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Novel therapeutics for targeting checkpoint dysfunction in cancer

Award Number: R01CA203824
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Novel therapeutics for targeting checkpoint dysfunction in cancer - Abstract Normal cells employ several fundamental brake mechanisms to tightly coordinate the execution of different cell cycle phases. Loss of these checkpoint controls is a hallmark of cancer. Our goal is to devise therapeutic strategies targeting newly discovered checkpoint perturbation mechanisms in cancers harboring mutant p53. Tumor suppressor p53 is a key regulator for G1 cell cycle checkpoint. Mutant p53 mediates gain of functions to promote tumor progression and drug resistance. Nevertheless, how to target mutant p53 in cancer remains a big challenge. Our preliminary study identifies several novel mechanisms by which mutant p53 interacts with a checkpoint activator protein TopBP1 physically and functionally to perturb the checkpoint control, and induces ACTL6A to promote cisplatin resistance. We propose that the mutant p53-TopBP1 axis is a valid therapeutic target in cancer. We have developed two classes of novel TopBP1 inhibitors that can target the mutant p53- TopBP1 axis. In this proposal, we will determine their therapeutic potential in targeting checkpoint dysfunction in cancer. First, we will study how the mutant p53-TopBP1 axis perturbs replication control. Second, we will determine the functional interaction between mutant p53 and ACTL6A in growth control and cisplatin resistance. Third, we will investigate new combinations of targeted therapy against breast and ovarian cancers. The novel TopBP1 inhibitors that we have developed will greatly enhance the feasibility and impact of this proposal. In short, the proposed study will elucidate novel mechanisms of checkpoint perturbation and translate our discoveries into new therapeutics for a broad range of cancers.


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: 2026 ( Subtotal = $344,222 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	10	12/17/2025	NON-COMPETING CONTINUATION	$344,222
														Subtotal = $344,222

Issue Date FY: 2025 ( Subtotal = $382,469 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	9	1/13/2025	NON-COMPETING CONTINUATION	$344,222
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	001	9	6/26/2025	NON-COMPETING CONTINUATION	$38,247
														Subtotal = $382,469

Issue Date FY: 2024 ( Subtotal = $363,346 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	001	8	4/17/2024	NON-COMPETING CONTINUATION	$19,124
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	8	1/3/2024	NON-COMPETING CONTINUATION	$344,222
														Subtotal = $363,346

Issue Date FY: 2023 ( Subtotal = $374,819 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	7	2/1/2023	NON-COMPETING CONTINUATION	$374,819
														Subtotal = $374,819

Issue Date FY: 2022 ( Subtotal = $382,469 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	001	6	1/20/2022	COMPETING CONTINUATION	$382,469
2022	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	003	6	6/7/2022	COMPETING CONTINUATION	$147,509
2022	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	5	1/14/2022	NON-COMPETING CONTINUATION	$0
2022	2021	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	002	5	6/7/2022	NON-COMPETING CONTINUATION	-$147,509
														Subtotal = $382,469

Issue Date FY: 2021 ( Subtotal = $362,569 )
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	5	11/4/2020	NON-COMPETING CONTINUATION	$344,440
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	001	5	1/22/2021	NON-COMPETING CONTINUATION	$18,129
														Subtotal = $362,569

Issue Date FY: 2020 ( Subtotal = $362,569 )
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	4	11/7/2019	NON-COMPETING CONTINUATION	$326,312
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	001	4	1/13/2020	NON-COMPETING CONTINUATION	$36,257
														Subtotal = $362,569

Issue Date FY: 2019 ( Subtotal = $351,691 )
2019	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	3	11/19/2018	NON-COMPETING CONTINUATION	$351,691
														Subtotal = $351,691

Issue Date FY: 2018 ( Subtotal = $362,569 )
2018	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	2	11/16/2017	NON-COMPETING CONTINUATION	$326,312
2018	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	001	2	5/22/2018	NON-COMPETING CONTINUATION	$36,257
														Subtotal = $362,569

Issue Date FY: 2017 ( Subtotal = $362,569 )
2017	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	1	12/15/2016	NEW	$362,569
														Subtotal = $362,569

Grand Total All Awards = $3,649,292

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Novel therapeutics for targeting checkpoint dysfunction in cancer

Award Number: R01CA203824

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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