We also explore emerging diagnostic tools hold transform clinical practice patient care.

Language: Английский

Citations

2
Recent advances in immunotherapy for small cell lung cancer DOI
Ziyuan Ren,

Shijie Shang,

Dawei Chen

et al.

Current Opinion in Oncology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 4, 2024

This review aims to provide an overview of recent advances in immunotherapy for small cell lung cancer (SCLC), with a focus on the current status immune checkpoint inhibitors (ICIs), novel combination strategies, and key biomarkers.

Language: Английский

Citations

2
Animal Models of Human Disease 2.0 DOI Open Access
Sigrun Lange, Jameel M. Inal

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(24), P. 13743 - 13743

Published: Dec. 23, 2024

The use of animal models is crucial for advancing translational research by identifying effective treatment targets and strategies clinical application in human disease [...]

Language: Английский

Citations

2
Nonviral CRISPR/Cas9 mutagenesis for streamlined generation of mouse lung cancer models DOI Creative Commons
Irene Lara‐Sáez, Ángeles Mencía,

Enrique Recuero

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(28)

Published: July 3, 2024

Functional analysis in mouse models is necessary to establish the involvement of a set genetic variations tumor development. A modeling platform facilitate and cost-effectively analyze role multiple genes carcinogenesis would be valuable. Here, we present an innovative strategy for lung mutagenesis using CRISPR/Cas9 ribonucleoproteins delivered via cationic polymers. This approach allows simultaneous inactivation genes. We validate effectiveness this system by targeting group suppressor genes, specifically Rb1 , Rbl1 Pten Trp53 which were chosen their potential cause tumors, namely small cell carcinoma (SCLC). Tumors with histologic transcriptomic features human SCLC emerged after intratracheal administration CRISPR/polymer nanoparticles. These tumors carried loss-of-function mutations all four at targeted positions. findings reproduced two different pure backgrounds. provide proof principle simplified tumorigenesis functional testing cancer-related

Language: Английский

Citations

1
Mouse models for cancer research – current state and the perspective DOI Open Access

Katarina Gercakova,

Martina Poturnajova, Silvia Tyčiaková

et al.

Neoplasma, Journal Year: 2024, Volume and Issue: 71(02), P. 99 - 116

Published: Jan. 1, 2024

Cancer is one of the leading causes death worldwide.We still do not understand all details carcinogenesis, and effective treatment lacking for many oncological diseases.Animal models provide an irreplaceable tool to observe growth spreading neoplastic cells in environment living organisms, test efficacy cancer treatment, side effects, toxicity, study tumor microenvironment.Mice are most often used model organisms because their easy handling, short reproductive period, multiple strains, complete DNA sequencing.An ideal should accurately recapitulate each step development.Recent techniques have established that enable different aspects cancer, but choosing a particular depends on application output data.This article aimed review induced, transplantable, engineered mice highlight significance recent future research.

Language: Английский

Citations

0