# Experimental Therapeutics by targeting Spleen Tyrosine Kinase

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $375,163

## Abstract

In this study we investigate the translational potential of targeting Spleen Tyrosine Kinase (SYK) as a new
regimen in developmental therapeutics in ovarian cancer. Ovarian cancer is one of the most aggressive types
of women cancer and an effective therapy is an unmet need to improve the clinical outcome in patients at
advanced stages. Our recent study demonstrates that ovarian cancer cells surviving paclitaxel treatment have
higher levels of activated SYK. Inactivating SYK using gene knockdown, knockout and small compound
inhibitors can re-sensitize resistant cells to paclitaxel by enhancing microtubule stability. This effect is
presumably due to SYK inhibitor mediated de-phosphorylation of microtubule-associated proteins (MAPs), a
mechanism distinct from paclitaxel-induced microtubule stability (binding the β-tubulin). The above result
indicates a potential use for combining paclitaxel and SYK inhibitors that have been tested in late-phase
clinical trials (in autoimmune diseases and hematopoietic malignancies) in enhancing paclitaxel cytotoxicity.
Our recent unpublished studies further suggest that SYK inhibition alone can also harness cancer cells by
inhibiting their motility and invasion. Phospho-proteomic analyses in ovarian cancer cells demonstrate that in
addition to the MAPs recently reported by us, actin-associated proteins, cortactin and cofilin, and survival
signaling molecules, EGFR, ErbB2 and STAT3, are also substrates of SYK. Inactivation of these pathways
may protect cells from chemotherapy-induced cell death. Thus, targeting the SYK pathway using SYK inhibitor
represents an innovative strategy to sensitize tumors to paclitaxel and inhibit tumor spreading. To test the
hypotheses, we proposed the following Aims.
Aim 1: Elucidate the mechanisms behind how SYK mediates paclitaxel resistance.
Aim 2: Determine whether inactivating SYK signaling in ovarian cancer cells reduces cell migration and
invasion via altering cytoskeletal dynamics.
Aim 3: Evaluate the efficacy of SYK inhibitor and paclitaxel combination in patient-derived xenograft (PDX)
models and identify predictive markers.
Our data will provide the critical pre-clinical data to support future clinical trials to determine whether the
clinically available SYK inhibitors can improve clinical outcome in ovarian cancer patients either as a drug to
sensitize paclitaxel or as a monotherapy to delay disease recurrence. The results of this study will have an
impact on the timely translation of our bench discoveries to the clinic, and will renew our hope for better patient
outcome by augmenting conventional chemotherapy.

## Key facts

- **NIH application ID:** 9873935
- **Project number:** 5R01CA215483-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** IE-MING SHIH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,163
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873935

## Citation

> US National Institutes of Health, RePORTER application 9873935, Experimental Therapeutics by targeting Spleen Tyrosine Kinase (5R01CA215483-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873935. Licensed CC0.

---

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