Malignant gliomas are the most commonly diagnosed tumors of the central nervous system (CNS). Despite clinical management, median time of survival after diagnosis is 12 to 15 months. Current treatment modalities are suboptimal in slowing glioma progression, creating a critical need to develop more effective therapies. Due to tumor heterogeneity, a strategy to target highly active pathways that play multiple roles in the disease progression could be of major benefit. Modulation of the immune system is also a promising strategy as innate and adaptive immunity play important roles in cancer progression. The co-receptor of VEGF-R, Neuropilin 1 (Nrp1), is responsible for amplifying pro-angiogenic signaling within the tumor microenvironment and its expression level in glioma cells correlates with the degree of malignancy. Nrp1 also amplifies signaling of additional pathways and plays a role in the behavior of innate immune cells. Macrophages and microglia, the resident macrophages of the CNS, can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenicity of the glioma-associated microglia and macrophages (GAMs), causing them to secrete factors that support the tumor's spread and growth. Some of these glioma-generated cytokines also signal via Nrp1 and its co-receptors. The objective in this proposal is to identify how Nrp1- mediated signaling pathways affect glioma progression. The central hypothesis is that gliomas suppress the immunoreactivity of GAMs via soluble factors that interact with Nrp1, and that inhibiting Nrp1-mediated signaling pathways in the GAMs will reduce tumor growth, angiogenesis, and local immunosuppression. In the first aim of this proposal glioma progression and interactions between glioma cells, GAMs, and the tumor microenvironment will be evaluated in vitro and in vivo using a mouse model in which the GAMs lack Nrp1 expression. Glioma cell proliferation and migration as well as GAM polarity, Nrp1-associated pathway activation, GAM migration, and GAM phagocytic activity will be assessed. In the second aim, Nrp1-deficient bone marrow will be transplanted into wild-type recipient mice and the glioma disease course evaluated as in Aim 1 to address whether the addition of GAMs that are resistant to having their anti-tumorigenicity suppressed by the gliomas will override the wild-type, suborned GAMs. In the third aim, mice will be administered a novel small molecule Nrp1 inhibitor and glioma progression, GAM polarization, and interactions between the GAMs and glioma cells will be evaluated as in aim 1. This research is expected to have a positive impact by evaluating Nrp1 and its downstream effectors as candidate therapeutic targets in glioma.
Malignant gliomas, the most common form of primary brain tumor, are diagnosed at a rate of 17,000 new cases per year in the United States. Despite clinical management, this disease is rapidly fatal and there is urgent need for the development of more effective therapies to slow growth of the cancer. The goal of this proposal is to define potential therapeutic targets for the treatment of glioma by investigating the effects of pharmacologic and genetic manipulation of the innate immune cells that populate the tumor microenvironment.
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