P2, N=252, Active, not recruiting, PTC Therapeutics | Recruiting --> Active, not recruiting | Trial completion date: Jul 2024 --> Aug 2025 | Trial primary completion date: Mar 2024 --> Feb 2025

P2, N=30, Completed, Abivax S.A. | Phase classification: P2a --> P2

P1, N=74, Recruiting, Skyhawk Therapeutics, Inc | Not yet recruiting --> Recruiting

P3, N=1050, Recruiting, Abivax S.A. | Trial primary completion date: Dec 2029 --> Jan 2026

P2, N=250, Enrolling by invitation, PTC Therapeutics | Recruiting --> Enrolling by invitation

P3, N=1050, Recruiting, Abivax S.A. | Trial completion date: Jun 2026 --> Jan 2030 | Trial primary completion date: Jan 2026 --> Dec 2029

P2/3, N=0, Withdrawn, Abivax S.A. | Phase classification: P2a --> P2/3 | N=30 --> 0 | Unknown status --> Withdrawn

P3, N=612, Recruiting, Abivax S.A. | Trial primary completion date: Dec 2024 --> Mar 2025

P3, N=612, Recruiting, Abivax S.A. | Trial primary completion date: Dec 2024 --> Mar 2025

P3, N=1050, Recruiting, Abivax S.A. | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Apr 2025 --> Jan 2026

P2, N=212, Not yet recruiting, Abivax S.A.

P2, N=32, Completed, Abivax S.A. | Phase classification: P2a --> P2

P3, N=612, Recruiting, Abivax S.A. | Trial completion date: Jun 2024 --> Feb 2025 | Trial primary completion date: May 2024 --> Dec 2024

P3, N=612, Recruiting, Abivax S.A. | Trial completion date: Jun 2024 --> Feb 2025 | Trial primary completion date: May 2024 --> Dec 2024

The AU-rich elements (AREs) within the long 3' UTR of H2AFY mRNA enhance mRNA stability and translation activity, resulting in promoting cell proliferation and invasion, which potentially facilitate the establishment and rapid formation of metastatic tumors mediated by CTC clusters. These findings provide new insights into the mechanisms driving CTC cluster metastasis.

Moreover, the efficiency of CTLA-4 RNA splicing was increased in tumor-infiltrating Treg cells from patients with colorectal cancer. These findings highlight the immunological relevance of RNA splicing in Treg cells and provide important insights into the environmental mechanism governing CTLA-4 expression in Treg cells.

P2, N=250, Recruiting, PTC Therapeutics

P2, N=203, Active, not recruiting, Abivax S.A. | Recruiting --> Active, not recruiting | Trial completion date: Apr 2026 --> Apr 2027 | Trial primary completion date: Feb 2023 --> Feb 2027

P2, N=252, Recruiting, PTC Therapeutics | Phase classification: P2a --> P2

Meayamycin D induced alternative splicing of MCL-1, showed strong synergism with venetoclax in drug-resistant lung cancer cells, and was cancer-specific over normal cells. Meayamycin D incorporates an alkyl ether and shows a long half-life in mouse plasma. The characteristics of meayamycin D may provide an approach to designing other bioactive L-shaped molecules.

We designed and synthesized novel 4-acetoxypentanamide derivatives of spliceostatin A, whose 4-acetoxypentenamide moiety is reduced (7), isomerized (8), or substituted with methyl at the α-position (9). The results of biological evaluation against AR-V7 and the docking analysis of each derivative suggest that the geometry of the 4-acetoxypentenamide moiety of spliceostatin A is important for its biological activity.

ConclusionOur results suggest that targeting RNA splicing may be a promising approach for treatment of therapy-refractory MRT. Further pre-clinical in vivo studies are warranted to fully establish a rationale for clinical evaluation of SM09419 in MRT patients.

Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments.

Pre-treatment of cohesin-mutant cells with H3B-8800 for 3 days increased their sensitivity to the PARP inhibitor talazoparib 10-fold, while the sensitivity of wild-type cells to talazoparib was unaffected (Figure 1A)...In addition to talazoparib, we demonstrated significantly improved overall survival of STAG2-mutant AML PDX mice receiving sequential treatment of E-7107 and standard induction chemotherapy (doxorubicin and cytarabine), further expanding this strategy beyond PARP inhibitors...In summary, our study identifies a critical connection between cohesin mutations and splicing modulation in AML, creating a novel therapeutic strategy for these patients with very limited treatment options and poor outcomes. Our findings not only expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS/sAML but we also propose this as a broader strategy for therapeutic targeting of other DNA damage-repair deficient cancers.

These findings demonstrate how distinct GBM cell populations arise during tumour growth. Targeting this mechanism may decrease GBM heterogeneity and facilitate therapy.

However, in contrast, multiple malignant tumors, including HCC that target the pro-apoptotic favoring isoforms/variants favor apoptotic induction and make chemotherapy effective. Herein, we discuss different splicing events, aberrations, and antisense oligonucleotides (ASOs) in modulating RNA splicing in HCC tumorigenesis with a possible therapeutic outcome.

Specifically, FD-895 and pladienolide B significantly downregulates Wnt signaling pathway-associated transcripts (GSK3β and LRP5) and both transcript and proteins including LEF1, CCND1, LRP6, and pLRP6 at the transcript, total protein, and protein phosphorylation's levels. These results indicate FD-895 and pladienolide B inhibit Wnt signaling by decreasing LRP6 phosphorylation and modulating mRNA splicing through induction of intron retention in solid tumors.

Expression of Gdf5, Sox5, Sox6, melanoma inhibitory activity, noggin, odd-skipped related transcription factor 2, matrilin 4, and versican was positively correlated with Dcx expression. Our results demonstrate that Dcx expression defines a subpopulation of Gdf5 cells with chondrogenic potentials in E12.5 mouse embryonic limbs.

To alleviate this problem, the domain was divided into three overlapping fragments, reducing the complexity of the spectra and enabling almost complete backbone resonance assignment of the full domain. These solution NMR chemical shift assignments represent the first steps towards understanding, at atomic resolution, how the low-complexity domain of EWS contributes to the aberrant functions of its oncogenic fusion proteins.

One of the two BI-ALCL samples showed a complex karyotype, raising the possibility that genomic instability may be responsible for intra-chromosomal fusions in BI-ALCL. Moreover, transcriptional analysis revealed similar upregulation of the PI3K/Akt pathway, associated with enrichment in the expression of neurotrophin signaling genes, which was more conspicuous in BI-ALCL, as well as differences, i.e., over-expression of genes involved in the RNA polymerase II transcription program in BI-ALCL and of the RNA splicing/processing program in cALCL.

Furthermore, mice transplanted with leukemia cells expressing mutant U2AF1 had significantly reduced tumor burden and improved survival after the wild-type U2af1 allele was deleted compared to when it was not deleted. These results suggest that selectively targeting the wild-type U2AF1 allele in heterozygous mutant cells could induce cancer cell death and be a therapeutic strategy for patients harboring U2AF1 mutations.

Subsequently, we determined CBLL1, FTO, YTHDC1, HNRNPA2B1 as crucial m6A regulators of prostate cancer. Premised on the expression of CBLL1, we also identified potential therapeutic agents for prostate cancer, and knockdown of HNRNPA2B1 prominently inhibited prostate cells migration and invasion in vitro experiment.

Our discovery showed that many RNA binding proteins involved in the progress of cervical cancer, which could probably serve as prognostic biomarkers and accelerate the discovery of treatment targets for CC patients.

In addition, the results from immunohistochemical analyses showed that LW1497 downregulated EMT markers and Slug. In conclusion, LW1497 suppresses cancer progression through the inhibition of EMT by downregulating Slug.

More importantly, we found that ORF57 binds translationally active polysomes and enhances PABPC-1 but prevents Ago2 association with polysomes. Data provide a compelling evidence on how ORF57 in KSHV infected cells might regulate protein synthesis by blocking Ago2's hostile activities on translation.

NGS facilitates the diagnosis of unexplained cytopenias. The monitoring and management of CCUS is necessary, also cardio-cerebrovascular embolism events in patients with CH need attention in the clinical practice.

A deep-intronic pathogenic splice variant could now be identified for two of them (25%). These results suggest that targeted RNAseq can be successfully used to detect pathogenic RNA splicing variants in NF1.

We demonstrated exon deletion and splice site detection technology with an expanded RNA sequencing Oncomine panel that includes more than 1,000 gene fusion targets and assays for novel fusion detection. The approach is compatible with Ion systems, requires low input material, and retains simple workflows and fast turn-around time.

Second, mutation profile can be used, eventually in combination with cytogenetic, histopathologic, hematologic, and clinical variables, to risk stratify patients regarding thrombosis, overall survival, and rate of transformation to secondary leukemia. This review outlines the molecular landscape of MPN and critically interprets current information for their potential impact on patient management.