Concurrent RB1 loss andBRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma DOI Creative Commons
Flurina A.M. Saner, Kazuaki Takahashi, Timothy Budden

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 10, 2023

ABSTRACT Background Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations homologous recombination DNA repair genes including BRCA1 and BRCA2 ( BRCA ). We examined whether expression was associated survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade (LGSC)), how co-occurrence germline pathogenic variants influences long-term large series HGSC. Patients methods protein patterns were classified by immunohistochemistry epithelial carcinomas 7436 patients from 20 studies participating Ovarian Tumor Tissue Analysis consortium assessed for associations overall (OS), accounting patient age at diagnosis FIGO stage. status subset 1134 HGSC, related genotype to survival, infiltrating CD8+ lymphocyte counts transcriptomic subtypes. Using CRISPR-Cas9, we deleted HGSC lines without mutations model co-loss treatment response. also performed genomic analyses on 126 primary explore molecular characteristics concurrent deficiency loss. Results most frequent (16.4%) highly correlated mRNA expression. longer OS (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 × 10 -7 ), but poorer prognosis ENOC (HR 2.17, CI 1.17-4.03, 0.0140). Germline co-occurred < 0.0001). both had superior 0.38, 0.25-0.58, 5.2 x10 -6 ) compared either alteration alone, their median three times than non-carriers whose tumours retained (9.3 years vs. 3.1 years). Enhanced sensitivity cisplatin 0.01) paclitaxel 0.05) seen mutated knockout. Among whole-genome transcriptome sequence data, combined evidence transcriptional markers enhanced interferon response, cycle deregulation, reduced epithelial-mesenchymal transition lymphocytes prevalent -deficient . Conclusions Co-occurrence mutation exceptionally long potentially due better response immune stimulation.

Language: Английский

Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low-dose treatment of high-grade serous ovarian carcinoma DOI Creative Commons
Jan Benada, Daria Bulanova, Violette Azzoni

et al.

NAR Cancer, Journal Year: 2023, Volume and Issue: 5(3)

Published: June 9, 2023

Abstract Ovarian cancer is driven by genetic alterations that necessitate protective DNA damage and replication stress responses through cell cycle control genome maintenance. This creates specific vulnerabilities may be exploited therapeutically. WEE1 kinase a key kinase, it has emerged as promising therapy target. However, adverse effects have limited its clinical progress, especially when tested in combination with chemotherapies. A strong interaction between PKMYT1 led us to hypothesize multiple low-dose approach utilizing joint inhibition would allow exploitation of the synthetic lethality. We found exhibited synergistic eradicating ovarian cells organoid models at low dose. The synergistically promoted CDK activation. Furthermore, combined treatment exacerbated catastrophe, leading increase genomic instability inflammatory STAT1 signalling These findings suggest new harness potency lethal contribute development treatments for cancer.

Language: Английский

Citations

11
Unveiling radiobiological traits and therapeutic responses of BRAFV600E-mutant colorectal cancer via patient-derived organoids DOI Creative Commons
Peiyuan Mu, Shaobo Mo, Xingfeng He

et al.

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

Published: March 11, 2025

Abstract Background Radiotherapy (RT) is an essential treatment for colorectal cancer (CRC), yet the factors influencing radiosensitivity remain unclear. In quest to enhance therapeutic efficacy in CRC, interplay between genetic mutations and RT sensitivity has emerged as a pivotal enigmatic area. Methods We harness fidelity of patient-derived organoids (PDOs) dissect molecular landscape radiosensitivity, with particular emphasis on BRAF V600E mutations. To further investigate, cohort 9 -mutant 10 wild-type PDOs constructed systematically assess radiobiological traits including morphology, cell viability, DNA damage, while also evaluating their responses chemotherapy chemoradiotherapy. Results Our systematic investigation unveils profound correlation mutation status radioresistance, which validated by clinical responses. Intriguingly, exhibit reduced conventional chemotherapy, demonstrate enhanced response combined chemoradiotherapy, characterized increased apoptosis. The results are through vivo analyses using organoid xenograft mouse models aligned patient outcomes. Conclusions This study outlines distinct profile underscoring critical role radiotherapy comprehensive strategies. work not only advances our understanding CRC but paves way precision medicine, offering valuable insights decision-making management CRC.

Language: Английский

Citations

0
Transforming cancer treatment: integrating patient-derived organoids and CRISPR screening for precision medicine DOI Creative Commons

Ziyi Zhu,

John Paul Shen,

Paul Chi-Lui Ho

et al.

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

Published: March 25, 2025

The persistently high mortality rates associated with cancer underscore the imperative need for innovative, efficacious, and safer therapeutic agents, as well a more nuanced understanding of tumor biology. Patient-derived organoids (PDOs) have emerged innovative preclinical models significant translational potential, capable accurately recapitulating structural, functional, heterogeneous characteristics primary tumors. When integrated cutting-edge genomic tools such CRISPR, PDOs provide powerful platform identifying driver genes novel targets. This comprehensive review delves into recent advancements in CRISPR-mediated functional screens leveraging across diverse types, highlighting their pivotal role high-throughput genomics microenvironment (TME) modeling. Furthermore, this highlights synergistic potential integrating CRISPR immunotherapy, focusing on uncovering immune evasion mechanisms improving efficacy immunotherapeutic approaches. Together, these technologies offer promise advancing precision oncology.

Language: Английский

Citations

0
Concurrent RB1 loss andBRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma DOI Creative Commons
Flurina A.M. Saner, Kazuaki Takahashi, Timothy Budden

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 10, 2023

ABSTRACT Background Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations homologous recombination DNA repair genes including BRCA1 and BRCA2 ( BRCA ). We examined whether expression was associated survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade (LGSC)), how co-occurrence germline pathogenic variants influences long-term large series HGSC. Patients methods protein patterns were classified by immunohistochemistry epithelial carcinomas 7436 patients from 20 studies participating Ovarian Tumor Tissue Analysis consortium assessed for associations overall (OS), accounting patient age at diagnosis FIGO stage. status subset 1134 HGSC, related genotype to survival, infiltrating CD8+ lymphocyte counts transcriptomic subtypes. Using CRISPR-Cas9, we deleted HGSC lines without mutations model co-loss treatment response. also performed genomic analyses on 126 primary explore molecular characteristics concurrent deficiency loss. Results most frequent (16.4%) highly correlated mRNA expression. longer OS (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 × 10 -7 ), but poorer prognosis ENOC (HR 2.17, CI 1.17-4.03, 0.0140). Germline co-occurred < 0.0001). both had superior 0.38, 0.25-0.58, 5.2 x10 -6 ) compared either alteration alone, their median three times than non-carriers whose tumours retained (9.3 years vs. 3.1 years). Enhanced sensitivity cisplatin 0.01) paclitaxel 0.05) seen mutated knockout. Among whole-genome transcriptome sequence data, combined evidence transcriptional markers enhanced interferon response, cycle deregulation, reduced epithelial-mesenchymal transition lymphocytes prevalent -deficient . Conclusions Co-occurrence mutation exceptionally long potentially due better response immune stimulation.

Language: Английский

Citations

0