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DRUG:

eprenetapopt (APR-246)

i
Other names: APR-246, PRIMA-1MET, APR 246
Company:
Aprea
Drug class:
p53 reactivator
1m
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.
Review • Journal • Real-world evidence • Real-world
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
eprenetapopt (APR-246) • idasanutlin (RG7388) • magrolimab (ONO-7913) • sabatolimab (MBG453)
5ms
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.
Journal • IO biomarker
|
TP53 (Tumor protein P53)
|
eprenetapopt (APR-246)
5ms
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.
Preclinical • Journal
|
TP53 (Tumor protein P53) • PMAIP1 (Phorbol-12-Myristate-13-Acetate-Induced Protein 1) • SLC7A11 (Solute Carrier Family 7 Member 11) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • SESN2 (Sestrin 2) • BBC3 (BCL2 Binding Component 3)
|
eprenetapopt (APR-246) • arsenic trioxide
6ms
TP53 Mutations in Acute Leukemias and Myelodysplastic Syndromes: Insights and Treatment Updates. (PubMed, Am Soc Clin Oncol Educ Book)
The most heavily investigated and targeted agent for patients with TP53-mutant MDS and AML has been APR-246 (eprenetapopt) a p53 reactivator, in combination with azacitidine, but also in triplets with venetoclax...Other agents, like magrolimab (anti-CD47 antibody), failed to demonstrate improved activity in TP53-mutant MDS and AML...Delivering prognostic information in a dismal disease like TP53-mutated MDS and AML is particularly challenging. The physician should balance hope and realism, describing the trajectory of possible treatments and at the same time indicating the poor outcome, together with promoting adaptive coping in patients and elaborating on the nature of the disease.
Review • Journal
|
TP53 (Tumor protein P53) • CD123 (Interleukin 3 Receptor Subunit Alpha) • IL3RA (Interleukin 3 Receptor Subunit Alpha)
|
TP53 mutation
|
Venclexta (venetoclax) • azacitidine • eprenetapopt (APR-246) • magrolimab (ONO-7913)
11ms
TP53 structure-function relationships in metastatic castrate-sensitive prostate cancer and the impact of APR-246 treatment. (PubMed, Prostate)
DN TP53 mutations correlated with worse prognosis in prostate cancer patients and higher metastatic potential, which could be counteracted by APR-246 treatment suggesting a potential future therapeutic avenue.
Journal • Metastases
|
TP53 (Tumor protein P53)
|
TP53 mutation • TP53 wild-type • TP53 R175H
|
eprenetapopt (APR-246)
12ms
Establishment of ganglioside GD2-expressing extranodal NK/T cell lymphoma cell line with scRNA-seq analysis. (PubMed, Exp Hematol)
The molecular target agents eprenetapopt, tazemetostat, and vorinostat efficiently induced apoptosis in ENKL-J1 cells in vitro. Furthermore, GD2-directed chimeric antigen receptor T cells showed cytotoxicity against ENKL-J1 cells in vivo. These findings not only contribute to understanding the molecular and genomic characteristics of ENKL; they also suggest new treatment options for patients with advanced or relapsed ENKL.
Preclinical • Journal • IO biomarker
|
PD-L1 (Programmed death ligand 1) • BCL2 (B-cell CLL/lymphoma 2) • TET2 (Tet Methylcytosine Dioxygenase 2) • BCL2L1 (BCL2-like 1) • ABCC1 (ATP Binding Cassette Subfamily C Member 1) • HDAC2 (Histone deacetylase 2) • FOXO3 (Forkhead box O3) • ATG5 (Autophagy Related 5) • DDX3X (DEAD-Box Helicase 3 X-Linked)
|
Zolinza (vorinostat) • eprenetapopt (APR-246) • Tazverik (tazemetostat)
12ms
Targeting mutant-p53 for cancer treatment: Are we there yet? (PubMed, Curr Mol Pharmacol)
The progress of developing a cancer treatment that may successfully and efficiently target mutant p53 is on the verge of development. Mutant p53 proteins not only initiate oncogenesis but also cause resistance in cancer cells to certain chemo or radiotherapies, further endorse cancer cell survival and promote migration as well as metastasis of cancerous cells. With this regard, many mutant p53 inhibitors have been developed, some of which are currently being evaluated at the pre-clinical level and have been identified and discussed. To date, APR-246 is the most prominent one that has progressed to the Phase III clinical trial.
Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
eprenetapopt (APR-246)
1year
Characterization and Preclinical Evaluation of AS-1763, an Oral, Potent and Selective Noncovalent BTK Inhibitor, in Chronic Lymphocytic Leukemia (ASH 2023)
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).
Preclinical • IO biomarker
|
MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • CCL3 (C-C Motif Chemokine Ligand 3) • CD86 (CD86 Molecule)
|
BCL2 expression • BTK C481S • MCL1 expression • BTK mutation • BTK C481
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • eprenetapopt (APR-246) • Jaypirca (pirtobrutinib)
1year
APR-246 increases tumor antigenicity independent of p53. (PubMed, Life Sci Alliance)
We propose that the immunogenic effect of MQ can be linked to its thiol-reactive alkylating ability as we observed similar immunogenic effects with the broad-spectrum cysteine-reactive compound, iodoacetamide. Our results thus indicate that combination of APR-246 with immunomodulatory agents may elicit effective antitumor immune response irrespective of the tumor's p53 mutation status.
Journal • IO biomarker
|
CD8 (cluster of differentiation 8) • TLR4 (Toll Like Receptor 4) • CD40 (CD40 Molecule)
|
TP53 mutation
|
eprenetapopt (APR-246)
1year
Integrative analyses reveal outcome-associated and targetable molecular partnerships between TP53, BRD4, TNFRSF10B, and CDKN1A in diffuse large B-cell lymphoma. (PubMed, Ann Hematol)
Promisingly, in vitro MDM2 inhibition with Idasnutlin and TP53 reactivation via Eprenetapopt was able to renew TNFRSF10B protein expression. Additionally, applying the BRD4-degrading PROTAC ARV-825 and the CDK4/6 inhibitor Abemaciclib as single-agents and in synergistic combination significantly reduced TP53-altered DLBCL cell line viability. Our analysis presents key associations within a genomic network of actionable targets capable of providing clarity within the evolving precision CAR-T treatment landscape.
Licensing / partnership • Journal • IO biomarker
|
TP53 (Tumor protein P53) • CD8 (cluster of differentiation 8) • BRD4 (Bromodomain Containing 4) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • TNFRSF10B (TNF Receptor Superfamily Member 10b)
|
TP53 expression
|
Verzenio (abemaciclib) • eprenetapopt (APR-246) • ARV-825
1year
The Impact of TP53 Mutations and Use of the TP53-Mutation-Reactivating Agent APR-246 on Metastatic Castrate-Sensitive Prostate Cancer. (PubMed, Int J Radiat Oncol Biol Phys)
DN TP53 mutations were associated with poorer survival outcomes for mCSPC patients. DN TP53 mutations also promoted prostate cancer pro-metastatic behaviors in vitro, which was effectively counteracted by APR-246, making it a promising treatment option that should be explored further in early-phase clinical studies.
Journal • Metastases
|
TP53 (Tumor protein P53)
|
TP53 mutation • TP53 wild-type • TP53 R175H
|
eprenetapopt (APR-246)
1year
TP53-mutated acute myeloid leukemia and myelodysplastic syndrome: biology, treatment challenges, and upcoming approaches. (PubMed, Ann Hematol)
The triple combination of azacitidine and venetoclax with either magrolimab or eprenetapopt have demonstrated safety in early trials, with phase III trials currently underway, and promising interim clinical results. This review compiles background on TP53 biology, available and emerging therapies along with their mechanisms of action for the TP53m disease entity, current treatment challenges, and recently published data and status of ongoing clinical trials for TP53m AML/MDS.
Review • Journal • IO biomarker
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
Venclexta (venetoclax) • azacitidine • eprenetapopt (APR-246) • magrolimab (ONO-7913)
1year
The p53 reactivator PRIMA-1 synergises with 5-fluorouracil to induce apoptosis in pancreatic cancer cells. (PubMed, Invest New Drugs)
The synergism of the combination was associated with significant apoptosis induction through p53-dependent and p53-independent pathways. Preclinical confirmation of these data in in vivo models is highly recommended.
Journal
|
TP73 (Tumor Protein P73)
|
TP53 mutation • TP53 wild-type
|
5-fluorouracil • eprenetapopt (APR-246)
1year
The Impact of TP53 Mutations and Use of the TP53-Mutation-Reactivating Agent APR-246 on Metastatic Castrate-Sensitive Prostate Cancer (ASTRO 2023)
DN TP53 mutations were associated with poorer survival outcomes for mCSPC patients. DN TP53 mutations also promoted prostate cancer pro-metastatic behaviors in vitro , which was effectively counteracted by APR-246, making it a promising treatment option that should be explored further in early-phase clinical studies.
Metastases
|
TP53 (Tumor protein P53)
|
TP53 mutation • TP53 wild-type • TP53 R175H
|
eprenetapopt (APR-246)
over1year
APR-246 in Combination With Acalabrutinib or Venetoclax Based Therapy in Subjects With R/R Non Hodgkin Lymphomas (NHL) (clinicaltrials.gov)
P1/2, N=1, Terminated, Aprea Therapeutics | N=100 --> 1 | Suspended --> Terminated; Sponsor decision
Enrollment change • Trial termination • Combination therapy
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
Venclexta (venetoclax) • Rituxan (rituximab) • Calquence (acalabrutinib) • eprenetapopt (APR-246)
over1year
APR-246 enhances colorectal cancer sensitivity to radiotherapy. (PubMed, Mol Cancer Ther)
APR-246 mediated radio-sensitization effects through p53-dependent and -independent ways. The results may provide evidence for a clinical trial of the combination in rectal cancer patients.
Journal
|
TP53 mutation • TP53 wild-type
|
eprenetapopt (APR-246)
over1year
Building on Foundations: Venetoclax-Based Combinations in the Treatment of Acute Myeloid Leukemia. (PubMed, Cancers (Basel))
Frontline acute myeloid leukemia (AML) treatment is determined by a combination of patient and genetic factors. These combinations include isocitrate dehydrogenase-1/2 (IDH1/2) inhibitors (i.e., ivosidenib and enasidenib), fms-like tyrosine kinase 3 (FLT3) inhibitors (i.e., gilteritinib), anti-CD47 antibodies (i.e., magrolimab), mouse double minute-2 (MDM2) inhibitors, and p53 reactivators (i.e., eprenetapopt). This review summarizes ongoing trials aimed at overcoming known VEN resistance mechanisms and improving outcomes beyond that observed with HMA + VEN combinations in the treatment of AML.
Review • Journal
|
FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
|
Venclexta (venetoclax) • Xospata (gilteritinib) • Tibsovo (ivosidenib) • eprenetapopt (APR-246) • Idhifa (enasidenib) • magrolimab (ONO-7913)
over1year
Restoring p53 activity as an approach to target aggressive stem-like childhood sarcomas (EACR 2023)
Drugs that target the p53 pathway (mutant p53 re-activator PRIMA-1MET, dual MDM2/MDMX inhibitor RO-5963, and LEM3, a new molecule targeting interactions of MDM2/p53 family proteins) markedly inhibited viability of tumorigenic Ewing's sarcoma cells, demonstrating their increased vulnerability to restoring the p53 activity compared with nontumorigenic cells. Treatment with RO-5963 and LEM3 in tumorigenic cells stabilized p53 and induced apoptosis in a dose-dependent manner.ConclusionSOX2 expression and the p53 pathway deregulation are associated with sarcoma stemness. Our results indicate that enhanced p53 activity might effectively target aggressive stem-like childhood sarcomas, therefore showing promising clinical potential for p53 pathway re-activation in sarcoma therapy.
Clinical
|
SOX2 • POU5F1 (POU Class 5 Homeobox 1) • NANOG (Nanog Homeobox)
|
TP53 mutation • TP53 expression • SOX2 expression
|
eprenetapopt (APR-246)
over1year
In silico and in vitro investigation of dual targeting Prima-1 as precision therapeutic against lungs cancer. (PubMed, J Biomol Struct Dyn)
A significant decrease in intracellular ROS was observed and resulted in disruption of mitochondrial transmembrane potential. This study uncovers the underlying mechanism of Prima-1 and could be helpful to design further leads against lung cancers.Communicated by Ramaswamy H. Sarma.
Preclinical • Journal
|
EGFR (Epidermal growth factor receptor) • TP53 (Tumor protein P53)
|
TP53 expression
|
eprenetapopt (APR-246)
over1year
Therapeutic Targets in Myelodysplastic Neoplasms: Beyond Hypomethylating Agents. (PubMed, Curr Hematol Malig Rep)
Pevonedistat (NEDD-8 inhibitor) and APR-246 (TP53 reactivator) both did not meet trial endpoints. Due to intolerance, primary, and secondary resistance to HMA, there is a large unmet need to develop new safe and effective therapies for patients with MDS. In this review, we focus on the current management strategies and novel therapies in development for treatment of high-risk MDS.
Review • Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • FLT3 (Fms-related tyrosine kinase 3) • BCL2 (B-cell CLL/lymphoma 2) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
|
eprenetapopt (APR-246) • pevonedistat (MLN4924)
over1year
The impact of TP53 mutations and use of the TP53-mutation-reactivating agent APR-246 on metastatic castrate-sensitive prostate cancer. (ASCO 2023)
DN TP53 mutations were associated with poorer survival outcomes for mCSPC patients. DN TP53 mutations also promoted prostate cancer pro-metastatic behaviors in vitro, which was effectively counteracted by APR-246, making it a promising treatment option that should be explored further in early-phase clinical studies.
Metastases
|
TP53 (Tumor protein P53)
|
TP53 mutation • TP53 wild-type • TP53 R175H
|
eprenetapopt (APR-246)
over1year
Therapy of TP53 Mut MDS (MDS 2023)
These data supported the phase 3 study of APR-246 in combination with azacitidine versus azacitidine alone (NCT03745716)...We have reported the phase Ib study combining magrolimab with azacitidine in treatment-naïve higher risk MDS patients (26% with TP53 mutations) with the most recent data update at EHA 2022 11...Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3, an immune regulator expressed on immune cells and myeloid leukemic progenitors 13...Lastly, venetoclax is an oral BCL-2 inhibitor with promising synergy with azacitidine and is a standard of care for elderly AML patients 15...TP53 mutant MDS/AML patients represent a molecular cohort with very poor outcomes and lack of disease modifying therapy. Ideally, future translational data will further elucidate the underpinnings driving the poor outcomes for this molecular subgroup to lead to additional novel therapeutic strategies.
IO biomarker
|
TP53 (Tumor protein P53) • SIRPA (Signal Regulatory Protein Alpha)
|
TP53 mutation
|
Venclexta (venetoclax) • azacitidine • eprenetapopt (APR-246) • magrolimab (ONO-7913) • sabatolimab (MBG453)
over1year
The anti-cancer agent APR-246 can activate several programmed cell death processes to kill malignant cells. (PubMed, Cell Death Differ)
The sensitivity of non-transformed cells to APR-246 also depended on the cell type. These findings reveal that the clinical testing of APR-246 should not be limited to cancers expressing mutant TP53 but expanded to cancers that express wt TP53 or are TP53-deficient.
Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation • TP53 wild-type • MYC expression • TP53 expression
|
eprenetapopt (APR-246)
over1year
Eprenetapopt combined with venetoclax and azacitidine in TP53-mutated acute myeloid leukaemia: a phase 1, dose-finding and expansion study. (PubMed, Lancet Haematol)
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.
P1 data • Clinical Trial,Phase I • Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
Venclexta (venetoclax) • azacitidine • eprenetapopt (APR-246)
over1year
Therapeutic Targeting of P53: A Comparative Analysis of APR-246 and COTI-2 in Human Tumor Primary Culture 3-D Explants. (PubMed, Genes (Basel))
COTI-2 activity correlated with nitrogen mustard, cisplatin and gemcitabine, doxorubicin and selumetinib, with a trend for APR-246 with doxorubicin. Cisplatin synergy is consistent with P53's role in DNA damage. Different mechanisms of action may underlie disease specificity and offer better disease targeting.
Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
cisplatin • gemcitabine • Koselugo (selumetinib) • doxorubicin hydrochloride • eprenetapopt (APR-246) • COTI-2 • Mustargen (mechlorethamine)
over1year
APR-246 cytotoxic effects are TP53 independent in endometrial cancer cell lines (AACR 2023)
To further evaluate for a time-dependent effect, 2 representative variants (R248Q and R273C) after 6 and 24 hours of incubation with 50μM APR-246 and 10μM of Nutlin-3. APR-246 demonstrated a negative, dose-dependent effect on cell viability in all EC cell lines. Our results demonstrate that APR-246's cytotoxic effects in EC seem to be p53-independent. Potential mechanisms for the anti-neoplastic effects of APR-246 include activity targeting antioxidant pathways demonstrated in other solid tumors and provides an area for further investigation in TP53mut EC.
Preclinical
|
TP53 (Tumor protein P53) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
TP53 mutation • TP53 wild-type • TP53 R248Q • TP53 Y220C • TP53 R273H • TP53 R273C
|
eprenetapopt (APR-246) • Nutlin-3
almost2years
Transplant for TP53-mutated MDS and AML: because we can or because we should? (PubMed, Hematology Am Soc Hematol Educ Program)
Recent data indicate that the TP53 allelic state, co-occurring somatic mutations, and the position of the TP53 mutation within the clonal hierarchy define genetic heterogeneity among TP53-mutated MDS and acute myeloid leukemia that may influence clinical outcomes, thereby informing the selection of patients most suitable for transplantation. Further, novel therapeutic methods such as antibody-based agents (monoclonals or dual-affinity retargeting antibodies), cellular therapies (natural killer cells, chimeric antigen receptor T cells), or targeted agents (eprenetapopt) may offer opportunities to modify the approach to pretransplant conditioning or posttransplant maintenance and improve clinical outcomes.
Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
eprenetapopt (APR-246)
almost2years
Novel Therapies for De Novo or Relapsed/Refractory AML with TP53 Mutations : A Glimmer of Hope (ASH 2022)
We screened 2300 articles and included articles citing novel therapies such as "Venetoclax" (VEN), "Hypomethylating agents (HMA), 5-azacytidine (5-AZA), "checkpoint inhibitors, and "MDM2 inhibitors"...VEN with low-dose cytarabine (LDAC) had 27% CR, whereas LDAC alone had 7%.Checkpoint inhibitors such as nivolumab showed favorable responses, as in the phase II study of nivolumab in combination with azacitidine in relapsed/refractory (R/R) AML; it demonstrated acceptable toxicity and an overall response rate (ORR) of 33%. However, increased response rates were seen in HMA-naïve patients.HDAC inhibitors : In two phase II trials incorporating AZA vs AZA + entinostat, the CR was 46% vs 44%..., the combination therapy of Decitabine and valproic acid showed CR of 34% and mOS of 11.9 months...described a remission of 82% with a median OS of 14.7 months in Eprenetapopt + 5-AZA. The most common grade ≥ 3 hematological adverse events were anemia, neutropenia, thrombocytopenia, and leukopenia.MDM2 Inhibitors : In the MIRROS trial, a phase III trial incorporating idasanutlin + cytarabine + placebo + cytarabine in R/R AML; 436 patients were enrolled...Still a daunting challenge, a combination of these therapies may ultimately be necessary to obtain adequate and sustained responses. Participation in clinical trials for all newly diagnosed AML patients should be encouraged to promote the development of innovative therapeutics.
PD(L)-1 Biomarker • IO biomarker
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
Opdivo (nivolumab) • Venclexta (venetoclax) • cytarabine • azacitidine • decitabine • eprenetapopt (APR-246) • idasanutlin (RG7388) • Jingzhuda (entinostat)
almost2years
Immunotherapy against the Cystine/Glutamate Antiporter xCT Improves the Efficacy of APR-246 in Preclinical Breast Cancer Models. (PubMed, Biomedicines)
Overall, we demonstrate that DNA vaccination against xCT can synergize with APR-246 treatment and enhance its therapeutic effect. Thus, APR-246 treatment in combination with xCT immunetargeting may open new perspectives in the management of breast cancer.
Preclinical • Journal • IO biomarker
|
SLC7A11 (Solute Carrier Family 7 Member 11)
|
TP53 mutation
|
eprenetapopt (APR-246)
2years
The DLBCL Axis of Low TNFRSF10B Expression, TP53 Loss, and a Cold Immune Microenvironment May be Addressed By the Synergistic Combination of Eprenetapopt and Idasnutlin (ASH 2022)
Our results suggest the presence of an interconnected genomic DLBCL phenotype characterized by TP53 loss, reduced TNFRSF10B expression, and a debilitated immune presence, collectively predictive of an inferior CD19 CAR-T response. We applied the targeted therapies Eprenetapopt and Idasnutlin vs. cell line models, with both displaying anti-tumor activity as single agents.
IO biomarker
|
TP53 (Tumor protein P53) • CD19 (CD19 Molecule) • MDM2 (E3 ubiquitin protein ligase) • IFNG (Interferon, gamma) • TNFRSF10B (TNF Receptor Superfamily Member 10b)
|
TP53 mutation • TP53 expression
|
eprenetapopt (APR-246)
2years
XPO1 Overexpression Is a Mechanism of Resistance to Eprenetapopt and 5-Azacitidine Therapy That Can be Therapeutically Exploited for the Treatment of TP53 Mutated Myeloid Malignancies (ASH 2022)
To determine whether XPO1 can be therapeutically exploited in TP53-MNs, we performed in vitro viability assays with increasing doses of eprenetapopt and the XPO1 inhibitor selinexor and the second generation eltanexor. Our data collectively suggest that XPO1 is overexpressed after eprenetapopt and 5-azacitidine treatment resulting in re-folded TP53 being shuttled to the cytoplasm leading to therapeutic resistance. Patient derived xenograft assays testing this novel combination therapy in vivo with TP53-MN primary samples are underway and will be presented during the ASH meeting.
IO biomarker
|
TP53 (Tumor protein P53) • XPO1 (Exportin 1)
|
TP53 mutation • TP53 wild-type • TP53 R175H
|
azacitidine • Xpovio (selinexor) • eprenetapopt (APR-246) • eltanexor (KPT-8602)
2years
Pharmacological Profiling of Cells from Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Pirtobrutinib (ASH 2022)
We incubated peripheral blood mononuclear cells for three days with cBTKi – ibrutinib; glutathione inhibitor (also known as mtTP53 modulator) - APR-246; Bcl-2 antagonist - venetoclax; and Mcl-1 antagonist - AZD5991; as single agent and in double or triple combinations and apoptosis was assessed by flow cytometry. Patients were re-sensitized to ibrutinib after loss of C481S clone. Genomic and genetic profile along with pharmacological landscape provide precision medicine for these heavily pretreated patients whose disease is resistant to BTK inhibitors.
Clinical • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • MCL1 (Myeloid cell leukemia 1) • PLCG2 (Phospholipase C Gamma 2)
|
TP53 mutation • ATM mutation • NOTCH1 mutation • BTK C481S • BTK C481 • TS 12
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • eprenetapopt (APR-246) • Jaypirca (pirtobrutinib) • AZD5991
2years
Establishment of an acquired lorlatinib-resistant cell line of non-small cell lung cancer and its mediated resistance mechanism. (PubMed, Clin Transl Oncol)
This study demonstrated that the combination of p53 protein agonist and lorlatinib may provide a new therapeutic strategy for NSCLC patients with lorlatinib resistance and TP53 mutation. Furthermore, the results also provide guidance for selecting optimal chemo-regimens for NSCLC patients after ALK-TKIs failure.
Preclinical • Journal
|
ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • EML4 (EMAP Like 4)
|
TP53 mutation • EML4-ALK fusion • ALK fusion • ALK G1269A • EML4-ALK G1269A
|
cisplatin • Xalkori (crizotinib) • gemcitabine • paclitaxel • docetaxel • Lorbrena (lorlatinib) • eprenetapopt (APR-246)
2years
Mutant p53 gain of function mediates cancer immune escape that is counteracted by APR-246. (PubMed, Br J Cancer)
Breast carcinomas with mtp53 displayed enhanced inflammation. APR-246 boosted the interferon response or represses immune checkpoints in p53 mutant tumour cells, and restores cancer immune surveillance in vivo.
Journal • BRCA Biomarker
|
TP53 (Tumor protein P53) • CD8 (cluster of differentiation 8) • BRCA (Breast cancer early onset) • CD4 (CD4 Molecule)
|
TP53 mutation • TP53 wild-type • BRCA mutation
|
eprenetapopt (APR-246)
2years
Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use? (PubMed, Cancers (Basel))
Several such reactivating drugs are currently undergoing evaluation in clinical trials, including eprenetapopt (APR-246), COTI-2, arsenic trioxide and PC14586. With all of these ongoing trials, we should soon know if targeting mutant p53 can be used for cancer treatment. If any of these trials show clinical efficacy, it may be a transformative development for the treatment of patients with cancer since mutant p53 is so prevalent in this disease.
Review • Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
eprenetapopt (APR-246) • arsenic trioxide • rezatapopt (PC14586) • COTI-2
2years
How I Treat TP53-Mutated Acute Myeloid Leukemia and Myelodysplastic Syndromes. (PubMed, Cancers (Basel))
We discuss the possible/potential improvement in outcome based on recent results obtained with new drugs (especially eprenetapopt and magrolimab). We also focus on the impact of allogeneic hematopoietic stem cell transplantation (aHSCT) including post aHSCT treatment.
Review • Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
eprenetapopt (APR-246) • magrolimab (ONO-7913)
2years
Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade. (PubMed, J Clin Invest)
Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule-based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.
Journal • Checkpoint inhibition • PD(L)-1 Biomarker
|
TP53 (Tumor protein P53)
|
TP53 expression • TP53 overexpression
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Keytruda (pembrolizumab) • eprenetapopt (APR-246)
2years
Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status. (PubMed, Cancers (Basel))
We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death.
Journal
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TP53 (Tumor protein P53) • MDM4 (The mouse double minute 4)
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TP53 mutation
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eprenetapopt (APR-246)
over2years
Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes. (PubMed, J Clin Oncol)
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
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TP53 (Tumor protein P53)
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TP53 mutation
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azacitidine • eprenetapopt (APR-246)
over2years
APR-246 & Azacitidine for the Treatment of TP53 Mutant Myelodysplastic Syndromes (MDS) (clinicaltrials.gov)
P3, N=154, Completed, Aprea Therapeutics | Active, not recruiting --> Completed
Trial completion • Combination therapy
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TP53 (Tumor protein P53)
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TP53 mutation
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azacitidine • eprenetapopt (APR-246)
over2years
Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer. (PubMed, Oxid Med Cell Longev)
Scavenging ROS with N-acetylcysteine (NAC) disrupts the inhibitory effect of APR-246 on cisplatin-resistant cells. Mechanistically, NRF2 is specifically degraded by the proteasome following its own ubiquitylation in APR-246-treated cisplatin-resistant cells, which in turn decreases NRF2/SLC7A11/GSH axis activity. Our study provides new insights into the biology driving cisplatin resistance of lung cancer and highlights APR-246 as a potential therapeutic reagent for overcoming cisplatin resistance.
Journal
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SLC7A11 (Solute Carrier Family 7 Member 11)
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cisplatin • eprenetapopt (APR-246)