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Investigating a new vulnerability in oral squamous cell carcinoma

Award Number: R01DE033025
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: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Investigating a new vulnerability in oral squamous cell carcinoma - SUMMARY Oral squamous cell carcinoma (OSCC) is the most common oral malignancy and subtype of head and neck cancer and frequently identified by dentists during routine care. OSCC is the sixth most common cancer globally with incidence continuing to rise. Current therapies for OSCC are inadequate and OSCC are resistant to immune checkpoint inhibition (ICI), resulting in frequent reoccurrence and poor rates of patient survival. The development of targeted therapies for OSCC is hampered by the lack of common driving oncogene mutations, but inactivation of the p53 tumor suppressor is frequent in human papillomavirus (HPV) negative OSCC, which contributes to treatment resistance, immune cell suppression, and reduced patient survival. Therefore, new and innovative treatment approaches are desperately needed for OSCC and particularly those with inactivated p53. Thus, we sought to identify new vulnerabilities in HPV-negative OSCC. It was believed that if p53 was inactivated, cancer cells did not require Mdm2, which binds and regulates p53. However, challenging this long-held belief, our results with cancers arising in p53-null mice showed that the Mdm2 oncogene was required for the survival of p53-null murine cancers. Capitalizing on our paradigm-shifting discovery in mice, our preliminary data reveal Mdm2 is a previously unknown and unexpected vulnerability in p53-inactivated human OSCC. We propose that targeted loss of Mdm2 will effectively eliminate OSCC cells by activating p53- independent mechanisms that signal for apoptosis and pathways that contribute to increasing immunogenicity. Preliminary results with a novel Mdm2-targeted degrader we designed and synthesized support this hypothesis. To further test our hypothesis, we propose to 1) investigate the cytotoxicity mechanism(s), the required pathways, and in vivo efficacy with targeted Mdm2 loss with our Mdm2 PROTAC in OSCC cells with various p53 alterations; and 2) investigate improving the immunogenicity of OSCC tumors and overcoming ICI resistance with several approaches that include our Mdm2 PROTAC and immune competent syngeneic mouse models. Completion of this study will uncover the specific requirements of Mdm2 in OSCC, significantly increasing the mechanistic understanding of the p53-independent functions of Mdm2, and provide critical pre-clinical evaluation of potential novel therapy approaches for OSCC that increase immunogenicity and overcome ICI 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: 2025 ( Subtotal = $521,948 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Oral Diseases and Disorders Research	000	3	5/6/2025	NON-COMPETING CONTINUATION	$521,948
														Subtotal = $521,948

Issue Date FY: 2024 ( Subtotal = $511,509 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Oral Diseases and Disorders Research	000	2	4/1/2024	NON-COMPETING CONTINUATION	$469,754
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Oral Diseases and Disorders Research	001	2	6/12/2024	NON-COMPETING CONTINUATION	$41,755
														Subtotal = $511,509

Issue Date FY: 2023 ( Subtotal = $535,846 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Oral Diseases and Disorders Research	000	1	6/20/2023	NEW	$535,846
														Subtotal = $535,846

Grand Total All Awards = $1,569,303

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Investigating a new vulnerability in oral squamous cell carcinoma

Award Number: R01DE033025

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: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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