Immunomodulation by small molecules for prevention or treatment of cancer

Summary

Cancer is the second leading cause of deaths worldwide. Lung cancer and breast cancer, specifically, are two of the most common cancers in the U.S. except skin cancer. With the increasing medical and economic burden of these diseases, developing effective cancer prevention and treatment strategies is important and urgent. Cancer is characterized by uncontrolled cell proliferation. Targeting the tumor cells directly to inhibit their growth and increase cell death has been the major focus of... Show moreCancer is the second leading cause of deaths worldwide. Lung cancer and breast cancer, specifically, are two of the most common cancers in the U.S. except skin cancer. With the increasing medical and economic burden of these diseases, developing effective cancer prevention and treatment strategies is important and urgent. Cancer is characterized by uncontrolled cell proliferation. Targeting the tumor cells directly to inhibit their growth and increase cell death has been the major focus of cancer treatment since the last century. Cancer is also described as a wound that does not heal. Inflammation plays critical roles in cancer development and progression. The immune system is a powerful host defense mechanism against infections and diseases including cancer. However, tumor cells are able to edit and suppress the immune system to evade the immune attack. Targeting immune cells to unleash the power of immune surveillance has become a research priority. The recent breakthroughs in cancer immunotherapy have revolutionized the landscape of cancer treatment. As immunotherapy becomes the first line of therapy in cancer treatment, it is essential to understand how other drugs modulate the immune system, so that we can deliver more effective and less toxic combinations. In this thesis project, I focused on four therapeutic targets (bromodomain proteins, retinoid X receptors, Nrf2 transcription factors, poly (ADP-ribose) polymerase) and explored their effects on the immune cells. Small molecules targeting these proteins were tested in various preclinical mouse models in the context of either cancer prevention or treatment. My studies not only demonstrated enhanced efficacy and reduced toxicity with all four classes of compounds but also provided some novel insights into the immunomodulatory effects of these clinically relevant signaling pathways. This work is highly translational and could have direct impact on human patients. Show less