navitoclax (ABT 263)

Lung mesenchymal stem cells (MSCs; platelet-derived growth factor receptor α+ CD31- CD45- CD326- cells) were isolated and differentiated into myofibroblasts by culturing them with 15% fetal bovine serum (FBS) for 6 d. In asthmatic lungs, α-SMA+ myofibroblasts showed increased Bcl-xL expression, which was unaffected by dexamethasone (DEX) treatment. However, co-treatment with the Bcl-xL inhibitor navitoclax significantly restored steroid sensitivity...These findings indicate that Bcl-xL-expressing myofibroblasts contribute to the development of glucocorticoid resistance in fibrotic lungs in severe asthma. Targeting Bcl-xL may provide a novel therapeutic strategy to restore steroid responsiveness in severe asthma.

Functionally, PRMT5 inhibition induces senescence in LKB1-deficient cells and confers vulnerability to navitoclax, synergistically blunting tumor growth in vivo. Collectively, we identify PRMT5 as an actionable therapeutic vulnerability in LKB1-deficient lung cancer, and propose LKB1 status/NNMT expression as potential biomarkers for PRMT5 inhibition. These findings may expand the clinical utility of PRMT5-targeted therapies beyond MTAP-deleted cancers.

Significantly, YTHDC1-depleted senescent cells displayed enhanced sensitivity to the senolytic agent, ABT-263. Collectively, these findings uncover a previously unrecognized epitranscriptomic-telomerase axis that dictates senescence escape, establishing YTHDC1 as a central node linking RNA modification to telomere maintenance, cellular senescence, and tumor progression.

Navitoclax added to venetoclax/decitabine is safe and tolerable with preliminary activity in patients with high-risk myeloid malignancies.

TM4SF19 is a promising diagnostic and independent prognostic biomarker in BLCA, influencing tumor progression through signaling pathways and immune microenvironment modulation. Its association with chemotherapy resistance highlights its potential as a therapeutic target.

P1, N=6, Completed, Thomas Jefferson University | Active, not recruiting --> Completed

Integrated PK/PD model simulations suggested that a flat starting dose of navitoclax 200 mg for baseline platelets > 150 × 109/L, and 100 mg for ≤ 150 × 109/L with ruxolitinib minimized thrombocytopenia risk while maintaining efficacy. Dose reductions of 25 mg for the 100 mg start and 50 mg (plus 25 mg if needed) for the 200 mg start optimized the benefit-risk balance.

ECE2, NFE2L3, PFKFB3, FADS2, and SEPT3 are associated with pyrimidine metabolism in TNBC. A risk model and nomogram were successfully constructed based on these genes, providing a theoretical basis for the treatment of TNBC patients. We confirm the model's validity in TNBC by validating SEPT3 (a key PyMRG) regulates TNBC cell proliferation, migration, and invasion.

P1/2, N=96, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

Head and neck squamous cell carcinoma (HNSCC) is currently the sixth most prevalent cancer worldwide and is marked by a high tumor relapse frequency due to acquired chemoresistance, requiring alternative strategies to sensitize resistant tumor cell populations to treatment. In vivo studies confirmed that SG treatment followed by ABT-263 limited tumor progression and extended survival without notable toxicity. Thus, SG in combination with senolytic treatment may be an effective strategy for suppressing the growth of cisplatin-resistant HNSCC cells.

P1, N=17, Active, not recruiting, City of Hope Medical Center | Trial completion date: Apr 2026 --> Mar 2027 | Trial primary completion date: Apr 2026 --> Mar 2027

The CDK4/6 inhibitors abemaciclib and palbociclib have demonstrated promising results in patient-derived xenograft models of PM...While some cells showed sensitivity to Bcl-xL inhibitors, neither navitoclax nor the specific Bcl-xL inhibitor A-1331852, nor other BH3 mimetics targeting Bcl-2 (venetoclax) or Mcl-1 (S63845) increased cell death when combined with palbociclib...Therefore, we employed inhibitors of these pathways, such as dasatinib, momelotinib or Torin-1, which did not synergise with palbociclib to kill the cells...The differential effects of palbociclib and cisplatin on permanent growth arrest were verified by sorting PM cells based on size and β-galactosidase activity. Our findings underscore the importance of understanding the nature of therapy-induced senescence when assessing the effectiveness of senolytics in different tumour models.