[R01] Unraveling the protease puzzle: understanding composition and concentration in oral cancer pain
Ente: National Cancer Institute
Scadenza: 2031-06-30
Importo max: 667.815 EUR
Paese: US
Descrizione
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.
Istituzione: NEW YORK UNIVERSITY
PI: Donna G Albertson, Brian L Schmidt
Progetto: 1R01CA314054-01
Settori: National Cancer Institute
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