decitabine

Overexpression of anti-apoptotic protein BCL-2 and hypermethylation are hallmarks of acute lymphoblastic leukemia (ALL) and can be pharmacologically addressed by venetoclax (VEN) and hypomethylating agents (HMA) such as azacytidine (AZA) or decitabine (DEC). AZA-induced metabolic suppression as well as overall anti-leukemic activity alone and in combination with VEN was generally weaker compared to DEC. Altogether, we herein demonstrate that combined VEN and HMA application acts synergistically and significantly reduces the leukemic burden in ALL cell lines via impairment of tumor cell metabolism and mitochondrial function.

Based on treatment regimens, the patients were categorized into chemotherapy group ("3+7"regimen), demethylation therapy (HMA) group (decitabine-based therapy), and UCB group (venetoclax combined with azacitidine plus UCB reinfusion). Cytokine level analysis demonstrated that the direct co-culture group showed higher levels of TNF-α and IFN-γ, as well as lower levels of IL-6 compared to the control group (P<0.001). Immunocytes such as NK cells in UCB may promote immune function reconstruction and hematopoietic recovery in patients, thereby improving their prognosis.

While currently, hypomethylating agent therapy (azacitidine and decitabine) is mainly used in high-risk MDS patients, and ruxolitinib is primarily used in symptomatic primary myelofibrosis (PMF-MPN), their clinical efficacy remains suboptimal. In response, a new generation of immune checkpoint inhibitors are being developed to target the TME, including PD-1/CTLA-4 blockers, macrophage-directed agents including CD47 inhibitors, and T cell-targeting checkpoint inhibitors such as TIM-1 and LAG-3. This review will describe the functional role of key TME constituents in the progression of myeloid malignancies and explore the current landscape and future potential of advanced cellular and molecular immunotherapies in the treatment of these disorders.

P1, N=58, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Jun 2027 | Trial primary completion date: Jun 2026 --> Jun 2027

Mechanistic investigations uncovered that the tumor-suppressive effect of APCDD1 was mediated by promoter hypermethylation, and its expression could be restored by the demethylating agent Decitabine. We further propose Leflunomide as a novel therapeutic strategy for high-risk WT patients. These findings advance our understanding of WT biology and provide actionable insights for risk stratification and targeted intervention.

Here, we define a clinically actionable strategy that functionally targets PLK1 by combining inhibition of the AAA+ ATPase p97/valosin-containing protein (VCP) with the hypomethylating agent decitabine (DAC). In vivo, CB-5339/DAC is well tolerated, significantly prolongs survival, reduces leukemic burden, and suppresses PLK1 in bone marrow blasts. Together, these data establish p97 inhibition as a rational means to exploit replication and proteotoxic stress in AML and provide strong rationale for clinical evaluation of CB-5339 plus DAC in high-risk disease.

P2, N=20, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Nov 2026 --> Jun 2026 | Trial primary completion date: Nov 2026 --> Jun 2026

P1, N=27, Not yet recruiting, Washington University School of Medicine

Gene expression and DNA methylation data from DAC-treated and untreated T-47D (Luminal-A) and JIMT-1 (HER2-amplified, trastuzumab-resistant with a TNBC-like phenotype) breast cancer cell lines were obtained from a published dataset. Survival analysis identified 114 DAC-responsive genes associated with overall survival in ER/PR-positive BC and 8 in the JIMT-1-derived gene set. DAC induces subtype-dependent epigenomic and transcriptional remodeling, selectively disrupts age-associated regulatory programs, and underscores the need for subtype-stratified evaluation of epigenetic therapies in breast cancer.

Before conditioning, 20 patients received intensive induction chemotherapy, 1 received decitabine plus venetoclax, and 3 proceeded directly to transplant. In conclusion, our results suggest that achieving remission before alloHSCT in BP-MF is associated with favorable outcomes. The adverse impact of TP53 or EZH2 mutations supports early post-transplant strategies to prevent relapse.

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

Transferring the refined relationship matrix and learned weights to compound-induced perturbation data enables in silico drug screening, identifying BRD-K19103580 and decitabine as targeted therapeutic agents for apoptosis and ferroptosis, respectively. The pathway-resolved drug profiles can facilitate the rational design of combination therapies targeting complementary PCD pathways to overcome single-pathway resistance. Overall, xNNPCD offers a generalizable, interpretable approach for mapping the regulatory landscape and elucidating the molecular processes of PCD in cancer.