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Targeting Menin Protein Stability In AML

Award Number: R00CA279888
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/18/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Targeting Menin Protein Stability In AML - PROJECT SUMMARY Multiple Endocrine Neoplasia Type 1 (MEN1/MENIN) is a transcriptional regulator known to interact with Lysine Methyltransferase 2A (KMT2A/MLL1) driving aggressive subsets of leukemia including MLL1 rearranged (MLL-r), NPM1 mutated and NUP98 rearranged acute myeloid leukemia (AML) as well as other cancers including gastrointestinal stromal tumors. Early success has been reported in clinical trials using small molecule MENIN inhibitors (MI) that disrupt the MLL1/MENIN interaction to treat AML causing MENIN to emerge as an important drug target. As a result, efforts to understand MENIN function are paramount for the continued success of targeting this protein. I, as a research fellow working under the mentorship of Drs. Scott Armstrong and Eric Fischer, have recently characterized an exciting aspect of the mechanism driving the therapeutic effect of MI treatments. We have observed that protein stability changes to MENIN and other proteins is an essential feature of MI sensitivity. Our preliminary examination of this mechanism has uncovered that the loss of a specific E3 ligase can mediate decreased MI sensitivities via MENIN protein stabilization. These findings have inspired a new approach of targeting MENIN protein stability with the simple idea that more MENIN protein decreases drug sensitivity while less MENIN protein inhibits MLL-r transcriptional programs. The experiments outline in this proposal aim to characterize MENIN protein stability in AML by studying how this specific E3 ligase regulates MENIN contributing to MI sensitivity and investigate newly established rapid MENIN degradation systems as a proof-of-principle for improving both MENIN targeted therapies as well as the means to study MENIN function. We have recently established a novel set of tools to study MENIN protein function including (i) MLL-r leukemia cell lines with edited MEN1 loci inserting different protein tags enabling high throughput MENIN protein stability reporter systems and dTAG based rapid MENIN degradation systems, (ii) specific CRISPR libraries targeting MENIN protein function and (iii) early candidate small molecule MENIN proteolysis targeting chimeras (PROTAC). This proposal is also designed to provide additional training experiences in advanced methods of transcriptional analysis, biochemical binding assays, small molecule PROTAC design and mass spectrometry-based co- immunoprecipitation as well as mentoring in manuscript/grant writing and leadership skills. Anchored by the guidance of two well-resourced and established mentors, an excellent scientific advisory committee composed of experts in the fields of leukemia and chromatin biology and a highly dynamic research environment at DCFI, funding for this proposal will enable me to transition to an independent investigator.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $302,386 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Treatment Research	001	3	6/4/2025	EXTENSION WITH OR WITHOUT FUNDS	$24,901
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Treatment Research	002	3	6/17/2025	EXTENSION WITH OR WITHOUT FUNDS	$53,386
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Research Manpower	000	3	3/5/2025	EXTENSION WITH OR WITHOUT FUNDS	$224,099
														Subtotal = $302,386

Grand Total All Awards = $302,386

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Targeting Menin Protein Stability In AML

Award Number: R00CA279888

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/18/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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