Blocking Tumor-Associated Macrophages to Overcome Chemoresistance in Ovarian Cancer
Abstract
Ovarian cancer is the most lethal gynecological malignancy, with only a 45% survival rate. The poor survivability of this disease is partly due to the fact that after an initial response to treatment, most women s ovarian cancer returns. Furthermore, recurrent ovarian cancer is often resistant to chemotherapy. Overcoming this treatment resistance will be key to improving survival in patients diagnosed with ovarian cancer. We believe that one way to accomplish this will be to target the interactions between ovarian cancer cells and non-cancerous host cells present within the tumor, such as members of the immune system. An extensive body of evidence has shown that particular immune cells, M2 macrophages, support cancer progression. We hypothesize that M2 macrophages also support chemotherapy resistance by interacting with tumor-initiating cells. Tumor-initiating cells are a subset of cancer cells that have been shown to be more resistant to chemotherapy. These cells are thought to persist after treatment and regrow the tumor, causing relapse. Based on recent findings, we propose that one of the mechanisms by which tumor-initiating cells survive chemotherapy treatment is through protective interactions with M2 macrophages. With this proposal, we aim to thoroughly investigate the influence of M2 macrophages on ovarian tumor-initiating cells. To do so, we will combine the chemotherapy drug paclitaxel with a CSF1R inhibitor to block M2 macrophages. We have previously shown that CSF1R inhibition reduces M2 macrophages in a mouse model of ovarian cancer. This provided a moderate therapeutic benefit by shrinking the tumor and reducing ascites. We expect that depleting M2 macrophages from the tumor will improve response to chemotherapy, as we have seen in prostate cancer. Using three models of ovarian cancer: a mouse model, a human cell line implanted into mice, and samples of human ovarian cancer implanted into mice, we will study M2 macrophages and tumor-initiating cells during chemotherapy treatment. We will further explore how interactions between M2 macrophages and tumor-initiating cells support chemoresistance by disrupting M2 macrophages with CSF1R inhibition. We expect that combination therapy of CSF1R inhibition and paclitaxel will render the ovarian tumor-initiating cells more sensitive to chemotherapy treatment. Not only could this novel treatment improve response rates, but the elimination of the cells thought to cause relapse could improve long-term patient outcomes as well.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710160
Entities
People
- Lily Wu
Organizations
- United States Army
- University of California, Los Angeles