- |||||||||| Identifying novel 'druggable' targets via Npm1A-turboid fusion and mass spectrometry to overcome genetic or adaptive resistance to menin inhibitors in mtNPM1 AML (OCCC - West Halls B3-B4) - Nov 4, 2025 - Abstract #ASH2025ASH_2685;
Treatment with revumenib may also cause emergenceof hot spot mutations in menin (e.g., S160T, M327V, M327I, G331D, G331R, and T349M) exhibitingreduced affinity to MI-binding...OCI-AML3 MEN1-M327I cells were resistant toSNDX-50469, ziftomenib, and DS1594b, but sensitive to the second-generation MI, bleximenib, aspreviously reported.To identify novel 'druggable' targets in mtNpm1 AML cells either sensitive or resistant to MI, we knockedin TurboID by CRISPR/Cas9 into the C-terminus of the mtNpm1 gene in OCI-AML3 cells...When combined with a BET inhibitor (pelabresib) ora novel dual BET/HAT inhibitor (NEO2734/EP31670), both RocA and talazoparib induced synergisticlethality in the sensitive OCI-AML3 and OCI-AML2-Npm1A KI, as well as the MI-resistant (OCI-AML3-Menin-M327I or the OCI-AML3 MITR) cells...Exvivo treatment with EP31670 and RocA or talazoparib induced synergistic loss of viability in MI (SNDX-50469)-resistant, patient-derived (N = 3) mtNpm1 AML cells. In the PDX model of luciferized mtNpm1 +FLT3-ITD AML cells engrafted in NSG mice, compared to vehicle control, monotherapy with EP31670 (7.5mg/kg QD), talazoparib (0.25 mg/kg QD) or RocA (0.5 mg/kg 3x/wk) significantly reduced AML burden.Collectively, these findings highlight the newly discovered, preclinical efficacy of inhibitors of eIF4A andPARP against mtNpm1 AML cells and support the rationale for further evaluating the efficacy ofcombinations involving these agents.
- |||||||||| Review, Journal: Therapeutic Implications of Menin Inhibitors in the Treatment of Acute Leukemia: A Critical Review. (Pubmed Central) - Jul 25, 2025
We discuss their efficacy, safety profiles, and potential roles within the current treatment algorithm. The continued clinical evaluation of menin inhibitors may redefine treatment paradigms for NPM1m and KMT2Ar AML and other acute leukemia with the aberrant MEIS1-HOXA axis, offering new hope for patients with limited therapeutic options.
- |||||||||| Discerning the Landscape of Menin Inhibitor Resistance (Seaport Ballroom ABCD (Manchester Grand Hyatt San Diego)) - Nov 6, 2024 - Abstract #ASH2024ASH_2068;
An in vitro technique leveraging large starting cell numbers validates this base editor screening approach, which resulted in rapid development of resistant MEN1 mutant clones in less than 4 weeks of treatment. Identifying MEN1 mutations in patients receiving MIs is important because there may be opportunities for patients with select MEN1 mutations to derive benefit from an alternate MI-based therapy, provided that the precise mutational profile of each inhibitor is known.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, emilumenib succinate (DS-1594) / Daiichi Sankyo
Trial completion, Trial completion date, Trial primary completion date: DS-1594b With or Without Azacitidine, Venetoclax, or Mini-HCVD for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia (clinicaltrials.gov) - Nov 12, 2023
P1/2, N=17, Completed,
Identifying MEN1 mutations in patients receiving MIs is important because there may be opportunities for patients with select MEN1 mutations to derive benefit from an alternate MI-based therapy, provided that the precise mutational profile of each inhibitor is known. Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> Nov 2023 | Trial primary completion date: Nov 2024 --> Nov 2023
- |||||||||| Review, Journal: Targeting the undruggable: menin inhibitors ante portas. (Pubmed Central) - Apr 27, 2023
The clinical development of novel menin-MLL inhibitors is well in line with the currently ongoing paradigm shift towards targeted therapies seen in the AML treatment landscape. Moreover, the clinical assessment of combinations of these inhibitors with established therapy options in AML could be the fuel for an improved outcome of MLL/NPM1 patients.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, emilumenib succinate (DS-1594) / Daiichi Sankyo
Trial completion date, Trial primary completion date: DS-1594b With or Without Azacitidine, Venetoclax, or Mini-HCVD for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia (clinicaltrials.gov) - Mar 16, 2023
P1/2, N=20, Active, not recruiting,
Moreover, the clinical assessment of combinations of these inhibitors with established therapy options in AML could be the fuel for an improved outcome of MLL/NPM1 patients. Trial completion date: Nov 2022 --> Nov 2024 | Trial primary completion date: Nov 2022 --> Nov 2024
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, emilumenib succinate (DS-1594) / Daiichi Sankyo
Enrollment closed, Enrollment change: DS-1594b With or Without Azacitidine, Venetoclax, or Mini-HCVD for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia (clinicaltrials.gov) - Sep 8, 2022
P1/2, N=20, Active, not recruiting,
Combination effects show synthetic lethality in almost all cell lines except OCI-AML3. Recruiting --> Active, not recruiting | N=122 --> 20
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, emilumenib succinate (DS-1594) / Daiichi Sankyo
Enrollment open, Trial initiation date: DS-1594b With or Without Azacitidine, Venetoclax, or Mini-HCVD for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia (clinicaltrials.gov) - Apr 7, 2021
P1/2, N=122, Recruiting,
Recruiting --> Active, not recruiting | N=122 --> 20 Not yet recruiting --> Recruiting | Initiation date: Jul 2021 --> Mar 2021
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