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Tyrosine phosphorylation of p27Kip1 as a biomarker to identify Cdk4/6 inhibitor response

Award Number: R01CA249667
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/10/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Tyrosine phosphorylation of p27Kip1 as a biomarker to identify Cdk4/6 inhibitor response - SUMMARY While the CDK4 targeting drugs (CDK4i), Palbociclib, Abemaciclib, and Ribociclib, have shown clinical promise in the treatment of metastatic breast cancer (BC), lack of a companion diagnostic to identify responsive patients remains a problem. While CDK4i therapy increases progression-free survival (PFS) in some metastatic HR+ patients, many patients exhibit primary resistance to CDK4/6 inhibition and do not derive any benefit from these agents, switching to chemotherapy within 6 months. Development of a biomarker to identify the presence of the active CDK4 target, and therefore CDK4i sensitive patients, would enable responsive metastatic breast cancer patients to be pinpointed at the onset of therapy. As CDK4/6 is downstream of all oncogenic signaling pathways, it is also likely that this class of drugs will have efficacy in at least a subset of additional tumor types, and a biomarker for CDK4i responsiveness would accelerate the expansion of this class of therapy into tumor types, such as metastatic Her2+, Triple negative breast or ovarian cancer, which have few therapeutic options. A biomarker to predict effectiveness of CDK4i would mean more rapid benefit to the correct patients, a cost and time savings and reduced toxicity for patients who would not be benefited and extended use of these therapies across tumor types where novel therapies are desperately needed. In essence: a biomarker would help get the right drug to the right patients. This translational project will focus on the utility of a novel diagnostic marker, p27Kip1 pY88, to identify patients who would respond to the currently used CDK4i therapy. In published and presented work, we have shown that pY88 serves as a surrogate marker for CDK4 activity and in turn CDK4i responsiveness, in cell lines, primary explant culture, and now in biopsies from patients treated clinically with CDK4i therapy. The goal of this RO1 project is to demonstrate that p27 pY is a diagnostic biomarker to identify CDK4/6i-responsive patients and then also to reconcile why pY might demarcate resistance by associating it to mechanisms of resistance, with the idea that this will further inform potential uses of the CDK4/6i drugs. In Aims 1 and 2 (translational aims) we plan to test an IHC based assay to determine if pY88 can serve as a biomarker to predict significant PFS improvement in patients with HR+/HER2- BC treated with CDK4/6i. In Aim 3 (mechanism aim), we will determine how pY status relates to CDK4/6i sensitivity and resistance. Aim 1: To test the ability of the pY biomarker to predict significant PFS, by comparing pY88 status in biopsy material from patients with HR+ BC treated clinically with CDK4/6i with patient outcome data. Aim 2. To test the validated pY test in clinically relevant cohorts, from two completed and ongoing clinical trials. Aim 3: To determine how pY status relates to CDK4/6i sensitivity and resistance, by using biochemical studies to examine pY status in in vitro and in vivo models of CDK4/6i resistance.


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 = $623,507 )
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Cancer Detection and Diagnosis Research	001	5	4/16/2026	NON-COMPETING CONTINUATION	$62,350
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Cancer Detection and Diagnosis Research	000	5	12/12/2025	NON-COMPETING CONTINUATION	$561,157
														Subtotal = $623,507

Issue Date FY: 2025 ( Subtotal = $624,848 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Cancer Detection and Diagnosis Research	000	4	11/20/2024	NON-COMPETING CONTINUATION	$562,364
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Cancer Detection and Diagnosis Research	001	4	6/2/2025	NON-COMPETING CONTINUATION	$62,484
														Subtotal = $624,848

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Cancer Detection and Diagnosis Research	000	3	7/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $612,351 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Cancer Detection and Diagnosis Research	000	3	6/1/2023	NON-COMPETING CONTINUATION	$612,351
														Subtotal = $612,351

Issue Date FY: 2022 ( Subtotal = $620,808 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Cancer Detection and Diagnosis Research	001	2	8/25/2022	NON-COMPETING CONTINUATION	$620,808
2022	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Cancer Detection and Diagnosis Research	000	1	4/1/2022	NEW	$0
														Subtotal = $620,808

Issue Date FY: 2021 ( Subtotal = $675,099 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	450 CLARKSON AVE	BROOKLYN	NY	11203	KINGS	USA	Cancer Detection and Diagnosis Research	000	1	6/10/2021	NEW	$675,099
														Subtotal = $675,099

Grand Total All Awards = $3,156,613

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Tyrosine phosphorylation of p27Kip1 as a biomarker to identify Cdk4/6 inhibitor response

Award Number: R01CA249667

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/10/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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