CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders.

NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.

The Effectiveness of the Buzzy Device in Reducing Pain in Children Undergoing Venipuncture: A Single-Center Experience.

OBJECTIVES: Needle-related procedures are among the most important sources of pain in children in different health care settings. Our study was aimed to evaluate the effectiveness of Buzzy (MMJ Labs, Atlanta, Ga.), a palm-sized bee/ladybug-shaped device combining vibration and cold, as a nonpharmacological strategy to manage needle-related pain in children. METHODS: In this single-center, randomized (1:1) controlled open-label study, we enrolled patients aged from 1 month to 18 years who had to undergo a planned outpatient blood sampling in Pisa University Hospital's Department of Pediatrics and randomly allocated them to either the BUZZY group (intervention group) or NO BUZZY group (control group). Pain was estimated using proper pain scales according to age. RESULTS: Between May 2021 and January 2022, 234 children aged 8.8 ± 5.1 years (50.8% girls) were enrolled and 117 were treated with the Buzzy device. In the study population, pain inversely correlated with age (r = -0.52, P < 0.001); the intervention group showed significantly lower pain (2.5 ± 2.4 vs 4.7 ± 2.8, P < 0.001) and no difference was found between boys and girls. Significant reduction in pain scores was confirmed when stratifying children by age (29 days to <3 years, P = 0.002; ≥3 to ≤8 years, P < 0.001; >8 years, P < 0.001). CONCLUSIONS: The Buzzy device effectively reduces pain caused by percutaneous antecubital venipuncture in children in different age groups and represents a cheap and easy-to-use strategy to manage routine needle-related procedures.

Orthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML.

The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogates EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACis-based combination therapies in patients with 3q26 AML.