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Exploiting POU2F3 addiction in the tuft cell variant of small cell lung cancer

Award Number: U01CA242919
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Exploiting POU2F3 addiction in the tuft cell variant of small cell lung cancer - Project Summary Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, which is associated with a high mitotic rate, early metastatic spread, and a rapid evolution of chemotherapy resistance. We recently discovered a novel form of SCLC that resembles the tuft cell lineage, which can be distinguished from the classical neuroendocrine form of this disease through immunohistochemical staining of POU2F3. Importantly, we have identified several molecular vulnerabilities that are specific to the variant form of this disease. In this research proposal, we seek to advance personalized therapies that exploit the unique lineage program present in the tuft cell variant of SCLC. Our innovative functional genomics strategy has already uncovered actionable dependencies that are unique to tuft cell variant of SCLC, such as the kinase IGF1R. In addition, we discovered a profound addiction of tuft cell variant SCLC tumors to POU2F3. Here we will investigate the molecular basis of POU2F3 addiction in SCLC, with the explicit intent to develop small molecules that interfere with POU2F3 function. The first Aim of this proposal will build upon the extensive epigenomic analyses we have performed in SCLC, which has defined a unique enhancer landscape sustained by POU2F3 in this disease. We will now employ two independent functional approaches to elucidate the critical POU2F3 binding sites/enhancers in the genome of SCLC cells, which will be leveraged to pinpoint the critical components of the tuft cell lineage circuit that might be targeted therapeutically. The second Aim will evaluate POU2F3 cofactors, which we have already nominated via an innovative ChIP-SICAP-mass spectrometry analysis of endogenous POU2F3 binding sites. We will perform CRISPR exon scanning and biochemical analysis of each cofactor to define the critical POU2F3:cofactor interactions that selectively support this malignancy. The final Aim of this proposal will employ functional genomics to devise drug combinations with the IGF1R inhibitor linsitinib that are rational and exploit synthetic- lethal genetic interactions. We will also employ our latest CRISPR innovation, homolog co-targeting CRISPR screens, to expose redundant kinase vulnerabilities that are linked with neuroendocrine versus tuft cell variants of SCLC. In summary, we estimate that the tuft cell-like variant is present in ~18% of SCLC cases, which corresponds to approximately 5,000 newly diagnosed SCLC cases and approximately 3,500 deaths in the United States alone each year. Hence, the proposed research could lead to a sustained impact that affects a large patient population for which novel medicines are desperately needed.


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 = -$114 )
2026	2023	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPG HBR	NY	11724	SUFFOLK	USA	Cancer Treatment Research	000	5	12/9/2025	NON-COMPETING CONTINUATION	-$114
														Subtotal = -$114

Issue Date FY: 2023 ( Subtotal = $430,416 )
2023	2023	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Treatment Research	000	5	8/1/2023	NON-COMPETING CONTINUATION	$430,416
														Subtotal = $430,416

Issue Date FY: 2022 ( Subtotal = $430,416 )
2022	2022	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Treatment Research	000	4	8/31/2022	NON-COMPETING CONTINUATION	$430,416
														Subtotal = $430,416

Issue Date FY: 2021 ( Subtotal = $439,200 )
2021	2021	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Treatment Research	000	3	7/13/2021	NON-COMPETING CONTINUATION	$439,200
														Subtotal = $439,200

Issue Date FY: 2020 ( Subtotal = $439,200 )
2020	2020	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Treatment Research	000	2	7/22/2020	NON-COMPETING CONTINUATION	$439,200
														Subtotal = $439,200

Issue Date FY: 2019 ( Subtotal = $439,200 )
2019	2019	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Treatment Research	000	1	7/19/2019	NEW	$439,200
														Subtotal = $439,200

Grand Total All Awards = $2,178,318

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Exploiting POU2F3 addiction in the tuft cell variant of small cell lung cancer

Award Number: U01CA242919

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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