eprenetapopt (APR-246)

Specifically, MRD negativity after cycle 12 strongly predicted OS (33.9 vs 20.4 months; P=.005) and EFS (33.9 vs 10.1 months; P=.004) with a trend for RFS (32.6 vs 13.5 months; P=.06). TP53 MRD was strongly predictive of outcomes, supporting incorporation of this assay in future novel strategies.

Moreover, PDK1 inhibition increased the therapeutic effect of APR-246 on TP53 mutant breast cancer in xenograft tumors. Our results suggested that intervention of PDK1 could potentially emerge as a new therapeutic strategy to impede the progression of TP53 mutant breast cancer.

The p53 reactivator APR-246 restores sensitivity of p53R273H-expressing cells to LT1-3. Therefore, LT1-3 possesses multifunctional antitumor properties, directly inhibiting tumor cells and enhancing the efficacy of cisplatin, without causing toxicity to normal cells. Combining LT1-3 with cisplatin holds promise as a first-line therapy for lung cancer, while LT1-3 alone may be suitable for maintenance therapy.

Aside from allogeneic transplantation, the current standard of care approach for higher-risk myelodysplastic syndromes/neoplasms (HR-MDS) remains monotherapy with a hypomethylating agent (HMA) including azacitidine, decitabine, or oral decitabine/cedazuridine...In this review, we discuss lessons learned from the recently reported negative trials of azacitidine in combination with eprenetapopt (APR-246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax...Instead, we advocate for using the IWG 2023 response criteria to better capture clinically meaningful benefits in HR-MDS. Lastly, we emphasize the need for the scientific community to access patient-level data and samples from failed phase 3 trials in an efficient and expedited fashion to inform the development of subsequent trials.

Furthermore, upon exposure to the combination of 10 μM Prima-1MET and 10 μM Tam, synergistic effects were detected, reflected by decreased viability, migration, altered morphology, and induction of apoptosis, along with downregulation of CCND1. Hence, these results emphasize the attractiveness of the combination of Prima-1MET and Tam as a therapeutic approach for TNBC and ER+ breast cancer, irrespective of p53 mutational status; therefore, these results encourage further preclinical and clinical studies, considering that the effective dose of Prima-1MET is less than the reported clinically achievable plasma level (∼80 μg/ml).

In this study, we investigated the effects of two purported p53 reactivators, HO-3867 and APR-246, on cell proliferation via half-maximal inhibitory concentration (IC50) analyses using CyQUANT DNA measurements, tumor growth in vivo and gene expression by bulk RNA sequencing in gynecologic cancer cell lines that harbor oncogenic mutations in p53. RNA sequencing data suggest that HO-3867 is acting through both p53-independent and p53-dependent pathways resulting in inhibition of DNA repair pathways including homologous recombination in p53 mutant cancer cells. Significance: The development of resistance to PARP inhibitors is a major problem and a cause of treatment failures in advanced gynecologic cancers, and we show that adding a p53 reactivator such as HO-3867 enhances the efficacy of PARP inhibitors in p53-mutant cancer models.

We demonstrate that XPO1 is overexpressed in patient samples after eprenetapopt and azacitidine treatment, elucidate the mechanism by which this occurs, and determine that it is necessary and sufficient for resistance to combination therapy. Finally, we validate in a variety of model systems including a novel patient derived xenograft model of TP53 mutant MDS, that eprenetapopt in combination with XPO1 inhibitors can overcome this resistance, providing preclinical rationale that this novel combination strategy is a viable therapeutic approach in TP53 mutant MDS/AML patients.

In this international, combined analysis of Phase 2 eprenetapopt + azacitidine patients, the combination was well-tolerated with synergistic response rates in mTP53 MDS/AML. Quality of response and NGS negativity strongly predicted OS, particularly in the setting of allo-HCT, validating NGS clearance as a critical biomarker of allo-HCT outcomes in mTP53 patients.

p53, often mutated in cancer, is reactivated using MDM2 antagonist Nutlin-3, refunctionalizing compound APR-246, or stapled peptides. HIF-1α, which regulates hypoxic responses and angiogenesis, is inhibited by agents like acriflavine or stabilized in anemia therapies by HIF-PHD inhibitor roxadustat...AP-1, implicated in cancer and arthritis, can be inhibited by T-5224 or kinase inhibitors JNK and p38 MAPK...Challenges remain, including the structural inaccessibility of TFs, functional redundancy, off-target effects, and delivery barriers. Despite these challenges, transcription factor modulation is emerging as a viable and promising therapeutic approach, with ongoing research focusing on specificity, safety, and efficient delivery methods to realize its full clinical potential.

These findings suggest that UBE2T plays a crucial role in the progression of IDH1/TP53 mutant astrocytoma and that targeting UBE2T with APR-246 could be a promising therapeutic strategy for patients with these mutations. Our study provides a foundation for further research into the role of UBE2T in glioma and the development of targeted therapies.

Venetoclax-resistant AML cell lines remain susceptible to ferroptosis, higher GPX4 expression maybe a critical marker for poor prognosis. Regulating the expression of ferroptosis-related genes and metabolites may enhance the efficacy of venetoclax and provide new treatment options for AML patients.

PRIMA-1Met and SAS combination synergistically reduced cell survival regardless of p53 status and further impaired antioxidant capacity, especially in mutant p53 cells, linking their cytotoxic effect to redox imbalance. Thus, the association of PRIMA-1Met with drugs targeting the antioxidant response could represent a valid strategy to kill CLL cells carrying either wt or mutant p53.