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Dual p300 and p53 reactivation in HPV+ head and neck cancer

Award Number: R01DE034300
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Dual p300 and p53 reactivation in HPV+ head and neck cancer - Project Summary Incidence of HPV+ OPC has been increasing for several decades and this upward trend is expected to continue until at least 2060. Current first-line modalities to manage HPV+ OPC patients are effective but not without limitations. A key event in HPV-driven tumorigenesis is the inactivation of the p53 tumor suppressor program. HPV oncogene, E6, inactivates p53 through two distinct pathways: HPVE6 promotes the assembly of the HPVE6-E6AP-p53 trimeric protein complex resulting in ubiquitination and degradation of p53, and HPVE6 directly binds to p300 to block p300-directed acetylation and activation of p53. We hypothesized that disrupting the HPVE6-p300 interaction will liberate sufficient p300 to restore p53 and p300 functionality simultaneously in HPV+ OPC. Our team initiated a drug discovery platform to target the HPVE6-p300 interaction. Our work showed that in HPV+ OPC models: (a) HPVE6 binds to the CH1 domain of p300, (b) our lead molecule, OHM1, a CH1/p300 ligand, disrupts HPVE6-p300 interaction and reactivates p53 and p300, (c) OHM1 is active in vitro and in vivo, and (d) concurrent OHM1+cisplatin combination treatment yields durable complete anti-tumor responses in vivo. Our results are very compelling and, supports further research and development of dual p53 and p300 reactivation as a therapeutic strategy for HPV+ OPC. In this project, we propose to extensively determine the mechanisms of action of p53 and p300 reactivation in response to OHM1 in HPV+ OPC. The specific aims are: (1) determine if OHM1 modulates the p53 post-translational modification code to control p53 functionality and levels, and promote anti-cancer activity in HPV+ OPC, (2) to determine if OHM1 reshapes the tumor-microenvironment and boost immunotherapy response in HPV+ OPC.


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 = $562,992 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Oral Diseases and Disorders Research	000	3	4/10/2026	NON-COMPETING CONTINUATION	$562,992
														Subtotal = $562,992

Issue Date FY: 2025 ( Subtotal = $562,898 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Oral Diseases and Disorders Research	001	2	5/8/2025	NON-COMPETING CONTINUATION	$56,290
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Oral Diseases and Disorders Research	000	2	3/24/2025	NON-COMPETING CONTINUATION	$506,608
														Subtotal = $562,898

Issue Date FY: 2024 ( Subtotal = $575,570 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Oral Diseases and Disorders Research	000	1	7/10/2024	NEW	$575,570
														Subtotal = $575,570

Grand Total All Awards = $1,701,460

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Dual p300 and p53 reactivation in HPV+ head and neck cancer

Award Number: R01DE034300

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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