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EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer
Robiya Joseph1, Santosh K Dasari1, Sujanitha Umamaheswaran1,2
1Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy. To discover potential synergistic partners for EphA2-targeted drugs, we performed a high-throughput drug screen and identified panobinostat, a histone deacetylase inhibitor, as a candidate. We hypothesized that combination therapy with an EphA2 inhibitor and panobinostat leads to synergistic cell death. Indeed, we found that the combination enhanced DNA damage, increased apoptosis, and decreased clonogenic survival in Ishikawa and Hec1A endometrial cancer cells and significantly reduced tumor burden in mouse models of endometrial carcinoma. Upon RNA sequencing, the combination was associated with downregulation of cell survival pathways, including senescence, cyclins, and cell cycle regulators. The Axl-PI3K-Akt-mTOR pathway was also decreased by combination therapy. Together, our results highlight EphA2 and histone deacetylase as promising therapeutic targets for endometrial cancer.
Insights
Combining an EphA2 inhibitor with panobinostat, a histone deacetylase inhibitor, shows promise for treating endometrial cancer by enhancing cell death and reducing tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Endometrial cancer is the most common female reproductive malignancy with limited effective treatments.
- EphA2 receptor tyrosine kinase is overexpressed in endometrial cancer, correlating with poor outcomes.
- EphA2-targeted therapies show modest efficacy in preclinical models.
Purpose of the Study:
- To identify synergistic partners for EphA2-targeted drugs in endometrial cancer.
- To investigate the efficacy of combining an EphA2 inhibitor with panobinostat.
Main Methods:
- High-throughput drug screening to identify synergistic compounds.
- In vitro studies using endometrial cancer cell lines (Ishikawa, Hec1A).
- In vivo studies using mouse models of endometrial carcinoma.
- RNA sequencing to analyze pathway alterations.
Main Results:
- Combination therapy of EphA2 inhibitor and panobinostat demonstrated synergistic cell death.
- Enhanced DNA damage, increased apoptosis, and decreased clonogenic survival were observed.
- Significant reduction in tumor burden in mouse models.
- Downregulation of cell survival pathways, including senescence, cyclins, cell cycle regulators, and the Axl-PI3K-Akt-mTOR pathway.
Conclusions:
- Combination therapy targeting EphA2 and histone deacetylase is a promising strategy for endometrial cancer.
- This approach offers a potential new therapeutic avenue for this prevalent malignancy.
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