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Targeting polo-like kinase 1 (PLK1) for treatment of small cell lung cancer

Award Number: R01CA273216
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Targeting polo-like kinase 1 (PLK1) for treatment of small cell lung cancer - PROJECT SUMMARY/ABSTRACT Small cell lung cancer (SCLC) is a significant health problem projected to afflict more than 35,000 new patients in the US in 2021. Less than 20% of newly diagnosed patients survive beyond 2 years. New and effective treatments are urgently needed to improve the poor outcome associated with this disease. SCLC is one of the most genomically unstable tumors but genomic-informed targeted therapy is currently not an established strategy in this disease. This is in part because most of the alterations in SCLC involve tumor suppressor genes such as TP53 and RB1, which cannot be targeted directly. We contend that while tumor suppressor gene alterations are not ideal targets for drug development efforts, the biological vulnerability conferred by these alterations can be exploited for therapeutic gains in SCLC. We employed an unbiased and agnostic preclinical screening to test several classes of targeted agents in a panel of SCLC cell lines. We discovered exquisite in vitro activity of four different polo like kinase 1 (PLK1) enzyme inhibitors, rigosertib, volasertib, CYC140 and Onvansertib. We subsequently confirmed the in vivo efficacy using traditional xenograft and patient-derived xenograft models of SCLC. We made the intriguing observation that SCLC cell lines harboring inactivating TP53 gene mutations are more sensitive to PLK1 inhibitors. We replicated this interesting observation using genetic depletion of wild type TP53 and overexpression of active mutant form of p53. These data therefore suggest that specific types of TP53 mutation could serve as potential predictive biomarkers to guide the development of PLK1 inhibitor as therapy of SCLC. We propose to test the hypotheses that (i.) Onvansertib, a potent PLK1 inhibitor, will have significant anticancer efficacy in relapsed SCLC patients and (ii.) Disruptive, inactivating TP53 gene mutation will predict efficacy of PLK1 inhibitors in patients. Also, that YAP1 positive subtype of SCLC will be vulnerable to PLK1 inhibitors alone and the combination with immune checkpoint blockade will further enhance efficacy in this subset of SCLC. We will pursue three innovative, independent but integrated specific aims: Aim 1: Conduct a phase II co-clinical trial to systematically assess the efficacy of onvansertib in patients with relapsed SCLC. A 2-stage phase II clinical trial will evaluate the efficacy of onvansertib in relapsed SCLC patients. Aim 2: Interrogate putative predictive biomarkers and elucidate whether and how inactivating TP53 gene mutations confer vulnerability to PLK1 inhibitors in SCLC. Preclinical efficacy of PLK1 inhibitors will be assessed in a large panel of genomically characterized SCLC cell lines. Activity will be correlated with specific types of TP53 mutations and with other biologically relevant genetic alterations in SCLC. Aim 3: Characterize mechanism(s) of acquired resistance to PLK1 inhibitor in SCLC and combination strategies to overcome resistance and enhance efficacy. Using lab and patient-derived preclinical models from the co-clinical trial, we will use machine learning and Artificial Intelligence approaches to interrogate putative resistance mechanisms and identify other strategies to enhance efficacy.


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 = $581,504 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	000	5	12/24/2025	NON-COMPETING CONTINUATION	$581,504
														Subtotal = $581,504

Issue Date FY: 2025 ( Subtotal = $648,269 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	003	4	6/2/2025	NON-COMPETING CONTINUATION	$64,826
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	002	4	12/9/2024	NON-COMPETING CONTINUATION	$583,443
2025	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	2	11/26/2024	NON-COMPETING CONTINUATION	-$9,420
2025	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	001	3	11/26/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$9,420
														Subtotal = $648,269

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	001	3	5/31/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$545,942
2024	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	2	5/31/2024	NON-COMPETING CONTINUATION	-$545,942
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $617,857 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	001	2	7/14/2023	NON-COMPETING CONTINUATION	$617,857
2023	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	1	7/14/2023	NEW	$0
														Subtotal = $617,857

Issue Date FY: 2022 ( Subtotal = $630,466 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	1	7/27/2022	NEW	$630,466
														Subtotal = $630,466

Grand Total All Awards = $2,478,096

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Targeting polo-like kinase 1 (PLK1) for treatment of small cell lung cancer

Award Number: R01CA273216

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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