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Unraveling the protease puzzle: understanding composition and concentration in oral cancer pain

Award Number: R01CA314054
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Unraveling the protease puzzle: understanding composition and concentration in oral cancer pain - PROJECT SUMMARY/ABSTRACT The oral cancer tumor microenvironment (TME) is replete with proteases that can activate protease-activated receptor 2 (PAR2), a G protein coupled receptor. PAR2 is a mediator of oral cancer and oral cancer pain. Oral cancers are heterogeneous, both in their expression of PAR2 activating proteases and patient reported pain phenotype. Clinical and laboratory research identified PAR2 activating proteases among genes that are overexpressed in metastatic (N+) cancers from patients reporting highest levels of pain (“pain and metastasis” genes). The focus of much research on PAR2 has been on canonical activation of PAR2 which results in sustained signaling from endosomes. Proteases overexpressed in painful N+ cancers, however, cleave PAR2 at non-canonical sites and promote protease-specific trafficking of PAR2 to different intracellular sites and signaling (biased agonism). While less potent than the canonical proteases expressed in oral cancer, non-canonical proteases overexpressed in painful N+ cancers can prevail over the canonical proteases when highly expressed. The underlying hypothesis is that the potency and efficacy of the individual proteases comprising the cocktails of PAR2 activating proteases in the TME contributes to the heterogeneity of oral cancer pain. Three aims are proposed to better understand the contribution of cancer proteases to the heterogeneity of pain phenotype. Aim 1 identifies the patient pain phenotypes associated with expression of the cocktails of PAR2 activating proteases in oral cancers. Protease expression in cancers assembled in a tissue microarray (TMA) will be measured by RNA in situ hybridization and expression correlated with pain and metastasis. Aim 2 identifies the PAR2 signaling and pain phenotypes promoted by cocktails of proteases representing relative concentrations of PAR2 activating proteases in different cancers. Protease cocktails representing cancers from patients reporting different pain levels determined in Aim 1 will be prepared. PAR2 trafficking and signaling elicited by the proteases will be measured in vitro and pain behavior in vivo due to the lack of in vitro models (e.g., organoids) or computer models. In Aim 3, a prospective study will investigate the cocktails of proteases in individual cancers and their association with patient reported pain. Proteases will be measured in patient saliva pre- and post-surgery and in microdialysate collected from patient tissues during surgery to remove the cancer. Greater understanding of how the composition of pain mediators varies among cancers and the relation with patient reported pain can provide insight into the heterogeneity of cancers and cancer pain.


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 = $667,815 )
2026	2026	NEW YORK UNIVERSITY	70 WASHINGTON SQ S FL 11	NEW YORK	NY	10012	NEW YORK	USA	Cancer Treatment Research	000	1	7/1/2026	NEW	$667,815
														Subtotal = $667,815

Grand Total All Awards = $667,815

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Unraveling the protease puzzle: understanding composition and concentration in oral cancer pain

Award Number: R01CA314054

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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