Abstract 2018: Elucidating the therapeutic potential of midbrain pathways that impact breast cancer

Abstract

Abstract Most chemotherapeutic agents for breast cancer have variable efficacy and produce unwanted side effects. While much focus is placed on dissecting the molecular mechanisms contributing to tumor development, the potential role of the brain in regulating tumor progression has not been described in detail. Previous evidence has shown that midbrain activity affects tumor growth and progression. Stimulation of the midbrain periaqueductal grey (PAG) increases metastasis in rats injected with Walker-256 carcinosarcoma cells, and the growth of prolactin-dependent mammary tumors. These findings suggest midbrain pathways play a prominent role in tumorigenesis. These studies, however, did not address the therapeutic potential of blocking PAG output for slowing tumor progression. Therefore, we are studying the mechanisms regulating midbrain-induced tumorigenesis and the therapeutic potential of altering midbrain activity to reduce metastatic activity and tumor growth. A common challenge in neuroscience has been identifying and manipulating specific neuronal populations in the brain. However, significant advances have been made in the field of optogenetics, the integration of optics and genetics, which allows precise control of specific neural pathways in vivo using light. Optogenetics is gaining considerable clinical interest as a novel strategy for treating human neurological disorders due to success observed in rodent and non-primate human models. Therefore, optogenetic alteration of PAG activity for treating breast cancer is plausible. Non-pharmacological, therapeutic strategies aimed at manipulating circuit activity to treat mood and anxiety disorders are already creating enthusiasm. Given that many of these strategies likely impact PAG activity, there is great potential for manipulating the same pathways to treat breast cancer. Before these types of novel strategies can be implemented, we must first delineate the biology of these circuits and their therapeutic potential in animal models of cancer. Thus far, we have identified that muscimol inhibition of PAG activity decreases breast cancer progression in a transgenic mouse model. We are continuing to investigate the distinct input/output mechanisms of the PAG that could be modified to treat breast cancer. Future studies have the potential to reveal novel avenues for targeting and preventing the development of breast cancer via the manipulability of specific neural pathways. Note: This abstract was not presented at the meeting. Citation Format: Madeline Chandra, John Lee, Patrick L. Sheets, Jenifer R. Prosperi. Elucidating the therapeutic potential of midbrain pathways that impact breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2018. doi:10.1158/1538-7445.AM2015-2018