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Yasmin A Lyons1, Sunila Pradeep1, Sherry Y Wu1
1Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
Anti-angiogenesis therapy has shown clinical benefit in patients with high-grade serous ovarian cancer (HGSC), but adaptive resistance rapidly emerges. Thus, approaches to overcome such resistance are needed. We developed the setting of adaptive resistance to anti-VEGF therapy, and performed a series of in vivo experiments in both immune competent and nude mouse models. Given the pro-angiogenic properties of tumor-associated macrophages (TAMs) and the dominant role of CSF1R in macrophage function, we added CSF1R inhibitors following emergence of adaptive resistance to anti-VEGF antibody. Mice treated with a CSF1R inhibitor (AC708) after anti-VEGF antibody resistance had little to no measurable tumor burden upon completion of the experiment while those that did not receive a CSF1R inhibitor still had abundant tumor. To mimic clinically used regimens, mice were also treated with anti-VEGF antibody and paclitaxel until resistance emerged, and then a CSF1R inhibitor was added. The addition of a CSF1R inhibitor restored response to anti-angiogenesis therapy, resulting in 83% lower tumor burden compared to treatment with anti-VEGF antibody and paclitaxel alone. Collectively, our data demonstrate that the addition of a CSF1R inhibitor to anti-VEGF therapy and taxane chemotherapy results in robust anti-tumor effects.
Insights
Combining CSF1R inhibitors with anti-VEGF therapy overcomes adaptive resistance in high-grade serous ovarian cancer (HGSC). This novel approach significantly reduces tumor burden, offering new hope for HGSC patients.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Anti-angiogenesis therapy, specifically targeting VEGF, offers clinical benefits for high-grade serous ovarian cancer (HGSC).
- Adaptive resistance to anti-VEGF therapy is a significant clinical challenge, necessitating novel therapeutic strategies.
- Tumor-associated macrophages (TAMs), crucial for angiogenesis, are regulated by CSF1R.
Purpose of the Study:
- To investigate the efficacy of combining CSF1R inhibitors with anti-VEGF therapy in overcoming adaptive resistance in HGSC.
- To evaluate the impact of CSF1R inhibition on tumor growth in mouse models resistant to anti-VEGF therapy.
Main Methods:
- Developed adaptive resistance models to anti-VEGF therapy in immune competent and nude mice.
- Administered CSF1R inhibitor (AC708) following the emergence of resistance to anti-VEGF antibody.
- Tested a combination regimen of anti-VEGF antibody, paclitaxel, and a CSF1R inhibitor in a clinically relevant setting.
Main Results:
- Treatment with a CSF1R inhibitor post-anti-VEGF resistance led to minimal measurable tumor burden.
- The addition of a CSF1R inhibitor to anti-VEGF antibody and paclitaxel restored therapeutic response.
- This combination therapy resulted in an 83% reduction in tumor burden compared to anti-VEGF and paclitaxel alone.
Conclusions:
- Combining CSF1R inhibitors with anti-VEGF therapy effectively overcomes adaptive resistance in HGSC.
- This combination strategy demonstrates robust anti-tumor effects and warrants further clinical investigation.
- Targeting TAMs via CSF1R inhibition presents a promising approach to enhance anti-angiogenesis therapy in ovarian cancer.
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