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Targeting TET DNA Dioxygenases as Therapeutic Principle in Myeloid Neoplasms

Award Number: R01CA257544
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Targeting TET DNA Dioxygenases as Therapeutic Principle in Myeloid Neoplasms - PROJECT SUMMARY/ABSTRACT Ten Eleven Translocation (TET1, TET2 and TET3) are α-ketoglutarate (αKG) and Fe2+ dependent DNA- dioxygenases that is a key regulator of epigenetic landscape. These enzymes progressively oxidize 5- methylcytosine to 5-hydroxymethylcytosine and further to 5-formylcytosine and 5-carboxylcytosine in DNA culminating into DNA demethylation essential for efficient transcription over large time scales. Loss-of-function TET2 mutations (TET2MT), is one of the most frequent pathogenic lesion in MDS and related hematologic malignancies in humans. TET2MT are found in all disease stages and levels of aggressiveness. In addition, recent studies have demonstrated that somatic TET2MT are very frequently found in “healthy” elderly. The presence of TET2MT in CHIP implies that it is an early event in the creation of hematologic disorders. It also supports murine study conclusions that TET2MT cause expansions of hematopoietic stem and progenitor cells (HSPC). Early events in the evolution of defective clones are rational targets for preventative strategies since clones in such stages are likely to be dependent on these events. Their presence in all cells can, however, also be exploited in late stages of the disease. For example, the combined loss of TET1 and TE2 in hematopoietic cells in murine models extends life substantially relative to TET2 loss alone. In addition, the proof of principle is also derived from observation in patients with IDH1/2MT whereby, these neomorphic mutations lead to the production of a weak TET inhibitor, 2-hydroxyglutyrate (2-HG), known inhibitor of dioxygenases. Our observations that IDH1/2MT are mutually exclusive with TET2MT, strongly supports our hypotheses that the TET inhibitor, 2-HG, prevents evolution of TET2MT clones. This observation was further substantiated in a cellular model of myeloid malignant cells and supports that synthetic lethality can be achieved through elimination of remaining TET-activity essential for efficient transcription for proliferation in TET-dioxygenase deficient TET2MT clones. Our overarching hypothesis is that rationally designed and synthesized small molecules TETi76 can be utilized to impede compensatory TET dioxygenase activity originating from TET3 and TET1, to cause either synthetic lethality or lineage redirection in cases with TET2MT inactivation. Our goal is to develop a novel therapeutic approach for TET2MT MDS by evaluating the potential use of TETi76 as targeted treatments in preclinical models. More specifically, we aim to: i) Study the mechanistic consequences of TET inhibition in normal and malignant hematopoiesis in vitro. ii) Establish the effects of TETi compounds in vitro using human and murine cellular models and iii) Characterize TETi preventative and therapeutic efficacy as well as tolerability in pre-clinical murine models. Our proposal, if successful, will lead to a novel class of therapeutic agents for TET2MT associated hematopoietic disorders, and perhaps also other dioxygenase mutations. This work could also have implications for cancers mutated in histone demethylase KDM6A, which is similar to TET2 and frequently mutated in bladder cancer.


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 = $608,324 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	5	7/3/2025	NON-COMPETING CONTINUATION	$608,324
														Subtotal = $608,324

Issue Date FY: 2024 ( Subtotal = $577,908 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	4	6/21/2024	NON-COMPETING CONTINUATION	$577,908
														Subtotal = $577,908

Issue Date FY: 2023 ( Subtotal = $596,157 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	3	7/26/2023	NON-COMPETING CONTINUATION	$596,157
														Subtotal = $596,157

Issue Date FY: 2022 ( Subtotal = $596,157 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	2	6/17/2022	NON-COMPETING CONTINUATION	$596,157
														Subtotal = $596,157

Issue Date FY: 2021 ( Subtotal = $608,324 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Treatment Research	000	1	6/15/2021	NEW	$608,324
														Subtotal = $608,324

Grand Total All Awards = $2,986,870

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Targeting TET DNA Dioxygenases as Therapeutic Principle in Myeloid Neoplasms

Award Number: R01CA257544

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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