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Reposition and Optimization of Deferiprone for Breast Cancer Therapy

Award Number: R01CA252720
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Reposition and Optimization of Deferiprone for Breast Cancer Therapy - Parent Grant Summary and Specific Aims In 2020 there will be ~ 276,480 estimated new cases of invasive breast cancer (BCa) among women in the US, causing an estimated ~ 42,170 deaths. Two common mechanisms for the sustenance of BCa are epigenetic dysfunction and the malfunction of endocrine proteins such as estrogen receptor (ER). The specific focus of the studies proposed in this application is to repurpose deferiprone (Def), an FDA-approved iron chelator, as a template for the discovery of novel histone lysine demethylase (KDM) inhibitors optimized for BCa therapy. Most compounds that have been or are being developed clinically exhibit greater efficacy for a subtype of BCa. In this regard, therapeutic interventions that capitalize on ER signaling malfunctions, a driver of more than 70% of BCas, have enjoyed measured success in BCa therapy and/or chemoprevention. However, despite initial benefits, most patients eventually relapse due to acquired resistance to these drugs. Additionally, there are no targeted treatment options for triple-negative breast cancer (TNBC), a BCa subtype lacking ER, Human Epidermal Growth Factor receptor 2 (HER2), and Progesterone Receptor (PR) which accounts for over 20% of BCa incidence. Therefore, there is an unmet medical need for increasingly selective and potent drugs to treat early and resistant stages of all BCa subtypes. BCa viability, regardless of ER expression status, depends on an extensive network of epigenetic modifiers - histone mark writers, readers and erasers. Bioinformatic and functional analysis have identified specific subfamilies of the amino oxidase and Jumonji family of histone lysine demethylases (KDMs), histone methyltransferases (HMTs) and histone deacetylase (HDACs) as essential in supporting ERα signaling activation. Among these epigenetic modifiers, KDM1, KDM3A, KDM5A, KDM5B and KDM6A are exquisitely wired into ERα signaling and are collectively vital for BCa cell viability. Moreover, studies have implicated KDMs such as KDM6A in other ER-independent epigenetic reprograming which sustains TNBC as well. Unlike ERα signaling, pharmacological inhibition of KDMs has not been clinically validated. Although inhibition of KDM3A, KDM5A, KDM5B and KDM6A caused BCa cells growth arrest in vitro and in vivo, there are however precedents for compensation among KDM paralogs in tumor models generated by selective deletion of a paralog member. We hypothesize that collective inhibition of KDM paralogs implicated in BCa etiology will blunt the possibility of compensation among KDM paralogs that could occur from paralog selective inhibition, resulting in novel selective and potent drugs to treat BCa regardless of the cell ER expression status. The proposed study is designed to test this hypothesis. The specific aims are: 1) Develop Def-based KDM inhibitors with favorable toxicological and pharmacokinetic (PK) properties. 2) Characterize the correlation between intracellular on-target effects and whole cell antiproliferative activity. 3) Investigate the in vivo efficacy of lead compounds in five BCa murine models.


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 = $399,479 )
2025	2025	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Treatment Research	002	5	5/22/2025	NON-COMPETING CONTINUATION	$39,947
2025	2025	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Treatment Research	001	5	5/2/2025	NON-COMPETING CONTINUATION	$0
2025	2025	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Treatment Research	000	5	2/12/2025	NON-COMPETING CONTINUATION	$359,532
2025	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Treatment Research	003	4	6/16/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $399,479

Issue Date FY: 2024 ( Subtotal = $495,505 )
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Treatment Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$23,679
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Treatment Research	002	4	7/29/2024	SUPPLEMENT FOR EXPANSION	$45,616
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Treatment Research	000	4	3/11/2024	NON-COMPETING CONTINUATION	$426,210
														Subtotal = $495,505

Issue Date FY: 2023 ( Subtotal = $532,229 )
2023	2023	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Treatment Research	000	3	3/14/2023	NON-COMPETING CONTINUATION	$532,229
														Subtotal = $532,229

Issue Date FY: 2022 ( Subtotal = $436,894 )
2022	2022	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Treatment Research	001	2	7/15/2022	NON-COMPETING CONTINUATION	$35,668
2022	2022	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Treatment Research	000	2	2/17/2022	NON-COMPETING CONTINUATION	$401,226
														Subtotal = $436,894

Issue Date FY: 2021 ( Subtotal = $505,386 )
2021	2021	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Treatment Research	000	1	3/1/2021	NEW	$505,386
														Subtotal = $505,386

Grand Total All Awards = $2,369,493

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Reposition and Optimization of Deferiprone for Breast Cancer Therapy

Award Number: R01CA252720

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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