Targeting Tumor Innervation for the Treatment of Ovarian Cancer
Abstract
One of the main challenges currently faced in ovarian cancer treatment is the fact that the primary therapy used to treat patients (platinum/taxane chemotherapy) is ineffective at meaningfully extending survival. The overall survival for ovarian cancer patients with advanced disease is less than 30%. This is due to the fact that the majority of patients develop resistant disease and recur within 5 years of initial therapy. Once resistant disease develops, there are very few second-line therapy options for patients to fall back on, which inevitably leads to disease progression. Thus, there is a critical need to identify new therapies that can overcome ovarian cancer chemoresistance and actually produce meaningful increases in patient survival. In recent years, new efforts have focused on targeting the tumor microenvironment (TME), the complex mixture of non-cancer cells that surrounds and supports the cancer cells within the tumor and promotes cancer progression and metastasis. Different strategies have evolved to target the TME—for example, activating immune cells within the tumor to attack and kill cancer cells or cutting off the tumor blood supply via angiogenesis inhibitors. However, these TME targeting therapies have limited effect when used to treat ovarian cancer patients. The majority of ovarian tumors have a microenvironment that is highly immunosuppressive (limiting the cytotoxic impact of immunotherapies) and do not respond or are resistant to angiogenesis inhibitors. Thus, new TME-targeting therapies must be developed that can (1) actually induce a therapeutic effect in ovarian tumors and (2) be used to treat the majority of ovarian cancer patients. One novel TME component that is ripe for therapeutic targeting (and has yet to be investigated in ovarian cancer) are the nerve fibers that infiltrate tumors in a process termed tumor innervation. Recent studies in several types of cancer have shown that tumor innervation has a direct impact on cancer progression and can promote tumor growth/metastasis. Importantly, ablation of tumor innervation decreases in vivo tumor growth and metastasis in mouse models. However, in ovarian cancer research, there is a gap in knowledge where the role of innervation in promoting cancer progression remains undefined. This application describes our aim to determine whether tumor innervation plays a significant role in driving ovarian cancer growth and metastasis. Our preliminary data show that sensory nerve fiber innervation in patient samples is much higher in ovarian tumors vs. normal tissue. In addition, the level of tumor innervation further increases between chemosensitive and chemoresistant tumors. We have also identified that exosomes secreted from ovarian cancer cells are likely the signaling vector that promotes tumor innervation. Using mouse tumor cell lines, we will conduct in vivo tumor formation experiments that will determine (1) the impact tumor innervation has on ovarian cancer growth and metastasis, (2) whether exosomes secreted from ovarian cancer cells are necessary to promote tumor innervation, and (3) whether BRCA1/2 mutation status has any effect on tumor innervation phenotypes. We will also profile the protein cargo in a panel of samples (derived from both murine and human sources), comparing the cargo of exosomes secreted from normal fallopian/ovarian epithelial cells vs. ovarian cancer cells. This will allow us to identify the key neurotrophic factors that mediate ovarian tumor innervation. These profiling experiments will serve as the foundation for future efforts to therapeutically target tumor innervation in ovarian cancer by identifying the key signaling pathways and molecular factors that drive innervation. Our proposed studies will provide a very high return on the invested effort, as they will cause a paradigm shift in how ovarian cancer is treated by opening up tumor innervation as a new area for therapeutic targeting (for example
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110643
Entities
People
- Matthew Knarr
Organizations
- United States Army
- University of Pennsylvania