RARA (Retinoic Acid Receptor Alpha)

P2, N=151, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027

P=N/A, N=400, Active, not recruiting, Groupe Francophone des Myelodysplasies | Recruiting --> Active, not recruiting | Trial completion date: Oct 2022 --> Jul 2026 | Trial primary completion date: Oct 2020 --> Jul 2026

Across multiple cancer types, tumors with higher PMC abundance are associated with more favorable clinical outcomes. These findings reveal the pivotal role of RA-RARα-CIITA signaling in mast cell reprogramming and suggest that pharmacologic induction of proinflammatory mast cells may represent a promising approach to enhance antitumor immunity.

Among the pathways disrupted, retinoic acid signaling is of particular interest, as retinoid receptors such as RARα and RARβ are frequently hypermethylated and repressed in EBVaGC. Our findings indicate that DNMT inhibition can partially reverse RA receptor silencing, supporting further investigation of DNMTi-RA combination strategies as a novel therapy for EBV + gastric cancer.

Despite a delayed progression in BMS641 + BMS961, RAR-specific agonists led to a variety of neuronal subtypes, astrocytes, and oligodendrocyte precursors. Spatially resolved transcriptomics performed in organoids revealed spatially distinct RAR isotype expression leading to specialization signatures associated with matured tissues, including a variety of neuronal subtypes, retina-like tissue structure signatures and even the presence of microglia.

Our findings reveal that TTMV integrates exclusively within intron 2 of the RARA gene via microhomology-mediated end joining (MMEJ), forming functional TTMV::RARA transcripts. Clinically, patients harboring this fusion were predominantly pediatric (72.

This phenotype was further exacerbated by chronic temozolomide treatment in both in vitro and in vivo glioblastoma models. Notably, CMA-activating compounds, including the RARA (retinoic acid receptor alpha) antagonist CA77.1, the class I phosphoinositide 3-kinase (PI3K) inhibitor paxalisib, and metformin, effectively reduced IDH1 and CCND1 levels while suppressing glioblastoma cell growth. Together, our findings suggest that dysfunction of the CMA-IDH1-CCND1 regulatory cascade drives progression of IDH1-wild-type glioblastoma and provide a mechanistic basis for repurposing CMA activators as potential therapeutic agents for these tumors.

Collectively, our results suggest that tamibarotene may elicit detrimental effects in patients with EBA by abolishing the recruitment of Tregs into skin. This warrants great caution when using tamibarotene in patients with EBA and possibly other pemphigoid diseases.

These findings confirm and extend established evidence by demonstrating that melittin's mitochondrial apoptotic mechanism is consistently active in promyelocytic HL-60 model (PML/RARα-negative). This retinoid-independent mechanism suggests potential therapeutic utility for ATRA-resistant cases or as a complementary strategy in APL treatment. However, selectivity validation in non-cancerous hematopoietic cells represents an important future research priority.

In APL, the PML/RARα fusion protein inhibited PU.1-dependent transactivation of lnc-SPI1U by hijacking the SE region that overlapped with lnc-SPI1U locus. Our study provides mechanistic insight into how SE-lncRNAs contribute to the precise regulation of transcription factor activity during myeloid differentiation.

Most patients with APL presented with fever and bleeding. The bcr1 transcript of PML-RARα was the most commonly observed. ATRA and ATO-based treatment was associated with high remission rates, manageable toxicity, and a low relapse rate.

The antineoplastic drugs arsenic trioxide and fulvestrant stand out as examples for leveraging a SUMOylation-ubiquitylation cascade to inactivate the oncogenic fusion proteins PML-RARα and estrogen receptor α, respectively. Recent proof-of-concept studies indicate that proximity-inducing modalities can recruit aggregation-prone proteins to the StUbL machinery, potentially mitigating the formation of neurotoxic inclusions. We review new insights on StUbL-based therapeutics and reflect perspectives of reprogramming SUMO-StUbL signaling for use in oncology and neurology.