Targeting adaptive changes to anti-VEGF therapy in ovarian cancer
Final Report Abstract
Ovarian cancer is the most deadly gynecologic malignancy with 5 year survival rates ranging from 45% for all stages combined to 27% for those with advanced stage disease (III or IV). The standard of care remains primary tumor reductive surgery followed by adjuvant platinum- and taxane-based chemotherapy, however, the recurrence rate is approximately 80% even for patients who respond to initial treatment. Treatment of recurrent ovarian cancer is complex and can vary based on patient and tumor specific characteristics. One important treatment option is the use of the anti-VEGF monoclonal antibody, bevacizumab, in combination with chemotherapy. Considering the proven efficacy of bevacizumab therapy in ovarian cancer, our laboratory sought to determine the mechanisms leading to anti-VEGF treatment resistance. This is especially important considering the proportion of ovarian cancer patients with recurrence who have been previously treated with bevacizumab will accelerate over the next few years given the likely FDA approval for its use in the upfront setting. To emulate the response seen in humans, we established a metastasis mouse model of ovarian cancer that develop adaptive resistance to the anti-VEGF antibody B20, which targets both mouse and human VEGF. We found that genomic profiles of tumors collected after one or several exposure to treatment revealed enrichment in TGF beta pathway after several exposure to treatment. This finding was particularly intriguing as TGF beta pathway is known to be related with neo-angiogenesis and immunosuppression, findings that were shown in our in vivo study. So the strategy of combining two agents, one for neutralizing the VEGF ligand and a TGFbeta inhibitor, might have the potential to overcome resistance to bevacizumab and revolutionize the treatment of ovarian cancer. All the data presented in this report is confidential. My second project investigated the role of exosome in emerging of adaptive resistance. Interesting observations regarding characteristics of endothelial cell derived exosomes, suggest that anti-VEGF resistant endothelial cell derived exosomes might be a mechanism leading to adaptive resistance. If this is the case, exosomes could be used as biomarkers in order to evaluate the anti-VEGF therapy efficacy, since there are no other available biomarkers to assess the response to therapy. Several in vitro and in vivo experiments have been discussed to be done in order to sustain my preliminary data. Nevertheless, the mechanism of chemotherapy resistance through resistant exosome uptake is a novel concept that needs to be further investigated. One of the aims of both projects in this grant proposal was to investigate emerging of adaptive resistance. While the first project identified a possible pathway which can be targeted through available therapies, the second project focused more on mechanism of adaptive resistance which needs to be further investigated. This research fellowship was instrumental in generating an adaptive resistance mouse model and explore the potential role of exosomes in anti-VEGF therapy.
Publications
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Anti-Angiogenesis Therapy in Ovarian Cancer: Which Patient is It Most Likely to Benefit? Oncology (Williston Park). 2019 Jul 16;33(7). pii: 629378
Chelariu-Raicu A, Coleman RL, Sood AK
