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Developing CDK12 inhibitors to overcome therapy resistance in HER2+ and KRAS driven breast and lung cancers

Award Number: R01CA262530
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/12/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Developing CDK12 inhibitors to overcome therapy resistance in HER2+ and KRAS driven breast and lung cancers - Project Summary Although the development of targeted therapies has improved overall cancer patient survival, adaptive responses by tumor cells can render these treatments ineffective. The development of agents that block adaptive responses, thereby increasing treatment durability is desperately needed. We and others have demonstrated that inhibitors of the transcriptional cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) are strong candidates to combat acquired drug resistance. The long-term goal of this proposal is to develop a highly effective CDK12/13 inhibitor with an aggregate set of properties suitable to advance as a safety assessment candidate to overcome therapy resistance in both TNBC and HER2+ breast cancers and KRAS inhibitor-resistant NSCLCs. The overall objective in this application is to identify targets and pathways altered by treatment-directed CDK12/13 rewiring and develop new therapeutics that render this rewiring - an exploitable vulnerability. The central hypothesis is that CDK12/13 acts as a driver of transcriptional and post-transcriptional adaptation and that targeting CDK12/13 will block drug-induced escape and improve treatment response in breast and lung cancer. The rationale for this project posits that: (i) multiple malignancies hijack CDK12/13 to provoke transcriptional and signaling plasticity as an adaptive stress resistance mechanism, and (ii) elucidation of mechanisms underpinning compound action will offer a strong scientific framework that will facilitate future clinical development of these new agents for improved patient outcome. The central hypothesis will be tested by pursuing three Specific Aims: (1) Optimize the drug-like properties of in-house CDK12/13 specific inhibitors; (2) Define and validate the mechanisms whereby CDK12/13 inhibition prevents or reverses treatment resistance in TNBC and HER2+ breast cancers (3) Define and validate the mechanisms whereby CDK12/13 inhibition prevents or reverses KRASG12C inhibitor resistance in NSCLC. Accordingly, using a battery of approaches, we will: a) optimize key CDK12/13 inhibitor parameters to deliver a safety assessment candidate; b) define and validate the transcriptional and translational mechanisms, whereby SR-4835 provokes resensitization to chemotherapy, and c) validate cell-based observations in pre-clinical xenograft models. The research approach of our Multi-PI application is innovative, as our team has developed exceptionally selective and novel small molecule CDK12/13 in vivo active molecular probes that will enable (i) interrogation of the roles of CDK12/13 during adaptation to treatment resistance (ii) evaluation that disrupting transcriptional control will counter-resistance mechanisms providing lasting, more durable anti-cancer responses or even cures; and (iii) understanding of the critical signaling nodes that drive drug resistance. The proposed research is highly significant and provides a strong scientific rationale for the continued development of novel CDK12/13 inhibitors. We submit that insight into the molecular underpinnings of the master effectors of CDK12 and CDK13-driven signaling, together with an optimized CDK12/13 inhibitor will offer new opportunities for improved combination treatments for breast and lung 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 = $681,912 )
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	5	6/26/2025	NON-COMPETING CONTINUATION	$681,912
														Subtotal = $681,912

Issue Date FY: 2024 ( Subtotal = $649,046 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	4	7/3/2024	NON-COMPETING CONTINUATION	$649,046
														Subtotal = $649,046

Issue Date FY: 2023 ( Subtotal = $738,951 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	001	3	8/7/2023	SUPPLEMENT FOR EXPANSION	$72,662
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	3	8/4/2023	NON-COMPETING CONTINUATION	$666,289
														Subtotal = $738,951

Issue Date FY: 2022 ( Subtotal = $770,199 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	2	8/17/2022	NON-COMPETING CONTINUATION	$666,846
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	002	2	9/15/2022	SUPPLEMENT FOR EXPANSION	$74,145
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	001	1	9/13/2022	SUPPLEMENT FOR EXPANSION	$29,208
														Subtotal = $770,199

Issue Date FY: 2021 ( Subtotal = $679,205 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	1	7/12/2021	NEW	$679,205
														Subtotal = $679,205

Grand Total All Awards = $3,519,313

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Developing CDK12 inhibitors to overcome therapy resistance in HER2+ and KRAS driven breast and lung cancers

Award Number: R01CA262530

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/12/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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