Synribo (omacetaxine mepesuccinate)

Our findings suggest the addition of HHT to VA might enhance response and mitigate the negative impact of certain genetic patterns in RR-AML while being well tolerated.

P=N/A, N=15, Recruiting, The First Hospital of China Medical University; The First Hospital of China Medical University

This review discusses several potent alkaloids, such as homoharringtonine, chaetominine, matrine, and jerantinine B, which induce apoptosis, cell cycle arrest, and autophagy and inhibit signaling pathways including PI3K/Akt/mTOR, MAPK, and NF-κB...In addition, targeting leukemia stem cells (LSCs) with alkaloids such as zalypsis offers promise due to its ability to induce apoptosis without significantly affecting normal hematopoietic stem cells...For example, jerantinine B targets AML cells, while vincristine has shown success in lymphocytic leukemia...However, adverse effects such as neutropenia and hepatotoxicity necessitate careful management. Collectively, these findings emphasize the need for further research into alkaloid-based combination therapies to enhance efficacy and minimize toxicity, providing a promising avenue for innovative leukemia treatments.

Taken together, our results confirm that HHT is a substrate for MDR1. It opens the door to a new opportunity to clinically evaluate HHT and its derivatives for the treatment of AML and other cancers.

P1/2, N=284, Recruiting, Ascentage Pharma Group Inc. | Trial completion date: Aug 2025 --> Aug 2026 | Trial primary completion date: Aug 2024 --> Aug 2025

P1/2, N=24, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Aug 2025 --> Sep 2024 | Trial primary completion date: Aug 2025 --> Sep 2024

The formation of the HIF-1α/ERβ/E2F1 feedforward loop promotes NSCLC growth and reveals a novel molecular mechanism by which HHT induces cell death in NSCLC.

In this study, we observed that combining homoharringtonine (HHT) with VEN plus azacitidine resulted in a significantly higher response and better survival than VA alone in patients with R/R-AML. Mechanistically, HHT sensitizes AML cells to VEN by downregulating the anti-apoptotic proteins MCL-1/BCL-xL, activating reactive oxygen species (ROS), leading to mitochondrial membrane potential loss, and attenuating fatty acid (FA) uptake. These findings adding HHT to VEN-based regimens may enhance outcomes in R/R-AML patients.

P=N/A, N=148, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

Our findings demonstrate that a combination of HHT/VEN is effective on ETP-ALL and represents the "backbone" of a promising and safe regimen for newly diagnosed and R/R patients with ETP-ALL.

P1/2, N=24, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Aug 2024 --> Aug 2025

Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib, are approved by the United States Food and Drug Administration (FDA) for first-line treatment of newly diagnosed CML in the chronic phase (CML-CP)...Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP and failure (due to resistance) of at least two TKIs and for all patients in advanced-phase disease. Older patients who have a cytogenetic relapse post-failure on all TKIs can maintain long-term survival if they continue a daily most effective/least toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, and others).

P=N/A, N=148, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

During the induction phase of the CCLG-AML-2019 treatment protocol, the DAH (Daunorubicin, Cytarabine, and Homoharringtonine) and IAH (Idarubicin, Cytarabine, and Homoharringtonine) regimens, in conjunction with targeted drug therapy, did not achieve remission. Subsequently, the patients were shifted to the relapsed/refractory chemotherapy regimen C + HAG (Cladribine, Homoharringtonine, Cytarabine, and G-CSF) for two cycles, which also failed to induce remission...The therapeutic conclusion is that pediatric AML patients with the aforementioned co-expression do not respond to chemotherapy. Non-remission transplantation, supplemented with tailor-made pre- and post-transplant strategies, may enhance treatment outcomes.

The patients were divided into DAH group (daunorubicin, cytarabine and homoharringtonine) and VAH group (venetoclax, cytarabine and homoharringtonine) according to induction regimen. FLT3 mutation was not conducive to morphological remission (OR=5.832, 95%CI: 1.778-19.124) and negative MRD (OR=4.166, 95%CI: 1.396-12.433). Venetoclax-based induction regimen is more effective than traditional chemotherapy regimen for newly diagnosed pediatric AML.

Our data confirmed the poor response of VA in AE-AML, whether used as frontline or salvage therapy. Adding HHT to VA may improve outcomes and enhance the efficacy of VEN in this population.

P2, N=56, Recruiting, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

The plant alkaloid homoharringtonine (HHT) is a Food and Drug Administration (FDA)-approved drug for the treatment of hematologic malignancies...While HHT did not affect the prominent TNF-induced pro-inflammatory NF-ĸB signaling cascade, the compound downregulated the VCAM1 mRNA expression in an IRF-1-dependent manner and diminished active ICAM1 mRNA translation as determined by polysome profiling. This study highlights HHT as an anti-inflammatory compound that efficiently hampers the leukocyte-endothelial cell interaction by targeting endothelial activation processes.

Mechanistically, HHT directly bound to HSF1, suppressing its expression and thereby inhibiting transcription of HSF1 target genes. In conclusion, our work presents a preclinical discovery and validation for HHT as a HSF1 inhibitor for PC treatment.

Mechanistically, HHT exerted anti-TC effects by downregulating TIMP1 expression and then inactivating the FAK/PI3K/AKT signaling pathway. Taken together, our study demonstrated that HHT could inhibit TC progression by inhibiting the TIMP1/FAK/PI3K/AKT signaling pathway.

P1/2, N=24, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=84 --> 24

P1/2, N=29, Active, not recruiting, University of Colorado, Denver | Trial primary completion date: Dec 2024 --> May 2024

P1/2, N=29, Active, not recruiting, University of Colorado, Denver | Trial primary completion date: Apr 2024 --> Dec 2024

P3, N=81, Recruiting, First Affiliated Hospital of Zhejiang University | Not yet recruiting --> Recruiting

Acute myeloid leukaemia (AML) is a fatal haematopoietic malignancy and is treated with the conventional combination of cytarabine (Ara-C) and daunorubicin (Dau). HHT synergistically induces apoptosis in combination with Ara-C in vitro and prolongs the survival of xenografts. We provide a new mechanism for AML treatment by regulating the p38 MAPK/H2AX/Mcl-1 axis to improve cytarabine therapy.

P3, N=81, Not yet recruiting, First Affiliated Hospital of Zhejiang University

Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identify MILIP as an RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment. LncRNA MILIP plays a key role in supporting protein production in TNBC by forming complexes with tRNAs and eEF1α1, which confers sensitivity to combined MILIP targeting and protein synthesis inhibitors.

Homoharringtonine, a Food And Drug Administration-approved translation elongation inhibitor, impedes CRPC progression in preclinical models and patients with CRPC. We construct an SCLPC-specific signature capable of stratifying patients for drug selectivity. Our studies reveal the existence of SCLPC in admixed PCa pathology, which may mediate tumor relapse, and establish SP1 and translation elongation as actionable therapeutic targets for CRPC.

Despite these promising in vitro effects, omacetaxine's efficacy in an orthotopic DIPG model was limited due to inadequate penetration across the blood-brain barrier. As such, further research and advancements are crucial to improve the drug's brain penetration, thus enhancing its overall therapeutic potential.

Y139D and T315I mutations are extremely resistant to asciminib. Ponatinib and omacetaxine show potential for treating asciminib-resistant chronic myeloid leukemia.

P=N/A, N=34, Recruiting, Huai'an First People's Hospital

The synergy of AZA+HHT on apoptosis was induced by activating c-MYC/DDIT3/PUMA-mediated ISR signaling. The combination of AZA and HHT exerts synergistic anti-AML effects by inhibiting cellular proliferation and promoting apoptosis through activation of the ISR signaling pathway via the c-MYC/DDIT3/PUMA axis.

P1/2, N=29, Active, not recruiting, University of Colorado, Denver | Recruiting --> Active, not recruiting | N=45 --> 29

P=N/A, N=90, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

P2, N=30, Recruiting, First Affiliated Hospital of Zhejiang University | Trial completion date: Aug 2024 --> Jun 2025 | Initiation date: Oct 2022 --> Jun 2023 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=45, Recruiting, University of Colorado, Denver | Trial primary completion date: Jun 2025 --> Apr 2024

GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.

P2, N=500, Recruiting, Children's Hospital of Soochow University | Not yet recruiting --> Recruiting

To diagnosis de novo acute leukemia with extensive and comprehensive cellular immune maker detection is available and credible, the expression of a single relatively nonspecific myeloid antigen as a immune maker to detect AUL or AUL associated with sarcoma is precise and effective in our case, which patient was benefit from HIA regiment.

P2, N=500, Not yet recruiting, Children's Hospital of Soochow University

Compared to HAG treatment alone, the combination of decitabine and HAG in the treatment of AML is safe, can significantly improve the immune function of the patients, regulate bFGF and VEGF levels, and improve overall treatment efficacy.

GRd might induce the differentiation of AML cells via regulating the ERK/GSK-3β signaling pathway.