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    DRUG CLASS:

    RARα agonist

    Related drugs:
    14d
    CDK9 recruits HUWE1 to degrade RARα and offers therapeutic opportunities for cutaneous T-cell lymphoma. (PubMed, Nat Commun)
    CDK9 also promotes degradation of retinoic acid receptor α (RARα) via recruiting the E3 ligase HUWE1. Co-administration of CDK9-PROTAC (GT-02897) with all-trans retinoic acid (ATRA) leads to synergistic attenuation of tumor growth in vitro and in xenograft models, providing a potential translational treatment for complete eradication of CTCL.
    Journal
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    RARA (Retinoic Acid Receptor Alpha) • CDK9 (Cyclin Dependent Kinase 9) • HUWE1 (HECT UBA And WWE Domain Containing E3 Ubiquitin Protein Ligase 1)
    3ms
    Successfully treatment of PLZF-RARα positive acute promyelocytic leukemia by Venetoclax combining with decitabine: a case report and literature review. (PubMed, Hematology)
    The patient did not respond to all-trans retinoic acid (ATRA), idarubicin, and arsenic trioxide (As2O3) combined induction chemotherapy. Then, the patient was treated with Venetoclax combining with decitabine as the salvage therapy and achieved morphological remission and PLZF/RARα gene negative. Venetoclax combining with decitabine can be used as an effective therapy in the PLZF-RARα positive APL.
    Review • Journal
    |
    RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia) • RARG (Retinoic Acid Receptor Gamma)
    |
    Venclexta (venetoclax) • decitabine • idarubicin hydrochloride • arsenic trioxide
    4ms
    Palmitoyltransferase ZDHHC3 is essential for the oncogenic activity of PML/RARα in acute promyelocytic leukemia. (PubMed, Acta Pharmacol Sin)
    The standard clinical therapies all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which induce PML/RARα proteolysis, have dramatically improved the prognosis of APL patients...Consistently, the depletion or inhibition of ZDHHC3 could significantly arrest the malignant progression of APL, particularly drug-resistant APL, whereas ZDHHC3 overexpression appeared to have a promoting effect on the malignant progression of APL. Thus, our study not only reveals palmitoylation as a novel regulatory mechanism that modulates PML/RARα oncogenic activity but also identifies ZDHHC3 as a potential therapeutic target for APL, including drug-resistant APL.
    Journal
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    RARA (Retinoic Acid Receptor Alpha)
    |
    arsenic trioxide
    4ms
    Halogenated retinoid derivatives as dual RARα and RXRα modulators for treating acute promyelocytic leukemia cells. (PubMed, Eur J Med Chem)
    Interestingly, the chlorinated compound 7 tends to activate RXRα and induce G2/M arrest and apoptosis, while the iodinated compound 8a tends to activate RARα and induce differentiation. Together, our work underscores several advantages and characteristics of halogens in the rational design of RARα and RXRα ligands, offering three promising drug candidates for treating both ATRA-sensitive and resistant APL.
    Journal
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    RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
    4ms
    Phase separation of PML/RARα and BRD4 coassembled microspeckles governs transcriptional dysregulation in acute promyelocytic leukemia. (PubMed, Proc Natl Acad Sci U S A)
    Finally, a series of experimental validations in primary APL patient samples confirm that PML/RARα forms microspeckles through condensates, recruits BRD4 to coassemble condensates, and co-occupies SEBP regions. Our findings elucidate the biophysical, pathological, and transcriptional dynamics of PML/RARα-assembled microspeckles, underscoring the importance of BRD4 in mediating transcriptional activation that enables PML/RARα to initiate APL.
    Journal
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    RARA (Retinoic Acid Receptor Alpha) • BRD4 (Bromodomain Containing 4)
    5ms
    Treatment of a STAT5b::RARα positive case of APL in a patient not eligible for intensive chemotherapy. (PubMed, Ir J Med Sci)
    Secondly, our patient represents, to the best of our knowledge, the first documented example of this rare disease that has been managed with, and shown sensitivity to low-dose cytarabine (LDAC) in combination with venetoclax (Ven). This case demonstrates that although treatment options are extremely limited for patients not eligible for intensive chemotherapy non-intensive options do show increasing promise.
    Review • Journal
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    RARA (Retinoic Acid Receptor Alpha) • STAT5B (Signal Transducer And Activator Of Transcription 5B)
    |
    Venclexta (venetoclax) • cytarabine
    7ms
    Spinal myeloid sarcoma presenting as initial symptom in acute promyelocytic leukemia with a rare cryptic PLZF::RARα fusion gene: a case report and literature review. (PubMed, Front Oncol)
    In the present study, we report the clinical features and outcome of a rare APL patient characterized by a cryptic PLZF::RARα fusion and spinal myeloid sarcoma (MS) as the initial presenting symptom. Our study not only offers valuable insights into the heterogeneity of APL clinical manifestations but also emphasizes the crucial need to promptly consider the potential link between APL and MS for ensuring a timely diagnosis and personalized treatments.
    Review • Journal
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    KIT (KIT proto-oncogene, receptor tyrosine kinase) • RARA (Retinoic Acid Receptor Alpha) • CD33 (CD33 Molecule) • ANPEP (Alanyl Aminopeptidase, Membrane) • MPO (Myeloperoxidase)
    8ms
    Synergistic Effects of the RARalpha Agonist Tamibarotene and the Menin Inhibitor Revumenib in Acute Myeloid Leukemia Cells with KMT2A Rearrangement or NPM1 Mutation. (PubMed, Cancers (Basel))
    The impact of revumenib on KMT2Ar or NPM1c AML cells was significantly enhanced when combined with tamibarotene, demonstrating synergistic differentiation or apoptosis initiation. These findings propose promising strategies for relapsed/refractory AML patients with defined molecular characteristics.
    Journal
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    NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • RARA (Retinoic Acid Receptor Alpha) • CDK6 (Cyclin-dependent kinase 6) • CEBPA (CCAAT Enhancer Binding Protein Alpha)
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    NPM1 mutation • KMT2A rearrangement • MLL rearrangement
    |
    Revuforj (revumenib) • Amnolake (tamibarotene)
    9ms
    ATPR induces acute promyelocytic leukemia cells differentiation and cycle arrest via the lncRNA CONCR/DDX11/PML-RARα signaling axis. (PubMed, Gene)
    RNA immunoprecipitation (RIP) experiments showed that CONCR could bind to DDX11, the protein expression levels of DDX11 and PML-RARα were elevated after overexpression of CONCR. These results suggest that ATPR can regulate the expression of DDX11 through CONCR to affect the expression of PML-RARα fusion protein, which in turn induces the differentiation and maturation of APL cells.
    Journal
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    RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
    9ms
    USP22 regulates APL differentiation via PML-RARα stabilization and IFN repression. (PubMed, Cell Death Discov)
    Additionally, loss of USP22 upregulates interferon (IFN) and IFN-stimulated gene (ISG) expression in APL and induces PML-RARα stabilization and a potentiation of the cell-autonomous sensitivity towards all-trans retinoic acid (ATRA)-mediated differentiation. Our findings imply USP22-dependent surveillance of PML-RARα stability and IFN signaling as important regulator of APL pathogenesis, with implications for viral mimicry, differentiation and cell fate regulation in other leukemia subtypes.
    Journal
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    RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia) • USP22 (Ubiquitin Specific Peptidase 22)
    10ms
    Clinical analysis of 82 cases of acute promyelocytic leukemia with PML-RARα short isoform in children and adults. (PubMed, Front Oncol)
    The 3-year OS and the 3-year DFS of the low and intermediate-risk group were better (P=0.019 and P=0.017, respectively). ATRA combined with arsenic and anthracycline had significant impact on outcomes in APL with PML-RARα short isoform.
    Journal
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    FLT3 (Fms-related tyrosine kinase 3) • BCR (BCR Activator Of RhoGEF And GTPase) • RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
    10ms
    Clinical Relevance of Differential RARα and PPARβ/δ Expression in Myelodysplastic Syndromes. (PubMed, In Vivo)
    RARα and PPARβ/δ genes are putative biomarkers that may be associated with the diagnosis and prognosis of MDS.
    Journal
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    RARA (Retinoic Acid Receptor Alpha)
    11ms
    A machine learning model identifies M3-like subtype in AML based on PML/RARα targets. (PubMed, iScience)
    M3-like patients exhibited distinct genomic features, low immune activity and better clinical survival. The initiative identification of patients similar to M3 subtype may help to identify more patients that would benefit from ATO/ATRA treatment and deepen our understanding of the molecular mechanism of AML pathogenesis.
    Journal • Machine learning
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    RARA (Retinoic Acid Receptor Alpha)
    |
    Vesanoid (tretinoin)
    11ms
    A Biomarker-Directed Phase 2 Trial of Tamibarotene (SY-1425) in Participants With Acute Myeloid Leukemia or Myelodysplastic Syndrome (clinicaltrials.gov)
    P2, N=155, Completed, Syros Pharmaceuticals | Active, not recruiting --> Completed
    Trial completion
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    azacitidine • Darzalex (daratumumab) • Amnolake (tamibarotene)
    11ms
    WYC-209 inhibited GC malignant progression by down-regulating WNT4 through RARα. (PubMed, Cancer Biol Ther)
    Mechanically, WYC-209 significantly promoted the binding between retinoic acid receptor α (RARα) and WNT4 promoter. WYC-209 exerts anti-tumor effects in GC by down-regulating the expression of WNT4 via RARα.
    Journal
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    RARA (Retinoic Acid Receptor Alpha)
    1year
    Phase I/II Study of SY-1425 (Tamibarotene) in Combination With Azacitidine and Venetoclax for Patients With Chronic Myelomonocytic Leukemia (clinicaltrials.gov)
    P1/2, N=0, Withdrawn, M.D. Anderson Cancer Center | Not yet recruiting --> Withdrawn
    Trial withdrawal • Combination therapy
    |
    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    1year
    Phase I/II Study of SY-1425 (Tamibarotene) in Combination With Azacitidine and Venetoclax for Patients With Chronic Myelomonocytic Leukemia (clinicaltrials.gov)
    P1/2, N=52, Not yet recruiting, M.D. Anderson Cancer Center
    New P1/2 trial • Combination therapy
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    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    1year
    An electrochemiluminescence resonance energy transfer biosensor based on CDs/PAMAM/rGO nanocomposites and Au@AgS nanoparticles for PML/RARα fusion gene detection. (PubMed, Mikrochim Acta)
    Based on the ECL-RET biosensing strategy, the Au@AgS NPs-labeled assistant probes and target DNA could pair with capture probes to form the sandwich-type DNA structure and the distance between donor and accepter was closed, leading to quenching of the ECL signal of CDs. The ECL-RET biosensor represented eminent analytical performance for PML/RARα fusion gene detection with a wide linear relationship from 5 fM to 500 pM and a low detection limit of 0.72 fM, which provided a novel technical means and theoretical basis for detection and diagnosis of acute promyelocytic leukemia.
    Journal
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    RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
    over1year
    Flexible genosensors based on polypyrrole and graphene quantum dots for PML/RARα fusion gene detection: A study of acute promyelocytic leukemia in children. (PubMed, J Pharm Biomed Anal)
    In addition, genetic tools could identify the PML-RARα oncogene in purified samples, plasmids, and clinical specimens from pediatric patients diagnosed with APL with high bioanalytical performance. Therefore, biosensors represent a valuable alternative for the clinical diagnosis of APL and monitoring of MRD with an impact on public health.
    Journal
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    RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
    over1year
    Use of tamibarotene, a potent and selective RARα agonist, in combination with azacitidine in patients with relapsed and refractory AML with RARA gene overexpression. (PubMed, Leuk Lymphoma)
    In 21 response-evaluable patients, the complete remission/complete remission with incomplete hematologic recovery (CR/CRi) rate was 19%, and median time to initial CR/CRi was 1.2 months. The favorable safety profile and preliminary clinical activity support the development of combination therapies with tamibarotene in myeloid malignancies with RARA overexpression.
    Journal • Combination therapy
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    RARA (Retinoic Acid Receptor Alpha)
    |
    RARA overexpression
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    azacitidine • Amnolake (tamibarotene)
    over1year
    Rapid promyelocytic blast crisis of chronic myeloid leukemia with PML-RARα fusion gene: a case report and literature review (PubMed, Zhonghua Xue Ye Xue Za Zhi)
    No abstract available
    Review • Journal
    |
    RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
    over1year
    The clinically relevant CHK1 inhibitor MK-8776 induces the degradation of the oncogenic protein PML-RARα and overcomes ATRA resistance in acute promyelocytic leukemia cells. (PubMed, Biochem Pharmacol)
    The current treatment approach for APL involves differentiation therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Overall, the ability of MK-8776 to induce PML-RARα degradation and stimulate differentiation of immature APL cancer cells into more mature forms recapitulates the concept of differentiation therapy. Considering the in vivo tolerability of MK-8776, it will be relevant to evaluate its potential clinical benefit in APL patients resistant to standard ATRA/ATO therapy, as well as in patients with other forms of acute leukemias.
    Journal
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    RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia) • CASP3 (Caspase 3) • ITGAM (Integrin, alpha M)
    |
    arsenic trioxide • MK-8776
    over1year
    The Promise of Retinoids in the Treatment of Cancer: Neither Burnt Out Nor Fading Away. (PubMed, Cancers (Basel))
    Since the introduction of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL) has become a highly curable malignancy, especially in combination with arsenic trioxide (ATO)...Furthermore, recent super-enhancer (SE) analysis has identified a novel AML subgroup characterized by high expression of RARα through strong SE levels in the gene locus and increased sensitivity to tamibarotene. Combined with a hypomethylating agent, synthetic retinoids have shown synergistic anti-leukemic effects in non-APL AML preclinical models and are now being studied in phase II and III clinical trials.
    Review • Journal
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    RARA (Retinoic Acid Receptor Alpha) • CYP26A1 (Cytochrome P450 Family 26 Subfamily A Member 1)
    |
    Vesanoid (tretinoin) • arsenic trioxide • Amnolake (tamibarotene)
    over1year
    Tamibarotene targets heparin-binding protein for attenuating lung injury in sepsis. (PubMed, Allergol Immunopathol (Madr))
    These findings demonstrated that tamibarotene lessens sepsis-induced lung injury, and the effect could be exerted by targeting HBP and thereby deregulating the NF-κB signaling pathway.
    Journal
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    IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • IL17A (Interleukin 17A) • IL1B (Interleukin 1, beta)
    |
    Amnolake (tamibarotene)
    over1year
    Fatal intracranial haemorrhage in acute promyelocytic leukemia patients with short isoform of PML-RARα: Review of molecular and radiological data. (PubMed, Saudi J Biol Sci)
    In conclusion, PML-RARα isoform expression at diagnosis in selective patients influences disease course over time and may even lead to early mortality due to haemorrhage. Thus, timely reporting of the specific PML-RARα isoform by clinical laboratories and CNS assessment by radiology can prevent complications leading to death in some APL patients.
    Review • Journal
    |
    BCR (BCR Activator Of RhoGEF And GTPase) • RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
    |
    arsenic trioxide
    over1year
    AML AND MDS WITH RARA OVEREXPRESSION: MOLECULAR AND CLINICAL FEATURES OF PATIENTS ENROLLED IN A PHASE 2 TRIAL EVALUATING TAMIBAROTENE-BASED THERAPY (EHA 2023)
    AML and MDS with RARA overexpression present with molecular features similar to those described in published datasets. Notably, SRSF2 was the most common mutation in the ND older unfit AML cohort, consistent withpublished series. While the small number of RARA -positive MDS patients precludes definitive characterization of molecular profiles, data in AML patients suggest that RARA overexpression may be agnostic to known molecular features.
    P2 data • Clinical
    |
    TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • ETV6 (ETS Variant Transcription Factor 6) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • RARA (Retinoic Acid Receptor Alpha) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2)
    |
    SRSF2 mutation • U2AF1 mutation • RARA overexpression • RARA positive
    |
    Oncomine Myeloid Assay GX
    |
    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    over1year
    Targeting HDAC3 to overcome the resistance to ATRA or arsenic in acute promyelocytic leukemia through ubiquitination and degradation of PML-RARα. (PubMed, Cell Death Differ)
    All-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) or chemotherapy highly improves the prognosis of APL patients...Using both cell line- and patient-derived xenograft models, we demonstrated that treatment with an HDAC3 inhibitor or combination of ATRA/ATO reduced APL progression. In conclusion, our study identifies the role of HDAC3 as a positive regulator of the PML-RARα oncoprotein by deacetylating PML-RARα and suggests that targeting HDAC3 could be a promising strategy to treat relapsed/refractory APL.
    Journal
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    RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia) • PIAS4 (Protein Inhibitor Of Activated STAT 4) • HDAC3 (Histone Deacetylase 3)
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    arsenic trioxide
    over1year
    RARA-positive AML is a Novel Patient Subset with an Actionable Target for Treatment with SY-1425, an Oral, Selective RARα Antagonist (IASL 2023)
    No abstract available
    Clinical
    |
    RARA (Retinoic Acid Receptor Alpha)
    |
    RARA positive
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    Amnolake (tamibarotene)
    almost2years
    Tocotrienols-enriched Self-nanoemulsifying Drug Delivery System Enhances the Antileukemic Activity of All-trans Retinoic Acid but not Electrocardiogram Alterations Evoked by Its Combination with Arsenic Trioxide. (PubMed, AAPS PharmSciTech)
    SNEDDS-TRF-ATRA presents cytotoxicity in resistant APL cells (NB4-R2). Combined administration of ATO and SNEDDS-TRF-ATRA in mice prevented the prolongation of the QTc interval caused by ATO but evoked ECG abnormalities such as T wave flattening.
    Journal
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    RARA (Retinoic Acid Receptor Alpha)
    |
    arsenic trioxide
    almost2years
    All-trans retinoic acid improves NSD2-mediated RARα phase separation and efficacy of anti-CD38 CAR T-cell therapy in multiple myeloma. (PubMed, J Immunother Cancer)
    This study elucidates a mechanism of ATRA in regulating CD38 expression and expands the clinical potential of ATRA in improving immunotherapies against CD38 in patients with MM.Cite Now.
    Journal • CAR T-Cell Therapy • IO biomarker
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    RARA (Retinoic Acid Receptor Alpha) • PRKDC (Protein Kinase, DNA-Activated, Catalytic Subunit) • NSD2 (Nuclear Receptor Binding SET Domain Protein 2)
    |
    CD38 expression • Chr t(4;14) • CD8 negative
    almost2years
    All-trans retinoic acid enhances the cytotoxic effect of decitabine on myelodysplastic syndromes and acute myeloid leukaemia by activating the RARα-Nrf2 complex. (PubMed, Br J Cancer)
    These results demonstrate that combining DAC and ATRA has potential for the clinical treatment of HR-MDS/AML and merits further exploration.
    Journal
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    RARA (Retinoic Acid Receptor Alpha)
    |
    decitabine
    almost2years
    Heterogeneity of B cell lymphopoiesis in patients with premalignant and active myeloma. (PubMed, JCI Insight)
    Furthermore, we have defined significantly elevated levels of MMSET, MYD88, c-Myc, CD243, Notch-1, and CD47 from hematopoietic stem cells to PCs in myeloma B cell lymphopoiesis, noted even in premalignant conditions, with variably modulated expression of B cell development regulators, including IRF-4, Bcl-2, Bcl-6, and sXBP-1; aberrant PC markers (such as CD52, CD44, CD200, CD81, CD269, CD117, and CXCR4); and stemness-controlling regulators, including Nanog, KLF-4, octamer-binding transcription factor 3/4 (Oct3/4), Sox2, and retinoic acid receptor α2 (RARα2). This study provides the rationale for precise molecular profiling of patients with MM by CyTOF technology to define disease heterogeneity and prognosis.
    Journal • IO biomarker
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • BCL6 (B-cell CLL/lymphoma 6) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • TNFRSF17 (TNF Receptor Superfamily Member 17) • RARA (Retinoic Acid Receptor Alpha) • KLF4 (Kruppel-like factor 4) • NCAM1 (Neural cell adhesion molecule 1) • SOX2 • TCF3 (Transcription Factor 3) • CD200 (CD200 Molecule) • POU5F1 (POU Class 5 Homeobox 1) • IRF4 (Interferon regulatory factor 4) • CD52 (CD52 Molecule) • YBX1 (Y-Box Binding Protein 1) • NANOG (Nanog Homeobox) • NES (Nestin) • XBP1 (X-box-binding protein 1) • CD81 (CD81 Molecule) • NSD2 (Nuclear Receptor Binding SET Domain Protein 2) • SLAMF7 (SLAM Family Member 7)
    almost2years
    Pyrrolidine Dithiocarbamate Enhances the Cytotoxic Effect of Arsenic Trioxide on Acute Promyelocytic Leukemia Cells. (PubMed, Comb Chem High Throughput Screen)
    In conclusion, PDTC enhances the cytotoxic effect of ATO on APL, and the mechanism is, at least in part, related to the promotion of ATO-induced degradation of PML-RARα fusion protein via forming a complex PDTC-ATO.
    Journal • IO biomarker
    |
    BCL2 (B-cell CLL/lymphoma 2) • RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia) • CASP3 (Caspase 3)
    |
    BCL2 expression
    |
    arsenic trioxide
    almost2years
    Discovery of fusion circular RNAs in leukemia with KMT2A::AFF1 rearrangements by the new software CircFusion. (PubMed, Brief Bioinform)
    Benchmarking tests on simulated and real datasets of cancer samples with previously experimentally determined f-circRNAs showed that CircFusion provides reliable predictions and outperforms available methods for f-circRNA detection. We discovered and validated novel f-circRNAs in acute leukemia harboring KMT2A::AFF1 rearrangements, leading the way to future functional studies aimed to unveil their role in this malignancy.
    Journal
    |
    KMT2A (Lysine Methyltransferase 2A) • RARA (Retinoic Acid Receptor Alpha) • AFF1 (AF4/FMR2 Family Member 1) • MLLT3 (MLLT3 Super Elongation Complex Subunit)
    almost2years
    Small molecule-induced epigenomic reprogramming of APL blasts leading to antiviral-like response and c-MYC downregulation. (PubMed, Cancer Gene Ther)
    Upregulation of interferon alpha and gamma response and downregulation of c-MYC target genes, in function of c-MYC reduced expression (monitored in all the hematopoietic neoplasms tested), represent the most significant modulated pathways. These data demonstrate the ability of maltonis to epigenetically reprogram the gene expression profile of APL cells, inducing an intriguing antiviral-like response, concomitantly with the downregulation of c-MYC-related pathways, thus making it an attractive candidate for antileukemic therapy.
    Journal
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia)
    |
    MYC expression
    2years
    Clinical characteristics of a patient with de novo acute promyelocytic leukemia with JAK2 v617f mutation. (PubMed, Hematology)
    After ATRA and ATO dual induction and chemotherapy consolidation, the patient achieved complete remission (CR) with undetectable PML/RARα. However, the JAK2 V617F remained positive, and the patient developed MPN (PV/ET) 22 months later, which responded well to interferon therapy.AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; ATO, arsenic trioxide; BM, bone marrow; CR, complete remission; ET, essential thrombocythemia; Hb, hemoglobin; JAK2, Janus-associated kinase 2; MPN, myeloproliferative neoplasms; PLT, platelets; PMF, primary myelofibrosis; PML/RARα; PV, polycythemia vera; WBC, white blood cells.
    Journal
    |
    JAK2 (Janus kinase 2) • RARA (Retinoic Acid Receptor Alpha)
    |
    JAK2 V617F • JAK2 mutation • Chr t(15;17) • Chr t(15;17)/PML-RARA fusion
    |
    arsenic trioxide
    2years
    Targeting RARA Overexpression with Tamibarotene, a Potent and Selective RARα Agonist, is a Novel Approach in AML. (PubMed, Blood Adv)
    The combination of oral tamibarotene plus azacitidine was evaluated in a Phase 2 clinical study in 51 newly diagnosed unfit AML patients identified as RARA-positive (N = 22) or RARA-negative (N = 29) for RARA mRNA overexpression in peripheral blasts with a blood-based biomarker test. These results support further evaluation of tamibarotene-based treatment strategies in AML and MDS patients with RARA overexpression to provide a targeted approach with the goal of improving patient outcomes. This trial is registered at www.clinicaltrials.gov as NCT02807558.
    Journal
    |
    RARA (Retinoic Acid Receptor Alpha)
    |
    RARA overexpression • RARA positive
    |
    azacitidine • Amnolake (tamibarotene)
    2years
    Synergistic activation of RARβ and RARγ nuclear receptors restores cell specialization during stem cell differentiation by hijacking RARα-controlled programs. (PubMed, Life Sci Alliance)
    Using RAR isotype knockout lines exposed to RAR-specific agonists, interrogated by global transcriptome landscaping and in silico modeling of transcription regulatory signal propagation, revealed major RARα-driven gene programs essential for optimal neuronal cell specialization and hijacked by the synergistic activation of the RARβ and RARγ receptors. Overall, this study provides a systems biology view of the gene programs accounting for the previously observed redundancy between RARs, paving the way toward their potential use for directing cell specialization during nervous tissue formation.
    Journal
    |
    RARA (Retinoic Acid Receptor Alpha)