eprenetapopt (APR-246) / Aprea - LARVOL DELTA

Posttransplant MRD monitoring by TP53 duplex sequencing with APR-246 + azacitidine maintenance predicts outcomes. (PubMed, Blood Adv) - No abstract available

Biomarker • Journal • Transplantation • TP53

Inhibitory effects of induction of massive apoptosis (PRIMA-1MET) on tumorigenic chemokines in ovarian cancer cells (AACR 2026) - "PRIMA-1MET restores mutant p53 function and inhibits NF-κB-driven chemokine signaling, thereby restraining ovarian cancer progression and metastasis. These findings highlight its promise as targeted therapy."

Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • CCL20 • CXCL1 • CXCL8 • IL1B

Depletion of dominant-negative mutant p53 improves the efficacy of mutant p53 reactivators (AACR 2026) - "Reactivators include APR-246 (PRIMA1met) and arsenic trioxide (ATO). Moreover, our RT-PCR studies demonstrated that the combination of reactivator with depleters significantly increased mRNA expression of p53 downstream targets, as compared to that of the reactivator treatment alone. These results strongly suggest that the combination of reactivator drugs with depleter drugs could improve the treatment efficacy of reactivators to suppress mutp53-carrying tumors."

Clinical • Oncology • CDC37 • DNAJB1 • TP53

Anti-ROR2 therapies target cancer stem cells in triple-negative breast cancer (AACR 2026) - "We generated a high-affinity, humanized monoclonal antibody (mAb) specific for human ROR2 (h6E6) that could block ROR2 signaling, analogous to the capacity of our previous anti-ROR1 mAb (zilovertamab) to block ROR1 signaling. In NSG mice with ROR2+ TNBC PDX, intravenous h6E6, compared to control hIgG1, reduced expression of cancer stemness and EMT genes, as well as ERK1/2, NF-κB, and NRF2 pathway targets (FDR<0.0001), and caused a 5-fold reduction in NQO1, the main NRF2 downstream target, and increased sensitivity to APR-246 (p<0.001). By integrating rigorous experimental controls in both in vitro and in vivo studies using early-passage PDX, our work demonstrates that anti-ROR2 antibody therapy, combined with redox-modulating agents like APR-246, can effectively target CSC-driven disease persistence and therapy resistance in TNBC, supporting future clinical trials of h6E6 targeting ROR2+ TNBC."

Cancer stem • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ITK • NQO1 • ROR2

Νοvel Therapies in High-Risk Myelodysplastic Syndromes. (PubMed, Eur J Haematol) - "Recent advances have led to the development of novel therapeutic strategies, such as BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, enasidenib), CD47 inhibitors (magrolimab), TIM-3 inhibitors (sabatolimab), XPO1 inhibitors (eltanexor), NEDD8-activating enzyme inhibitors (pevonedistat), TP53-targeted agents (eprenetapopt), liposomal chemotherapy (CPX-351), and oral HMA formulations. Combinations of hypomethylating agents with these new drugs, as first-line treatment, have to date not proven more efficacious than HMA monotherapy. This review summarizes the current therapeutic landscape on novel therapies for HR-MDS, highlighting their mechanism of action, efficacy, and demonstrates the unmet clinical need for more effective therapies."

Journal • Review • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • HAVCR2 • IDH1 • IDH2

Few Drug Approvals in MDS: Lessons and Insights from a Decade of Clinical Trials (ICKSH 2026) - "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/cedazurid ine...In this lecture , I will discuss lessons learned from the recently reported negative trials of azacitidine in combination with eprenetapopt (APR -246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax...Instead, I will advocate for using the IWG 2023 response criteria to better capture clinically meaningful benefits in HR-MDS. Lastly, I will 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."

Clinical • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • TP53

APR-246 drives ROS-dependent ferroptosis and apoptosis and enhances anti-PD-1 efficacy in bladder cancer. (PubMed, Sci Rep) - No abstract available

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

Integrated Organoid Profiling and Structural Modeling Identify a Molecularly Distinct TP53-Mutant NSCLC Subgroup Sensitive to APR-246 and TKI Combination Therapy (ELCC 2026) - No abstract available

Combination therapy • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • TP53

Leveraging p53 and MCL-1 as Therapeutic Targets in Small Cell Lung Cancer (IASLC-TTLC 2026) - "While chemoresistance is common after platinum-based strategies, lurbinectedin, or bispecific T-cell engagers, a need remains for novel therapeutic strategies in relapsed SCLC...New approaches with p53 reactivators, APR-246 and rezatapopt, can stabilize the conformation of mutant p53 to induce apoptosis... MCL-1i with p53 reactivators is a promising therapeutic combination for SCLC, independent of NE subtype or TP53 alteration. Mechanistic understanding of how BAX/BAK homeostasis may regulate this response in SCLC is underway."

IO biomarker • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ASCL1 • BCL2 • MCL1 • MDK

The impact of p53 mutation on tumor immune evasion: mechanistic insights and clinical implications. (PubMed, Front Immunol) - P1/2, P1b/2, P3 | "Therapeutic approaches include Mtp53 reactivators (e.g., APR-246, PC14586), degraders, synthetic lethal strategies, and neoantigen vaccines. Its combination with pembrolizumab (NCT04383938) demonstrated acceptable safety (immune-related adverse events in ∼12%) but limited efficacy, underscoring the need for biomarker-guided, precision-based combinations. Thus, a multidimensional biomarker platform is urgently needed-one integrating TP53 mutation subtypes (e.g., R175H vs. nonsense mutations), dynamic ctDNA monitoring (VAF ≥ 0.01%), tumor immune microenvironment (TIME) features (e.g., TILs, MDSCs), and spatial multi-omics-to enable precise molecular stratification and personalized intervention in Mtp53-driven cancers."

IO biomarker • Journal • P53mut • Review • Breast Cancer • Colorectal Cancer • Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • KRAS • TP53

Innovative Drug and Prodrug Candidates in Cancer Treatment Targeting TP53 Mutations: Challenge and Hope. (PubMed, Drug Dev Res) - "Small-molecule correctors, statins, Hsp90 inhibitors, and new drugs like Eprenetapopt and COTI-2 are among the therapeutic options proposed. Challenges such as medication resistance, side effects, and the chemical complexity of p53 pathways are also addressed, emphasizing the importance of ongoing research. This review contributes to our understanding of TP53-targeted cancer medicines, offering hope for more innovative treatments with improved outcomes."

Journal • Review • Hematological Malignancies • Leukemia • Oncology • Ovarian Cancer • CDC37 • TP53

Hotspot gene mutations and treatment response in myelodysplastic syndromes (MDS): predictive biomarkers and targeted strategies. (PubMed, Front Med (Lausanne)) - "Current research has revealed that ASXL1 mutations in MDS predict demethylating agents (HMAs) resistance, the combination of HMAs and Venetoclax (VEN) achieved an ORR of 87%. DNMT3A R882 mutations induce decitabine sensitivity via hemi-methylated enhancer trapping, and TET2 mutations enhance HMAs efficacy only in ASXL1 wild-type contexts (ORR 62.1% vs. co-mutated 19%). RUNX1 aberrations reduce chemotherapy responses (18.9% ORR in high-risk MDS) through DNA repair impairment, while BCOR/EZH2 loss drives cytarabine resistance. TP53 multi-hit lesions correlate with poor survival (OS <12 months) but respond to eprenetapopt-azacitidine (ORR 73%), and IDH1/2 inhibitors achieve durable remissions (ivosidenib ORR 83.3%, mOS 35.7 months). In this paper, we systematically illustrate the correlation between key gene mutations and the response to HMAs, chemotherapy and targeted therapies in MDS patients. This article summarizes the current evidence on gene mutations as predictive..."

Biomarker • Journal • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • ASXL1 • BCOR • DNMT3A • IDH1 • IDH2 • RUNX1 • TET2 • TP53

Eprenetapopt combined with venetoclax and azacitidine in TP53-mutated acute myeloid leukaemia: a phase 1, dose-finding and expansion study. (PubMed, Lancet Haematol) - P1 | "Eprenetapopt and venetoclax with azacitidine had an acceptable safety profile and encouraging activity, supporting further frontline evaluation of this combination in the treatment of TP53-mutated acute myeloid leukaemia."

Journal • P1 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Leukopenia • Myelodysplastic Syndrome • Neutropenia • Oncology • Septic Shock • Thrombocytopenia • TP53

Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes. (PubMed, J Clin Oncol) - P2 | "In patients with mTP53 AML and MDS, post-HCT maintenance therapy with eprenetapopt combined with azacitidine was well tolerated. RFS and OS outcomes were encouraging in this high-risk population."

Journal • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

Efficacy of novel agents in the treatment of acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis (ASH 2025) - "Newer agents included for AML were Guadectiabine, Magrolimab, Alvocidib, Enasidenib, Flotetuzumab, Vadastuximab, Mitoxantrone, Pevonedistat, Entospletinib, Eprenetapopt, Belinostat, Onvansertib, Panobinostat, Cediranib Maleate, Nilotinib, Emavusertib, and anti-CD45 antibody (DOTA-BC8). The newer agents investigated for MDS included Rigosertib, Imetelstat, Pembrolizumab, Enasidenib, Sabatolimab, Ivosidenib, Elitercept, Pevonedistat, Emavusertib, Atezolizumab, and Olutasidenib...All patients were treated concomitantly with either azacitidine (77%) or decitabine (23%)... This meta-analysis and systematic review demonstrate promising efficacy for novel agents in AML and MDS patients. There is a need for prospective trials with larger patient populations to investigate these agents further."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • TP53

Breast Cancer Therapy by Small-Molecule Reactivation of Mutant p53. (PubMed, Curr Oncol) - "Furthermore, we will demonstrate the effectiveness of PRIMA-1 at arresting xenograft growth in an animal model and go on to show that the PRIMA-1 analog APR-246 effectively restores wtp53 tumor suppressor activity in TNBC cells. A brief overview of current clinical trials aimed at reactivating p53 to treat certain cancers is provided. Finally, we discuss the possible use of naturally occurring compounds, which are generally non-toxic, to reactivate mutant p53 and control TNBC progression."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • TP53

Multiomics-guided ex vivo drug sensitivity testing in Relapsed/Refractory Acute Myeloid Leukemia (ASH 2025) - "DNMT3A mutation suggested response tonavitoclax and KPT-330 (OR 8.4, p=0.18; OR 4.2, p=0.5, respectively). Associations were also foundbetween FLT3 mutation or short relapse latency among navitoclax responders (OR 4.2, p=0.5; eachrespectively).FLT3 mutants were associated with ponatinib sensitivity which was linked to FGFR3/FGFR4 upregulationin responders (OR 4.2, p=0.5). Furthermore, samples of patients who relapsed quickly were sensitive toeprenetapopt, wherein responders had upregulation of target gene MDM2 (OR 2.7, p=0.6). All patientsamples were highly sensitive to Panobinostat...Crucially, this proof-of-concept results supports a precision-medicine framework combininggenomic insights with functional drug screening, might offer actionable options for a patient group that isotherwise limited to supportive care alone. Further validation in larger cohorts of specific targets andtranslating and repurposing drugs post exvivo DS through potential clinical trials are ongoing."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • BCL2L1 • DNMT3A • FGFR3 • FGFR4 • FLT3 • IDH2 • MDM2 • MIR15A • MIR182

Profiling drug sensitivity in CLL B cells after BTK inhibitor progression using a novel drug panel (ASH 2025) - " Using the Mayo Clinic CLL Database and the Mayo Clinic CLL Tissue Bank, we identified 47 patients with RR CLL, all of whom experienced disease progressionon a BTKi (35 ibrutinib +/- CD20 antibody, 10 acalabrutinib +/- CD20 antibody, 2 other)...We also observed that RR CLL cohort exhibited significantly increased drug resistance to most of the tested drugs in the presence of BMSCs with corresponding increases in IC50s (with vs. without BMSCs, fold-change respectively): LP-118 3.92-fold, venetoclax 1.98-fold, carfilzomib 2.58-fold, TP-0903 1.65-fold, panobinostat 204.23-fold, TCIP1 1.91-fold, crenolanib 1.31-fold, idasanutlin 1.69-fold, belinostat 6.14-fold, LP-168 1.29-fold, eprenetapopt 3.44-fold and GTE 1.08-fold (11 out of 12 with p -values <0.05 except for GTE which was not significant, Mann-Whitney U test)... Our results highlight the spectrum of currently available drugs that show promise for therapeutic use in patients with RR CLL who experience disease..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • AXL • BCL2 • STAT6 • TP53

TP53 mutation promotes diffuse large B-cell lymphoma progression via mediating lactylation of ATP5E at Lys44 (ASH 2025) - "In contrast, knockdown of WT-TP53 promoted cell proliferation and shortened the G0/G1 phase, and significantly decreased LDHAexpression and intracellular lactate levels, whereas knockdown of WT-TP53 had no notable effect.Moreover, knockdown of MUT-TP53 reduced cellular sensitivity to APR-246, a small-molecule inhibitortargeting MUT-TP53...Functionalanalyses indicated that MUT-TP53 knockdown increased mtROS levels and decreased mitochondrialmembrane potential. Taken together, these findings suggest that DLBCL tissues and cells exhibitwidespread elevated lactylation modification levels mediated by TP53 mutation.In conclusion, our results revealed that TP53 mutations recruit and enhance ATP5E K44la, stabilizing itsexpression and modulating mitochondrial functions, thus providing a novel mechanism for metabolicreprogramming in DLBCL."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • ATP5F1E • TP53

Synergistic enhancement of APR-246 anti-leukemic activity through ENO1 inhibition in TP53- and FLT3-mutated Acute Myeloid Leukemia (ASH 2025) - "HighENO1 expression correlated with shorter OS in TP53-mutant (HR 2.14, p = 0.008) and FLT3-ITD (HR 1.87, p= 0.013) cohorts.Functional loss-of-ENO1: shENO1 reduced clonogenicity by 48–64 % and increased APR-246 sensitivity(IC50 fold-reduction: MOLM-13 2.9, Kasumi-1 2.3; ZIP synergy 29–43).Ferroptosis signature: Combined ENO1 inhibition plus APR-246 elevated lipid-ROS 3.7-fold, decreasedGSH by 62 %, and triggered mitochondrial shrinkage/cristae loss—phenotypes reversed by ferrostatin-1.Molecular mechanism: RNA-seq revealed selective down-regulation of the glutathione/ferroptosis axis.ENO1 interacted with the E3-ligase NEDD4L; ENO1 loss augmented NEDD4L-mediated poly-ubiquitination and proteasomal degradation of SLC7A11 and GPX4, whereas MG132 restored GPX4levels.Genotype independence: Synergy was observed irrespective of TP53 or FLT3 status, indicating a p53-independent metabolic vulnerability.ConclusionsENO1 is an adverse prognostic biomarker in AML whose enzymatic or..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • ENO1 • FLT3 • GPX4 • SLC7A11 • TP53

Durability of complete response outperforms complete response rates as a surrogate endpoint for advancing to phase III trials in high-risk myelodysplastic syndromes (ASH 2025) - "The HMA plus venetoclax cohort (n=59) had a CRrate of 11.9% (7/59) with 8.5% (5/59) durable CR, equating to 71% (5/7) of CRs durable. Clinical trial pts(n=41) receiving HMA plus novel agents (magrolimab, eprenetapopt, or tamibarotene) had a higher CRrate of 29.3% (12/41) with 24.4% (10/41) durable CR, translating into 83% (10/12) of CRs being durable.In subgroup analysis of pts with TP53-mutated MDS treated with HMA alone (n=242), achieving a durableCR was associated with a 38% reduction in risk of death (HR 0.62; 95% CI 0.39–0.97; p=0.037). Only durable CR translates into a survival benefit in HR-MDS. CR >6 months is a practical, clinicallymeaningful surrogate endpoint and may improve assessment of treatment efficacy and accelerate drugdevelopment in HR-MDS."

Clinical • P3 data • Hematological Malignancies • Myelodysplastic Syndrome • TP53

Dual-functional copper nanoplatform potentiates cuproptosis through p53 reactivation and metabolic reprogramming. (PubMed, J Colloid Interface Sci) - "Here, we report the rational design of CuF16@246, an acid-responsive, dual-functional copper-based nanocoordination polymer that integrates Cu2+ and the p53 reactivator eprenetapopt (APR-246) within a single perfluorosebacic acid (PFSEA)-coordinated framework to synergistically induce cuproptosis and reverse tumor metabolic reprogramming...In vitro and in vivo studies demonstrate that CuF16@246 exhibits more efficient cellular uptake, more potent cytotoxicity, and more significant tumor growth inhibition than individual treatments, without inducing hemolysis or major organ toxicity. This work establishes a dual-functional strategy that combines metabolic reprogramming with sensitized cuproptosis, providing a promising framework for developing advanced copper-based nanomedicines for the treatment of mut-p53-positive cancers."

Journal • Hematological Disorders • Oncology • DLAT • FDX1 • LIAS • TIGAR

Characterization and Preclinical Evaluation of AS-1763, an Oral, Potent and Selective Noncovalent BTK Inhibitor, in Chronic Lymphocytic Leukemia (ASH 2023) - P1 | "In primary CLL samples, AS-1763, pirtobrutinib or ibrutinib induced a modest apoptosis...Evaluation of drug interaction models utilizing Compusyn and Synergy Finder applications predominantly indicated additive effects between AS-1763 with BCL-2 inhibitor, venetoclax as well as p53 activator APR-246... AS-1763 is a selective ncBTKi that inhibits both wild-type and mutant BTKs listed in Table 1. In CLL cells, AS-1763 was effective in inhibiting BCR pathway signaling and sensitized cells to other agents such as venetoclax. Based on these encouraging data we have initiated a clinical trial to test AS-1763 in patients with CLL and other B cell malignancies who have failed or are intolerant to at least two prior lines of systemic therapy, including cBTKi (NCT05602363 Clinical Trials.gov)."

IO biomarker • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • CCL3 • CD86 • MCL1

Post-transplant MRD Monitoring by TP53 Duplex Sequencing with APR-246 + Azacitidine Maintenance Predicts Outcomes. (PubMed, Blood Adv) - "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."

Biomarker • Journal • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

APR-246 Overcomes Resistance to Asparaginase in Lymphoid Malignancies By Targeting Metabolic Cell Vulnerabilities (ASH 2024) - "KHYG-1 cells were treated with Erwinase associated with a ferroptosis inducer (RSL3) and/or a ferroptosis inhibitor (ferrostatin-1). In our work, APR-246/Erwinase combination effectively disrupts the balance between ROS generation and antioxidation dependent on glutamine/GSH metabolism in ASNase-R cells and leads to cell death by ferroptosis. Prospective phase I/II studies are now required to confirm the clinical efficacy of APR-246/Erwinase combination in ASNase-R ENKTL and ALL patients."

Acute Lymphocytic Leukemia • CNS Disorders • Extranodal Natural Killer/T-cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Natural Killer/T-cell Lymphoma • Oncology • Psychiatry • T Cell Non-Hodgkin Lymphoma • ANXA5 • TP53