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PROTAC Targeting of Tip60 in Syngeneic Cancer Models Using Cereblon Knock-in Mice

Award Number: R01CA253320
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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PROTAC Targeting of Tip60 in Syngeneic Cancer Models Using Cereblon Knock-in Mice - Project Summary We will investigate whether therapeutic targeting of Tip60, a histone/protein acetyltransferase essential for the functions and survival of Foxp3+ T-regulatory (Treg) can significantly decrease Treg functions in vivo while preserving conventional T cell responses, leading to inhibition of lung tumor growth in murine models. We will also assess the effects of Tip60 targeting on the DNA damage response within tumors induced by conventional therapies for lung cancer, including irradiation and cisplatin therapy. We have developed Tip60 PROTAC (proteolysis targeting chimeric) molecules that recruit the Cereblon E3 ligase so as to promote Tip60 degradation, and we employ Cereblon knock-in (CrbnI391V) immunocompetent C57BL/6 mice in compound screening and tumor models to facilitate identification of compounds for subsequent clinical development. Aim 1 - Can Tip60i limit growth of tumors in immunocompetent hosts by decreasing Foxp3+ Treg suppressive function? We have developed several Tip60i, including Crbn- and VHL-based PROTAC compounds. We will test if Tip60i PROTAC compounds can modulate Treg function and control growth of experimental lung cancers by (1.1) optimizing Tip60i PROTAC compounds, and testing them (1.2) alone, or in conjunction with (1.3) vaccination or (1.4) checkpoint inhibitor therapy in CrbnI391V mice. We will also assess effects of Tip60i on 1.5) normal human Treg and/or Teff cells, and 1.6) human lung cancer associated Treg cells. Aim 2 – Determine if Tip60i disrupts DDR actions essential for tumor cell survival. Our molecular investigations will explore Tip60-dependent mechanisms that promote cellular resistance to genome instability and normal programmed mechanisms of death, and which underpin cancer initiation and chemotherapeutic resistance crucial for lung cancer cell survival. We will test if Tip60i compounds have direct anti-tumor effects by disrupting 2.1) Tip60-dependent p53 activation and/or 2.2) DNA repair mechanisms. Our studies will facilitate the development of new strategies for immunotherapy in patients with malignancies, given that the new Tip60-directed therapies have dual mechanisms of action, involving targeting Foxp3+ Treg cells and intrinsic tumor cell responses to therapy. The data to be generated will likely lead to clinical trials in patients with lung cancers, and should also have relevance to additional individuals, given the increasingly recognized potential for immunotherapy in the management of many other types 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 = $0 )
2026	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	5	11/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $376,197 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	5	5/22/2024	NON-COMPETING CONTINUATION	$376,197
														Subtotal = $376,197

Issue Date FY: 2023 ( Subtotal = $388,077 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	4	6/27/2023	NON-COMPETING CONTINUATION	$388,077
														Subtotal = $388,077

Issue Date FY: 2022 ( Subtotal = $388,077 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	3	6/28/2022	NON-COMPETING CONTINUATION	$388,077
														Subtotal = $388,077

Issue Date FY: 2021 ( Subtotal = $399,051 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	2	6/7/2021	NON-COMPETING CONTINUATION	$399,051
														Subtotal = $399,051

Issue Date FY: 2020 ( Subtotal = $427,654 )
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	1	5/12/2020	NEW	$427,654
														Subtotal = $427,654

Grand Total All Awards = $1,979,056

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PROTAC Targeting of Tip60 in Syngeneic Cancer Models Using Cereblon Knock-in Mice

Award Number: R01CA253320

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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