Cancer and heart disease: Shared disease mechanisms involving growth and inflammation
Jonathan D. Brown, M.D., Discovery Grant 2017
Sustained cell growth and altered inflammation are hallmarks of cancer. Drugs that disrupt growth and inflammation can halt disease progression or cure multiple types of cancer. Notably, these pathways of growth and inflammation turn genes on and off. As a result, drugs that selectively turn genes off can alter inflammation, tumor growth and death. However, these drugs may also affect tissues beyond the tumor. As such, a major knowledge gap exists in clinical medicine: namely, understanding the impact of drugs that turn genes off in non-cancer diseases that are characterized by increased inflammation and excessive cell growth such as heart disease.
Atherosclerosis—a form of heart disease caused by accumulation of cholesterol-laden white blood cells in arteries—remains the most common cause of death worldwide. Recently, it has been proposed that atherosclerosis shares fundamental biological properties with cancer. Specifically, cholesterol-laden white blood cells (and other types of cells) that cause atherosclerosis grow within the vessel wall, akin to tumor cells. This proliferation can increase atherosclerotic lesion size and instability, which are two features associated with more severe patient illness. In addition, cancer-associated mutations can affect white blood cells and increase an individual’s risk for both blood cancers and atherosclerosis. Finally, many risk factors for heart disease can cause inflammation and worsen this disease. Collectively, these observations reveal potential shared mechanisms between cancer and atherosclerosis involving abnormal cell growth and inflammation. Furthermore, these observations raise the possibility that cancer therapies targeting cell growth and inflammation may have therapeutic benefit in heart disease. Despite these intriguing connections between these two diseases, this concept remains untested.
CDK7 inhibition: A shared solution to cancer and heart disease?
We have tested the effect of a novel drug (THZ1) that blocks CDK7, an enzyme in tumor cells that enables them to grow. Preliminary data from the Brown Laboratory demonstrate that inhibition of CDK7 markedly reduces inflammation in macrophages—the primary cell in the blood vessel wall that causes atherosclerosis. We also identify that THZ1 significantly reduces atherosclerosis in an animal model. These preliminary data inform the central hypothesis of this VICC Discovery Grant: pathways involved in growth and inflammation in cancer also play a critical role in atherosclerosis. To test this hypothesis directly in this VICC Discovery Grant, we will focus on CDK7 as an example of a pathway that contributes to cancer and heart disease. We will use gain- and loss-of-function approaches to study how CDK7 controls proliferation and inflammation in cell and animal models of atherosclerosis.
Outcomes of this completed proposal
In the short-term, this specific project will demonstrate how a novel inhibitor of inflammation and cell proliferation can alter atherosclerosis. More importantly, over the long-term this work will provide new insights concerning how cancer and heart disease may arise by shared mechanisms and thus may lead to new insights concerning shared therapeutic strategies for these two deadly diseases.
