# Protease activated receptor-2 (PAR-2) signaling and metastatic ovarian cancer

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $353,419

## Abstract

SUMMARY
Ovarian cancer is the most lethal gynecological malignancy. One in 69 women will develop ovarian cancer,
and less than half will survive for five years. Despite a number of recent advances in our understanding of
ovarian cancer etiology and pathobiology, the survival rate of patients diagnosed with ovarian cancer is low
when compared to that of breast or prostate cancer. Factors contributing to this poor survival rate are tumor
persistence, tumor recurrence and chemoresistance. There is an urgent need to develop second line therapies
to both improve the therapeutic efficacy of conventional treatments and to provide alternative therapeutic
options for patients with recurrent ovarian cancer. Anti-angiogenesis therapies targeting the VEGF and the
angiopoietins/Tie2 pathways have shown clinical efficacy and are currently being actively pursued as adjunct
therapies for recurrent ovarian cancers. Unfortunately, outcomes of recent clinical trials have been mixed and
non-responsiveness or resistance to anti-angiogenic treatment, toxicities and subsequent tumor recurrence
and metastasis have limited therapeutic success. This is largely due to an incomplete of understanding of the
basic mechanisms involved. The scientific premise underlying this research is that differential triggering of
the G-protein coupled Protease Activated Receptor-2 (PAR-2) by different proteases modulates tumor
angiogenesis important for ovarian tumor metastasis. We discovered the membrane-anchored serine
protease, testisin (also known as PRSS21), to be aberrantly expressed in a broad range of ovarian cancers and
to be a potent cell surface proteolytic activator of PAR-2. Strong preliminary data show that the aberrent
constitutive expression of testisin in ovarian tumors promotes anti-angiogenic signaling and suppresses
ovarian tumor metastasis and ascites formation in a preclinical xenograft model of ovarian cancer. This
unique activity is unexpected, and reveals a major gap in our understanding of how PAR-2 angiogenic
signals are modulated by different proteases, specifically those in spatial proximity to PAR-2. Such `biased
agonism' may start to explain significant variations in patient responses to anti-angiogenic therapies in
ovarian cancer patients. The proposed research plan will utilize primary human ovarian tumor cells and cell
lines in concert with in vivo mouse models to address the following specific aims: 1) to determine
mechanisms by which testisin suppresses experimental ovarian tumor metastasis, and 2) to determine
molecular and cellular mechanisms associated with testisin-mediated desensitization PAR-2 and modulation
of angiogenesis. Augmentation of the natural antagonism resulting from the testisin-PAR-2 pathway could
find utility in combination with other anti-angiogenic therapies, to reduce therapeutic doses required, thereby
minimizing side effects and provide a unique therapy for managing this devastating disease. The fact that
females do not have a no...

## Key facts

- **NIH application ID:** 10204893
- **Project number:** 5R01CA196988-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Toni M Antalis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $353,419
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10204893

## Citation

> US National Institutes of Health, RePORTER application 10204893, Protease activated receptor-2 (PAR-2) signaling and metastatic ovarian cancer (5R01CA196988-05). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10204893. Licensed CC0.

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