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Targeting Macrophages in the Cancer Stem Cell Niche to Beat Chemoresistance

Institution: University of California, Los Angeles
Investigator(s): Allison Sharrow, Ph.D.
Award Cycle: 2018 (Cycle 27) Grant #: 27FT-0023 Award: $222,407
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract

Recent evidence supports the existence of a small population of cancer cells that are distinct from the rest of the tumor cells.  This subset of cancer cells has characteristics of stem cells that enable them to survive chemotherapy treatment.  These cells (termed “cancer stem cells”) are thought to remain in patients after treatment to cause relapse, metastasis, and ultimately death.  In addition to cancer stem cells, particular immune cells called M2 macrophages play a crucial role in cancer progression and may contribute to chemotherapy failure.  We propose that M2 macrophages associate with cancer stem cells to protect them from chemotherapy treatment and that drugs able to decrease M2 macrophages in the tumor may render cancer stem cells more vulnerable to chemotherapy.  Therefore, a novel treatment approach that combines blocking M2 macrophages with chemotherapy may improve our ability to successfully treat ovarian cancer.

Our project, “Targeting Macrophages in the Cancer Stem Cell Niche to Beat Chemoresistance”, will test this hypothesis by studying the effects of inhibiting M2 macrophages on chemotherapy response.  In our first Aim, we will treat the cells extracted from patient ascites samples with the macrophage inhibitor GW2580 to measure the effects of treatment on M2 macrophages.  We expect to see a decrease in these immunosuppressive cells, allowing a shift in the environment to one that supports tumor killing.  Our second Aim will better determine the effect of these M2 macrophages on ovarian cancer stem cells by measuring the properties of ovarian cancer stem cells when they are cultured together with M2 macrophages.  Of note, we predict that M2 macrophages will enhance the ability of ovarian cancer stem cells to survive chemotherapy treatment.  Finally, in Aim 3, we will test our hypothesis in animal tumor models.  Using two mouse models of ovarian cancer, we will first measure the effects of the chemotherapy drug paclitaxel on cancer stem cells and M2 macrophages.  We propose that chemotherapy will cause cancer stem cells to recruit M2 macrophages to the tumor.  Once there, they will associate with cancer stem cells and further protect them from chemotherapy treatment.  We will then test if disrupting this interaction renders cancer stem cells more vulnerable to death from chemotherapy.  We will do so by treating mice with a combination of the macrophage inhibitor GW2580 and the chemotherapy drug paclitaxel.  If our predictions are accurate, we will observe increased survival along with a reduction in tumors and ascites.  We will examine the residual tumors to confirm the effects on M2 macrophages and cancer stem cells.  If the results of our experiments support our hypothesis, then adopting this treatment strategy in patients with ovarian cancer may help to improve patient survival.