# "Exploring the potential of SYK inhibitors to sensitize ovarian cancer to the anti-tumor effects of paclitaxel"

> **NIH NIH P50** · JOHNS HOPKINS UNIVERSITY · 2020 · $307,924

## Abstract

PROJECT 4: SUMMARY/ ABSTRACT
The purpose of this proposal is to provide critical pre-clinical and early phase clinical evidence to determine
whether the Spleen Tyrosine Kinase (SYK) is a promising therapeutic target in ovarian cancer. We have
previously compared the proteomes of primary and recurrent/post-chemotherapy ovarian high-grade serous
carcinoma (HGSC) tissues from the same patients. Among the preferentially expressed proteins in recurrent
HGSCs, a non-receptor tyrosine kinase, SYK, was prioritized for study because small molecule inhibitors of
SYK including fostamatinib are available for pre-clinical testing and clinical trials. We were able to validate
overexpression of SYK and its active (auto)phosphorylated form in recurrent HGSC after carboplatin and
paclitaxel treatment compared to treatment naive tumors. SYK inhibition exhibited a synergistic cytotoxic effect
with paclitaxel, docetaxel, and vinorelbine, all of which target the microtubule network. Paclitaxel resistant
ovarian cancer cells exhibit higher levels of SYK expression than their carboplatin-resistant counterparts. Our
preliminary phosphoproteomic analysis revealed tubulins and several microtubule-associated proteins as SYK
substrates in ovarian cancer cells. Phosphorylation of these proteins has been shown to increase microtubule
dynamics, a process antagonizing the microtubule-stabilizing effect of paclitaxel. In a mouse tumor xenograft
model, the combination of R406 (the active form of fostamatinib) and paclitaxel significantly suppressed tumor
growth without overt signs of toxicity. Our pre-clinical studies support a novel hypothesis that SYK activity is
required for paclitaxel resistance and that SYK inhibition sensitizes HGSC to the cytotoxic effect of paclitaxel.
Therefore, SYK inhibitors represent a promising new strategy to treat ovarian cancer. To test the above
hypotheses, we propose the following Specific Aims:
Aim 1. Phase I/Ib clinical trial of combined Fostamatinib and paclitaxel in ovarian cancer.
Aim 2. Characterize the prioritized SYK substrates discovered in ovarian cancer cells.
Aim 3. Assess the efficacy of SYK-based combination therapy in mouse models..

## Key facts

- **NIH application ID:** 9975119
- **Project number:** 5P50CA228991-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** IE-MING SHIH
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $307,924
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975119

## Citation

> US National Institutes of Health, RePORTER application 9975119, "Exploring the potential of SYK inhibitors to sensitize ovarian cancer to the anti-tumor effects of paclitaxel" (5P50CA228991-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9975119. Licensed CC0.

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