eprenetapopt (APR-246) / Aprea - LARVOL DELTA

EFFICACY AND OUTCOMES OF NOVEL THERAPEUTIC AGENTS AS MONOTHERAPY OR IN COMBINATION WITH CONVENTIONAL THERAPY IN ACUTE MYELOID LEUKEMIA: A SYSTEMATIC REVIEW AND META-ANALYSIS (EHA 2025) - "Agents included Guadectiabine 28%, Magrolimab 7% Alvocidib 3%, Enasidenib 23%,, Flotetuzumab 4%, Vadastuximab 9%, Mitoxantrone 9%, Pevonedistat 2%, Entospletinib 3%, Eprenetapopt 20%, Belinostat 0.5%, Onvansertib 3%, Panobinostat 2%, Cediranib Maleate 1%, Nilotinib 2%, Emavusertib 0.5%, and anti-CD45 antibody (DOTA-BC8) 0.5%. The conventional therapies were azacitidine 20% and cytarabine 17%... This study shows the promising efficacy of novel agents in AML and highlights the need for further prospective trials with larger patient populations to better understand the efficacy and safety outcomes of these agents in patients with AML."

Combination therapy • Monotherapy • Retrospective data • Review • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Thrombocytopenia • TP53

Targeting the p53/xCT/GSH Axis with PRIMA-1Met Combined with Sulfasalazine Shows Therapeutic Potential in Chronic Lymphocytic Leukemia. (PubMed, Int J Mol Sci) - "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."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • SLC7A11

OUTCOMES OF RECENT NOVEL THERAPEUTIC AGENTS IN TP53-MUTATED ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC SYNDROME IN THE FRONTLINE SETTING (EHA 2025) - "Newer agents included Eprenetapopt (27%, n=52/194), Magrolimab (50%, n=97/194), and Entospletinib (23%, n=45 /194). All patients were treated concomitantly with either azacitidine (77%, 149/194) or decitabine (23%, 45/194)... This study demonstrated the promising efficacy of novel agents in TP53-mutated AML and MDS in the frontline setting with acceptable toxicity. However, the results are limited because of the small sample size, and large randomized studies are needed to investigate these newer agents in TP53-mutated myeloid neoplasms."

Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Thrombocytopenia • TP53

FERROPTOSIS: AN IRON-EXPLOITING STRATEGY TO TARGET ACUTE LYMPHOBLASTIC LEUKEMIA (FIEST-ALL) (EHA 2025) - "Drugs used included RSL3, APR-246, Erastin, and MI-463 (Cayman Chemicals). In conclusion, the results obtained on cell lines and primary samples indicate a novel combinatorial therapeutic approach for KMT2A-r patients, suggesting that the current targeted therapy can prime the cells to expose additional metabolic vulnerabilities."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • KMT2A

TP53-Mutated Acute Myeloid Leukemia: Unanswered Questions. (PubMed, Hematol Oncol) - "This review evaluates the efficacy of various treatment approaches, including intensive chemotherapy (IC), hypomethylating agents (HMAs), venetoclax-based regimens, and immune checkpoint inhibitors...Novel approaches, such as APR-246 (eprenetapopt) and MCL-1/CHK1 inhibitors, are under investigation, but their therapeutic impact remains uncertain...Future research should focus on integrating targeted inhibitors with immunotherapy and bone marrow microenvironment modifiers. While TP53-mutated AML remains a formidable challenge, ongoing advances in precision medicine and immunotherapy hold the potential to improve patient outcomes."

IO biomarker • Journal • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Transplantation • HAVCR2 • TP53

SMARCB1 Deficiency as a Driver of the Hallmarks of Cancer in Rhabdoid Tumours: Novel Insights into Dysregulated Energy Metabolism, Emerging Targets, and Ongoing Clinical Trials. (PubMed, Metabolites) - "Targeting glutathione metabolism with eprenetapopt may induce oxidative stress and apoptosis. Widespread epigenetic aberrations, including increased EZH2 activity, are being targeted with inhibitors such as tazemetostat...Future horizons in RT treatment include immunotherapies, epigenetic modifiers, and gene therapies. The synergy and optimal timing of targeted therapy with conventional treatment requires further characterisation for clinical translation."

IO biomarker • Journal • Review • Gene Therapies • Oncology • Rhabdoid Tumor • Sarcoma • CDKN2A • PD-L1 • SMARCB1

Little to show for much effort and investment: An industry perspective on MDS drug development (MDS 2025) - "Randomized studies incorporated lenalidomide, vorinostat, entinostat (MS-275), durvalumab, valproic acid, idarubicin, eltrombopag, pevonedistat (MLN4924), eprenetapopt (APR-246), sabatolimab (MBG453), magrolimab (Hu5F9-G4), or tamibarotene (SY-1425)...While the approval of luspatercept and imetelstat for lower-risk patients provides a glimmer of hope, this track record of failure in higher-risk MDS is enough to make a prudent investor or senior pharmaceutical executive think twice before committing further resources to development in this difficult group of diseases...Nor is it because the existing therapies are so good that they're hard to beat, although the practice of giving a few cycles of azacitidine or decitabine in local clinics before referring a patient to a trial center has been an unfortunate barrier to accrual...In this session I will discuss some potential fixes for a few of these problems. But solutions to other barriers are less clear, and will require..."

Acute Myelogenous Leukemia • Hematological Malignancies • Multiple Myeloma • Myelodysplastic Syndrome • Oncology • FLT3 • TP53

ABCB1 confers resistance to carboplatin by accumulating stem-like cells in the G2/M phase of the cell cycle in p53null ovarian cancer. (PubMed, Cell Death Discov) - "Notably, combinatorial treatment of carboplatin with the p53 reactivator, APR-246, proved effective in overcoming chemoresistance in OVCAR3 with the p53R248Q. Our findings suggest that the ΔNp73-ABCB1 axis is a promising molecular target for carboplatin-resistant ovarian cancers harboring p53null mutations, which we uncovered could be utilized to increase the efficacy of conventional anti-cancer therapies, to develop more efficient combinatorial therapeutic interventions directed toward overcoming the chemoresistance and improving the survival rates in patients with ovarian cancer."

Journal • Platinum resistant • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • ABCB1 • TP53

Reactivating P53 to treat osteosarcoma: A tetrahedral framework nucleic acids-based approach. (PubMed, Int J Biol Macromol) - "In vivo and in vitro experiments showed that T-APR-246 more efficiently promoted osteosarcoma cell apoptosis and inhibited osteosarcoma cell proliferation and metastasis than APR-246. Our findings provide new research insights into the treatment of osteosarcoma."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • TP53

Regulation and therapy: the role of ferroptosis in DLBCL. (PubMed, Front Pharmacol) - "This review highlights recent advances in ferroptosis-related genes (FRGs), including STAT3, Nrf2, and ZEB1, and focuses on the clinical potential of ferroptosis inducers such as IKE, α-KG, DMF, and APR-246, which are currently being explored in clinical studies for their therapeutic effects in DLBCL. Correlational studies provide a novel idea for the research and treatment of ferroptosis in DLBCL and other hematological malignancies and lay a solid foundation for future studies."

Journal • Review • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • STAT3 • ZEB1

Tumor microenvironment noise-induced polarization: the main challenge in macrophages' immunotherapy for cancer. (PubMed, Mol Cell Biochem) - "Moreover, we propose a mechanism to promote the appropriate epigenetic stability for immunotherapies involving macrophages, which includes p53 and APR-246 (eprenetapopt)...On the other hand, we conclude that macrophages may remain in the anti-tumoral state in types of cancer that exhibit less TP53 mutation, like colorectal cancer; in these cases, macrophages' immunotherapy may be more suitable. We finally mention the relevance of the epigenetic potential (Waddington's landscape) as the backbone for our study, which encapsulates the biological information of the system."

Biomarker • IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • TP53

Molecular Mechanisms of Synergistic Effect of PRIMA-1met and Oxaliplatin in Colorectal Cancer With Different p53 Status. (PubMed, Cancer Med) - "In summary, our research reveals the differential molecular mechanisms of combined PRIMA-1met and L-OHP in CRC with wild type p53 and mutant p53. Our data not only demonstrate that this combined regimen exerts synergistic anti-CRC effect in vitro and in vivo, but also suggest the benefit of PRIMA-1met on prevention of L-OHP-related side effects. These findings underscore the clinical potential of PRIMA-1met-L-OHP combination therapy in CRC, offering enhanced efficacy and reduced toxicity, warranting further clinical investigation."

Journal • Colorectal Cancer • Hematological Disorders • Oncology • Solid Tumor • DLD • TP53

Neuroblastoma response to RAS-MAPK inhibitors and APR-246 (eprenetapopt) co-treatment is dependent on SLC7A11. (PubMed, Front Oncol) - "Using erastin and sulfasalazine, both inhibitors of SLC7A11 and activators of ferroptosis, we were able to reverse the antagonistic effects of ERK1/2 inhibitors and demonstrate a strong synergistic action in vitro and in vivo in zebrafish models. These results demonstrated a pivotal role of the RAS-MAPK pathway in the NB cellular response to APR-246 via the modulation of intracellular concentrations of GSH and the transport of cystine through SLC7A11, phosphorylation of Hsp27, and programmed cell death. Combining APR-246 with RAS-MAPK pathway inhibitors can, in some cases, lead to antagonistic action, which can be reversed by combining APR-246 with the clinically approved drug sulfasalazine."

Journal • CNS Tumor • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • BCL2L11 • SLC7A11

Efficacy of glutathione inhibitor eprenetapopt against the vulnerability of glutathione metabolism in SMARCA4-, SMARCB1- and PBRM1-deficient cancer cells. (PubMed, Sci Rep) - "In addition, eprenetapopt decreased the amount of intracellular GSH and increased the intracellular amount of reactive oxygen species (ROS), followed by induction of apoptosis. Taken together, eprenetapopt could be a promising selective agent for SWI/SNF-deficient cancer cells derived from SMARCA4-deficient lung cancers, SMARCB1-deficient rhabdoid tumors, and PBRM1-deficient kidney cancers."

Journal • Genito-urinary Cancer • Kidney Cancer • Lung Cancer • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Rhabdoid Tumor • Sarcoma • Solid Tumor • ARID1A • PBRM1 • SLC7A11 • SMARCA4 • SMARCB1

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 • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Psychiatry • T Cell Non-Hodgkin Lymphoma • ANXA5 • TP53

Unraveling the Essential Role of Aberrant TET3 Expression in Acute Erythroid Leukemia, a Promising Epigenetic Target for Treatment (ASH 2024) - "We could detect a 32-41% increase in the drug sensitivity towards APR-246 upon KD of TET3 in the HEL cell line (n=3, p<0.01) indicating a potential benefit for combining drug treatment with TET3 targeting. Our results demonstrate an essential role of aberrant TET3 expression in AEL and identify TET3 as a promising epigenetic target for treatment in this challenging disease."

Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CD34 • IL2 • IL6 • JAK2 • STAT5 • TET2 • TET3 • TNFA

Measurable Residual Disease Monitoring By Duplex Sequencing for TP53 in the Post Allogeneic Stem Cell Transplantation Study with Eprenetapopt (APR-246) + Azacitidine Strongly Predicts Outcomes (ASH 2024) - "Conclusions Many patients with TP53 mutant MDS/AML are MRD positive both before and after allo-HSCT, supporting the need for novel pre- and/or post-HSCT strategies to decrease relapse. Following completion of maintenance therapy with eprenetapopt and azacitidine, TP53 MRD was strongly predictive of outcomes, supporting incorporation of this assay in future novel strategies."

Biomarker • Residual disease • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

Targeting p53 Improves Drug Resistance in Mantle Cell Lymphoma By Regulating Mitophagy-Dependent Ferroptosis (ASH 2024) - "MCL cell lines were treated with APR-246, an agent targeting mutant p53, and then cell proliferation, gene expression and ROS level were determined by CCK-8, qPCR and flow cytometry...However, these phenomena were not occurred in p53-deficient and p53-wild type cells. CUT&Tag assay revealed mechanistically that PINK1 was transcriptionally activated by p53.Conclusions : Our study elucidates the specific mechanism by which targeting mutant p53 could improve drug resistance in MCL by regulating mitophagy-dependent ferroptosis, and provides a new therapeutic strategy for chemotherapy resistant MCL patients."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • GPX4 • PINK1 • SLC7A11

Pan-cancer landscape of disulfidptosis across human tumors. (PubMed, Heliyon) - "Additionally, tumors with low disulfidptosis score exhibited higher sensitivity to a few small molecular compounds, e.g., Sabutoclax, PRIMA-1MET, BIBR-1532, and Elephantin. Knockdown of disulfidptosis gene GYS1 effectively hindered tumor progression. Collectively, our findings depict a pan-cancer map of disulfidptosis to inform functional and therapeutic research."

Journal • Pan tumor • Oncology • Solid Tumor

SNF2L maintains glutathione homeostasis by initiating SLC7A11 transcription through chromatin remodeling. (PubMed, Cell Death Dis) - "This results in decreased cystine uptake and impaired GSH biosynthesis. These findings suggest that targeting the SNF2L/SLC7A11 axis could enhance the effectiveness of APR-246 by depleting GSH and increasing ROS level in cancer cells, highlighting SNF2L as a promising therapeutic target."

Journal • Oncology • SLC7A11 • TP53

Managing the unmanageable: evidence-driven approaches to real-world patient prototypes of TP53-mutant myelodysplastic neoplasms and acute myeloid leukemia. (PubMed, Leukemia) - "The debate regarding whether allogeneic stem cell transplant should be offered to these patients is summarized. Finally, this review explores the recent unfortunate news of pauses in clinical trials for the leading investigational agents - eprenetapopt, magrolimab, sabatolimab, and idasanutlin - and offers solutions toward re-invigorating the pipeline of precision therapeutics in 2025."

Journal • Real-world • Real-world evidence • Review • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • TP53

Tale of two mechanisms: Is the p53 modulator COTI-2 a zinc chaperone instead? (ACS-Fall 2024) - "Although the p53 protein remains “undruggable” two small molecules looking to reactivate misfolded p53 have entered clinical trials: APR-246 and COTI-2. The effects on p53 mutants will be discussed. These findings underscore the potential role of COTI-2 in regulating intracellular zinc levels, showing that COTI-2 continues to hold promise as a cancer therapeutic."

Colorectal Cancer • Gynecologic Cancers • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • TP53

APR-246 as a radiosensitization strategy for mutant p53 cancers treated with alpha-particles-based radiotherapy. (PubMed, Cell Death Dis) - "Combining alpha-particles-based RT with p53 restoration via APR-246 triggered cell death, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors."

IO biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • TP53

Assessment and process optimization of high throughput biofabrication of immunocompetent breast cancer model for drug screening applications. (PubMed, Biofabrication) - "Moreover, we've conducted extensive validation, showcasing the efficacy of our platform through drug screening assays involving two potent anti-cancer drugs, 5-Fluorouracil and PRIMA-1Met. Through meticulous optimization and characterization, we've successfully developed a biomimetic immunocompetent breast cancer model, complete with microenvironmental cues and diverse cell populations. This breakthrough paves the way for rapid multiplex drug screening and the development of personalized cancer models, marking a paradigm shift in cancer research and pharmaceutical development."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor

Targeting mutant p53 with arsenic trioxide: A preclinical study focusing on triple negative breast cancer. (PubMed, Transl Oncol) - "Direct evidence of mutant p53 reactivation was the induction of multiple wild-type p53 canonical target genes such as CDKN1A, SLC7A11, BBC3, PMAIP1, SESN2, SRXN1 and TXNRD1. Our findings support the activation of mutant p53 by ATO and, furthermore, the possible repurposing of ATO to treat TP53-mutated TNBC."

Journal • Preclinical • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Triple Negative Breast Cancer • BBC3 • CDKN1A • PMAIP1 • SESN2 • SLC7A11 • TP53