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FoXM1 inhibition: a novel therapeutic avenue to treat breast cancers

Award Number: R01CA239227
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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FoXM1 inhibition: a novel therapeutic avenue to treat breast cancers - Defects in DNA damage response (DDR) is major factor that predispose normal cells to acquire oncogenic mutations. However, after a tumor develops, cancer cells manage their survival by repairing DNA damage resulting from unchecked DNA replication. Cancer cells can use the alternative or backup DNA repair programs to overcome their DDR defects. For example, cancer cells with deficiency in homologous recombination (HR) proteins (such as BRCA1) can repair their DNA by either relying on other highly expressed HR-related proteins (such as RAD51 or PARP1) or by using other DNA repair mechanisms such as alternative non-homologous end joining (ALT NHEJ) and basal excision repair (BER). The addiction of cancer cells to these rescue DNA repair pathways contributes to therapy-resistance; therefore, successful targeting of factor(s) that play critical role in multiple DNA repair pathways will have promising clinical outcomes. Alterations in DNA repair pathways commonly occur during breast cancer (BC) progression. For example, triple negative breast cancer (TNBC) an aggressive BC subtype that frequently relapses as distant metastases, have dysfunctional BRCA1 but expresses high levels of RAD51. Further, estrogen receptor positive BC (ER+BC), which accounts for ~70% of all BCs, employs ALT NHEJ, HR or BER to repair their DNA. Notably, ER+BCs acquire resistance to endocrine therapy and DNA-damaging chemotherapy drugs by inducing expression of DNA repair genes. A key factor that is involved in regulating multiple DNA repair pathways is FOXM1, which is highly expressed in TNBC and therapy resistant ER+BCs. FOXM1 is known to promote resistance to chemotherapy drugs and anti-estrogen therapies. In this proposal, we provide compelling evidence that imipramine blue (IB), a novel analogue of anti-depressant imipramine that we recently synthesized inhibits FOXM1-associated signaling impeding DNA repair ability of TNBCs and ER+BC. Using tumor explants from BC patients and tumor xenograft models, we have demonstrated that IB inhibits the growth of TNBC and ER+BC without inducing any toxicity. Further, our studies have shown that IB may sensitize endocrine resistant ER+BCs to tamoxifen (TAM) and improve the efficacy of DNA damaging chemotherapy drugs in TNBC. Based on these observations, we hypothesize that FOXM1 is a critical component of rescue DNA repair pathways that BCs get addicted to survive; that IB suppresses ER+BC and TNBC growth and progression as well as enhances the therapy response by targeting FOXM1 and its associated signaling; and that IB is a safe and effective drug for treating ER+BC and TNBC. In Aim 1, we will characterize the IB-target protein interaction and determine the mechanism(s) by which IB regulates its target genes in TNBC and ER+BC. In Aim 2, we will test the hypothesis that IB inhibits TNBC and ER+BCs growth, metastasis, and enhances therapy response by inhibiting backup DNA repair pathways that these cancers employ to survive. In Aim 3, we will test the safety and viability of IB by using patient derived xenografts in humanized mice and by using human breast cancer explant studies. We will also establish PK/PD parameters required for future clinical development of IB.


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: 2024 ( Subtotal = $387,449 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	5	11/29/2023	NON-COMPETING CONTINUATION	$357,936
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	003	5	4/17/2024	SUPPLEMENT FOR EXPANSION	$507
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	002	5	4/17/2024	NON-COMPETING CONTINUATION	$19,885
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	001	5	11/30/2023	SUPPLEMENT FOR EXPANSION	$9,121
														Subtotal = $387,449

Issue Date FY: 2023 ( Subtotal = $455,716 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	002	4	3/15/2023	NON-COMPETING CONTINUATION	$31,840
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	001	4	12/7/2022	SUPPLEMENT FOR EXPANSION	$60,302
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	4	12/6/2022	NON-COMPETING CONTINUATION	$358,214
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	003	4	3/15/2023	SUPPLEMENT FOR EXPANSION	$5,360
														Subtotal = $455,716

Issue Date FY: 2022 ( Subtotal = $432,022 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	002	3	6/22/2022	SUPPLEMENT FOR EXPANSION	$41,668
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	001	3	4/28/2022	NON-COMPETING CONTINUATION	$31,866
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	3	11/30/2021	NON-COMPETING CONTINUATION	$358,488
														Subtotal = $432,022

Issue Date FY: 2021 ( Subtotal = $416,086 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	2	11/17/2020	NON-COMPETING CONTINUATION	$395,281
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	001	2	1/28/2021	NON-COMPETING CONTINUATION	$20,805
														Subtotal = $416,086

Issue Date FY: 2020 ( Subtotal = $429,261 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	001	1	1/24/2020	NEW	$9,214
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	1	12/12/2019	NEW	$420,047
														Subtotal = $429,261

Grand Total All Awards = $2,120,534

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FoXM1 inhibition: a novel therapeutic avenue to treat breast cancers

Award Number: R01CA239227

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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