# Exploring PAR2 Trafficking in Oral Cancer: Implications for Pain Signaling and Drug Delivery

> **NIH NIH K99** · NEW YORK UNIVERSITY · 2024 · $137,050

## Abstract

PROJECT SUMMARY
Opioids remain the most efficacious, but insufficient, analgesic regimen for treating patients with oral cancer
pain. Oral cancer pain is generated at the primary cancer site and is associated with high levels of proteases
released in the cancer microenvironment. These proteases cleave distinct regions of the protease-activated
receptor 2 (PAR2) to activate PAR2 and mediate cleavage site-specific intracellular trafficking and signaling of
the receptor. Mice lacking PAR2 do not develop oral cancer pain, highlighting a central role for neuronal PAR2 in
oral cancer pain. The impact of oral cancer on PAR2 signaling and trafficking in trigeminal (TG) neurons is not
known. The long-term goal is to improve management of oral cancer patients by identifying components of the
PAR2 signaling cascade that are viable targets for development of location-selective drug delivery systems to
alleviate oral cancer pain. The overall objectives for this application are to augment my expertise in signaling
and nanoparticle drug development by gaining training in oral cancer pain and research with complex biological
systems, as well as undertaking career development activities to foster transition to an independent investigator.
The central hypothesis for the proposed research is that oral cancers release proteases that activate PAR2 and
induce sustained pain via PAR2 signaling from multiple cellular compartments in neurons. The rationale for this
project is that identification of cancer-induced PAR2 signaling and trafficking affords the opportunity to develop
drug delivery systems that specifically target these signaling pathways to treat cancer pain. The central
hypothesis will be tested by three Aims: K99, Determine oral cancer-induced changes in the 1) trafficking and 2)
signaling of PAR2 in TG neurons, and 3) R00, Develop nanoparticles to target PAR2 located at the plasma
membrane, endosomes and Golgi to alleviate oral cancer pain. In Aim 1, cancer induced changes in PAR2
trafficking will be investigated by confocal microscopy using TG neuron cultures from PAR2-muGFP mice bearing
oral cancers and controls. Aim 2 will evaluate the signaling of neuronal PAR2 by measuring cAMP and Ca2+ in
TG neuron cultures from cancer bearing and naïve mice expressing PAR2-muGFP in sensory (Nav1.8) neurons.
For aims 1 and 2, TG cultures will be challenged with (a) four oral cancer proteases, (b) a mixture of these
proteases, and (c) conditioned media (CM) from human oral cancers that contain pain mediators (proteases)
released by the cancers. The focus of the R00 phase will be on the development and in vitro and in vivo
evaluation of location-selective nanoparticles targeting PAR2 at the plasma membrane, endosomes and Golgi.
The proposed studies are innovative because they are motivated by previously unappreciated oral cancer-
induced PAR2 trafficking and signaling, and the drug targeting and delivery approach. The work is significant
because these studies will lay t...

## Key facts

- **NIH application ID:** 11055549
- **Project number:** 1K99DE033792-01A1
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Paulina Daniela Ramirez Garcia
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $137,050
- **Award type:** 1
- **Project period:** 2024-09-18 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11055549

## Citation

> US National Institutes of Health, RePORTER application 11055549, Exploring PAR2 Trafficking in Oral Cancer: Implications for Pain Signaling and Drug Delivery (1K99DE033792-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11055549. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*