NOTCH mutation

Mechanistically, IL-6 increase relies on loss of the negative control exerted by the p50 subunit on the IL-6 promoter. Our results reveal the Notch/NF-κB cross-talk in regulating myeloid-derived suppressor cell biology in T-cell leukemia, highlighting the need to consider carefully the pleiotropic effects of NF-κB-based therapy on the tumor microenvironment.

The presence of LRP1B mutation was significantly associated with longer overall survival (OS), whereas RB1 mutation and advanced TNM stage were associated with shorter OS. We identified frequently mutated genes and potential predictors of survival in patients with gastric NECs and MANECs.

Four of 10 patients were positive for PD-L1 and CD8+ T. By analyzing WES in three of these four patients, we notably identified the mutations of NOTCH1, FBXW7, and noncoding RNA intronic mutation in NOTCH2NLR in two of these three patients. This study may enable better selection of ICI therapy with CD8+ T-cell infiltration via PD-L1 expression for oral squamous cell carcinoma patients with mutations in Notch signaling pathway.

Cluster analysis by LymphGen classified 29/54 cases within definite groups, including BN2 in 14 (48.2%), ST2 in seven (24.2%) and MCD and EZB in four each (13.8%). Overall, these results indicate a preferential marginal zone origin for a consistent subgroup of HCV-associated DLBCL cases and suggest potential implications for molecularly targeted therapies.

dNKAP knockdown and oncogenic Ras, Notch, or Yki mutations show synergies in driving tumorigenesis, further supporting the tumor-suppressive role of dNKAP. In summary, this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.

Combination treatment with idasanutlin and navitoclax, a potent Bcl-2/Bcl-xL inhibitor, induces more consistent and potent synergistic killing of T-ALL PDX lines in vitro than venetoclax, a Bcl-2 specific inhibitor. Moreover, a marked synergic response to combination treatment with idasanutlin and navitoclax was seen in vivo in all four T-ALL xenografts tested, with a significant increase in overall survival in the combination treatment group. Collectively, these preclinical data show that the combination of idasanutlin and navitoclax is highly active in T-ALL and may merit consideration in the clinical setting.

However, HBV positive with NOTCH unmutated had no statistical difference in prognosis compared with HBV-negative patients (p = 0.1706 for OS and p = 0.2387 for TTT), which indicated that NOTCH pathway mutation contributed to inferior prognosis in HBV-infected CLL. In conclusion, a cohort of CLL patients with HBV positive displayed a worse clinical outcome and the status of the NOTCH signaling pathway might play a crucial role.

Mutations in ZMYM3 are mainly loss-of-function, associate with NOTCH1 signaling mutations and shorten TFT in CLL patients, suggesting that ZMYM3 mutational status may be a useful marker in the management of early stage CLL patients. Moreover, ZMYM3 mutations reduce histone H4 acetylation and cooperate with NOTCH1 mutations to dysregulate gene-expression, leading to impair DNA damage response and apoptosis evasion.

Venetoclax showed an additive benefit in 3 lines, but was only synergistic in 1 of 5 lines tested...We also evaluated ruxolitinib in combination with idasanutlin, as recent work has shown overlapping responses to inhibitors of Jak/Stat or Bcl-2 (Yuan et al...Idasanutlin and combination therapy samples clustered closely in PCA analysis, with p53 response a strongly-induced pathway, as expected. Our data suggest that the rational combination of idasanutlin and navitoclax is highly active against T-ALL, with greater synergic opportunity compared to other available idasanutlin combination treatments, through induction of a p53-dependent apoptotic cell death.

P2, N=23, Completed, Vanderbilt-Ingram Cancer Center | Active, not recruiting --> Completed

Therefore, it is of interest to document the molecular docking analysis of cetuximab with the NOTCH signaling targets such as NOTCH1, NICD, and HES1. These results suggest that targeting the NOTCH signaling with cetuximab might leads to the better outcome for suppression of invasion and metastasis in oral carcinoma.

The differential mutation genes of OBC and BCAx might be associated with their respective biological behaviors like invasiveness and prognosis. The differences in NOTCH pathway and enrichment analysis might cause the occult lesions in the OBC.

Furthermore, the NOTCH2-mediated tumorigenesis was mostly reversed after NF-κB inhibitor Bay11-7082 treatment. These findings identified the NOTCH2 P2113S mutation in ovarian carcinogenesis, and NOTCH2 P2113S is a potential target in treating OC.

Peripheral downregulation of select Notch target gene levels was observed with escalating doses. Future studies exploring CB-103 should enrich for patients with NOTCH-mutant ACC and investigate rational combinatorial approaches in tumors where there is limited success with investigational or approved drugs.

*Inverse variance method, no transformation, 0.5 continuity correction. ORR: CR + PR; DCR: CR + PR + SD Conclusions AL101 showed acceptable safety and tolerability in ACC pts with Notchmut and a response rate comparable to pooled estimates for available therapies in pts regardless of Notch status.

In conclusion, our study offers a comprehensive understanding of the genetic landscape of LS-SCLC patients with or without BM. We identify prognostic biomarkers associated with BM risk, which might facilitate the development of personalized treatment strategies. Additionally, our findings suggest predictive signatures associated with the survival benefit of PCI treatment, which may guide clinicians in selecting patients who are best suited for PCI treatment, minimizing unnecessary treatments, and improving the survival outcomes of LS-SCLC patients.

At the clinical level, mutated NOTCH genes are associated with aggressive features in MCL, such as the blastoid and pleomorphic variants, a shorter response to treatment, and inferior survival. In this article, we explore in detail the role of NOTCH signaling in MCL biology and the ongoing efforts toward targeted therapeutic interventions.

Jag1 mutation results in delayed hepatocyte differentiation blunting inflammatory signaling. Jag1 regulates immune cell development and competence, modifying the response to bacterial infection and cholestatic liver insult. The compromised immune response of thymocytes leads to milder-than-expected fibrosis.

These findings depict a peculiar RT-immune microenvironment and may explain the higher response rates to immune checkpoint inhibitors. The identification of early seeding of RT clones, appearing up to 19 years prior to RS diagnosis opens the questions of whether patients who go on to develop RT can be identified early in the course of CLL, whether small RT subclones may exist frequently in CLL patients, whether a failure of immune surveillance, therapeutic pressure or additional genetic or epigenetic events subsequently trigger the eventual emergence of transformation, and inspire future laboratory-based investigations into these open questions for preventing this complication of CLL.

P1/2, N=34, Recruiting, Glenn J. Hanna | Not yet recruiting --> Recruiting

In this context, molecular alterations have been identified and represent potential therapeutic targets: overexpression of human epidermal growth factor receptor 2 (HER2) and androgen receptors in salivary duct cancer, NOTCH mutations in adenoid cystic carcinoma, NTRK gene fusion in secretory carcinoma. Screening for these molecular alterations is mandatory in all patients with recurrent or metastatic salivary gland cancer as it may allow an individualized treatment.

In conclusion, single-cell transcriptomic analysis identified cell states with high plasticity that are characterized by aberrant differentiation trajectories, distinct transcriptional circuitries and enhancer rewiring resulting in treatment escape. Definition of state-specific transcriptional dependencies combined with BH3 profiling could predict response to NOTCH inhibition and allowed the identification of potential therapeutic targets to overcome Notch-inhibitor resistance in T-ALL. Drug resistance, Plasticity, T-ALL, RNA-seq

Our findings suggested that MAD is a practical and simple algorithm for assessing ITH, and populations with high MAD values are more likely to have EGFR mutations. MAD can be used as a potential biomarker to predict not only the prognosis of NSCLC but also the efficacy of immunotherapy and TKI therapy in patients with advanced NSCLC.

Clinical outcomes to axitinib plus avelumab were distinct between ACC-I and ACC-II subtypes, with ACC-II pts demonstrating an improved DCR and significantly longer PFS. Gene expression analysis revealed high expression of immune function-related genes in patients who benefited from axitinib plus avelumab in both ACC subtypes, indicating possible biomarkers predictive of benefit from the combination in ACC. Clinical trial information: NCT03990571.

P2, N=23, Active, not recruiting, Vanderbilt-Ingram Cancer Center | Trial completion date: Feb 2023 --> Sep 2023

Notch activation in AdCC contributes to bone metastasis through SPARC inhibition. The study results suggest that SPARC may represent a prognostic biomarker and potential therapeutic target.

P1/2, N=34, Not yet recruiting, Glenn J. Hanna

Notably, inactivation of TBK1 activity or JAK-STAT activity using specific small molecule inhibitors of TBK1 or JAK completely reversed the synthetic lethality between NOTCH and TRIM28 suggesting that the synthetic lethality phenotype is a consequence of hyperactivation of innate immune signaling, which is known to be cytotoxic. Together our findings uncover a novel vulnerability in SCLCs with LOF NOTCH mutations and perhaps other cancers with LOF NOTCH mutations and suggest a strategy that could also potentiate anti-tumor immunity by increasing innate immune signaling in tumor cells.

P2, N=23, Active, not recruiting, Vanderbilt-Ingram Cancer Center | Trial completion date: Nov 2022 --> Feb 2023

We not only depicted the genetic and immunologic landscape of Chinese MPA but also reveal its distinction from LUAD in genomic and immune context. Our findings may provide opportunities for therapeutic susceptibility among Chinese MPA patients.

Although NOTCH mutations (NOTCH ) are well studied in T-cell acute lymphoblastic leukemia (T-ALL), less is known about their incidence and prognostic implications in acute myeloid leukemia (AML). A total of 878 newly diagnosed patients with AML was retrospectively analyzed; it was found that the frequency of NOTCH was relatively low but was associated with an adverse prognosis.

In this largest multi-omic investigation undertaken into WM, we identified three distinct WM subtypes with distinct clinical and genomic features. Central these findings were the identification of BCL, PCL, and an earlier non-BCL/PCL evolving stage recognized through DPT modeling. The discovery of the DPT model for WM disease progression provides insight into the biology and targeting of WM progression.

Important biological indicators of risk may be missed when studying patients of a single genetic ancestral group or when focusing on averages for the entire cohort without taking into consideration variation in genetic ancestry. Analyses of survival by genetic ancestry within genomic groups are ongoing.

Importantly, NOTCH-ICD also strongly down-regulates the expression of CD19, possibly limiting the effectiveness of immune-therapies. These NOTCH-mediated immune escape mechanisms are associated with the expansion of exhausted CD8 T cells in vivo.

This study demonstrates the high yield of information in DLBCL using the NGS Lymphoma panel. Results also highlight the molecular heterogeneity of DLBCL subtypes which indicates the need for further studies to make the results of the NGS more clinically relevant.

The Notch signaling mutation can modulate the chemotaxis of immune cells by upregulating the chemokine levels of the tumor immune microenvironment, and CRC patients with Notch signaling pathway mutation have better overall survival after immune checkpoint inhibitor treatment.

Gene set enrichment analysis revealed NOTCH4-Mut tumor enhanced anti-tumor immunity. NOTCH4 mutation may promote tumor immunity and serve as a biomarker to predict good immune response in NRAS wildtype melanoma and guide immunotherapeutic responsiveness.