Cutaneous T-cell Lymphoma

Synergistic effects with bortezomib (BTZ) were analyzed...SNG exerts potent anticancer effects in CTCL by inducing ROS-dependent mitochondrial apoptosis and inhibiting the PI3K/AKT/GSK3 signaling pathway. Its synergy with BTZ and computational validation of AKT/Bcl-2 targeting underscore its potential as a novel therapeutic candidate for CTCL, warranting further preclinical investigation.

Notably, PS elevated intracellular reactive oxygen species (ROS), and scavenging ROS with N-acetylcysteine (NAC) significantly attenuated PS-driven cytotoxicity, supporting a ROS-dependent mechanism. Finally, PS combined with the proteasome inhibitor bortezomib produced greater anti-CTCL activity than either agent alone, consistent with a synergistic interaction. Together, these findings show that PS promotes ROS-dependent, mitochondria-mediated apoptosis in CTCL and support further evaluation of PS-based strategies for this malignancy.

P1, N=42, Recruiting, Medical College of Wisconsin | Not yet recruiting --> Recruiting | Trial completion date: Jul 2028 --> Jul 2029 | Trial primary completion date: Jan 2027 --> Jan 2028

P2, N=58, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2026 --> Jul 2027 | Trial primary completion date: Jul 2026 --> Jul 2027

Using a C57BL/6 intradermal T-cell lymphoma model, we evaluated IQDMA efficacy against conventional psoralen + UV-A (PUVA) phototherapy...Kinase-substrate network analysis revealed PAK1 substrates were 4.9-fold enriched among downregulated proteins (OR = 4.91, P = 0.011), validating the PAK-STAT axis as IQDMA's primary mechanism. These findings establish a CDC42-PAK-STAT nuclear transport axis wherein IQDMA simultaneously inhibits PAK2 kinase activity and depletes its CDC42 scaffold, creating cytoplasmic pY-STAT5 retention that uncouples phosphorylation from transcriptional execution-a dual mechanism distinct from selective JAK inhibitors that warrants clinical evaluation.

P1, N=17, Not yet recruiting, Kyowa Kirin Inc.

The 2020-2025 period brought meaningful therapeutic advances for CTCL, including new FDA approvals, breakthrough designations, and emergence of cellular therapy. Future development should prioritize patient-reported outcomes as co-primary endpoints, prospective biomarker validation, and combination strategies with non-overlapping toxicity profiles.

Considering the potential morbidities linked to lymph node biopsy, evaluating ultrasound features might be essential to patient selection. An earlier biopsy could be justified in younger patients with increased beta-2 microglobulin levels.

Myeloid cells exhibited expression of immunomodulatory genes (RUNX3, DDIT4, IL4I1), and malignant T-cells expressed exhaustion-associated markers (CXCL13, SOCS3, F2R, ETV1), as opposed to AD and healthy control samples. Thus, our results provide a novel insight into the immune-stroma crosstalk in the tissue microenvironment of early-stage MF vs. AD skin lesions.

Many of the mutations described implicate driver mutations in advanced-stage MF and have been associated with poor survival. While there is no evidence suggesting a singular mutation for the pathogenesis of LCT, the constellation of mutations may be responsible for histologic progression to LCT.

P=N/A, N=10, Not yet recruiting, Assistance Publique - Hôpitaux de Paris

High frequencies of PD-L1+memory B cells, PD-1+DC and PD-1+naïve CD4+ T cells correlated with shorter progression-free survival, whereas normal levels of PD-1+transitional monocytes were associated with longer overall survival. Lesion-specific aberrant T cells and TME remodeling may drive MF severity and contribute to future immunotherapy.