Activating Innate Signaling Pathways for Breast Cancer Prevention
Abstract
Cancer can be defined as a disruption of normal developmental homeostasis where cell proliferation is no longer checked and instead, on average, proceeds indefinitely. This results in an outgrowth of cells leading to tumor formation. However, the human body is a well-tuned regulatory machine and, by using the immune system, can in most cases scavenge such out-of-control cell growth events. Nevertheless, the processes of a nascent tumor can generate a biochemical environment that results in an evasion from immune surveillance. Consequently, immune cells are kept in an anergic state (lack of reaction by the body’s defense mechanism), thus permitting the tumor to grow and metastasize. Importantly, there is experimental and clinical evidence that indicates that there is a positive correlation between the number of immune cells within the tumor and disease-free survival, i.e., the greater the number of activated immune cells the better is the prognosis. So what can be done to activate these immune cells to attack and kill the tumor cells? A defining paradigm in immune-oncology is that if one can alter the biochemical environment surrounding the tumor cells in a manner that overrides the anergic state, then a productive immune response to effectively kill the tumor cells can be achieved. To do this, tumor cells have to be forced to produce signals that are immunoactivators rather than immunosuppressants. One such mechanism is to be attack the powerhouse, i.e., mitochondria, of the cancer cells. If the functions of the mitochondria can be disrupted to produce cancer cell death then immunogenic signals will be generated that will activate an immune response and prevent not only the tumor growth but also generate an “in situ” vaccine analogous to the processes involved with an immune response against infection. Collectively, our research will address three overarching challenges: (1) prevent breast cancer, (2) identify determinants of breast cancer initiation, risk or susceptibility, and (3) identify what drives breast cancer growth and determine how to halt it. In this regard, we have a small molecule that abrogates the function of a protein called DDX3 that is essential for mitochondrial activity. Also, we have evidence to show that by attacking the tumor cell mitochondria, we are able to activate the synthesis of pro-immune response signals that are essential to remove the anergic state of the immune cells. Our proposal is to expand on this strong preliminary finding to demonstrate that perturbing DDX3 in breast cancer cells will activate the innate immune system to prevent new tumor formation as well as curtail the development of metastatic breast cancers. The ultimate goal is to rev up the immune response to breast cancer as a frontline personalized therapy to prevent breast cancer progression and metastasis. Importantly, as we have already carried out extensive work with the small molecule inhibitor of DDX3, the clinical translatability to achieve a patient-related outcome will be within the next 3 to 5 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810483
Entities
People
- Venu Raman
Organizations
- Johns Hopkins University
- United States Army