While it is now well established that cancer is a consequence of genetic alterations, it is becoming increasingly clear that disruption of epigenetic mechanisms is also a hallmark of the disease. Those epigenetic mechanisms help control the expression of genes – whether they are turned on or off – without affecting the DNA sequence itself. Thus, whether a cell becomes cancerous depends not only on its genome (whether or not key genes are mutated), but also its epigenome (whether or not these genes are expressed appropriately). These epigenomes, as they are known, have become the focus of a rapidly emerging and important new area of cancer research.
Inappropriate epigenetic activity plays a significant role in cancer development but, unlike DNA mutations, which are permanent, epigenetic changes can be reversed. This means that it may be possible to find a way to regulate inappropriate epigenetic activity or to get a gene that is inappropriately expressed due to epigenetic changes to begin functioning normally again. The overarching goal of this Dream Team Project is to bring the promise of epigenetic therapy to clinical practice.
The team is using a combination of two drugs (a DNA-demethylating agent, and a histone deacetylase inhibitor) to reverse the epigenetic modifications that inappropriately turned genes on or off in cancer cells. Their approach is to use low doses of these drugs to prevent unwanted side effects to the patient. In addition, the team is also testing a new generation of the DNA-demethylating drug that they hope will be more effective.
Specific Research Goals:
- Develop biomarkers that can predict and monitor the efficacy of cancer epigenetic therapies;
- Self-renewing cancer cells, often called cancer stem cells are of great interest to researchers; they often remain unaffected by currently available drugs. Many scientists believe that it is essential to develop new therapies that target these cancer stem cells in order to improve the long-term outcomes of cancer treatment. The team will build on intriguing preliminary data suggesting that reversal of gene "silencing" leads to a loss of cancer stem cells.
- Develop a clinical trial that utilizes a new second generation epigenetic drug that may be able to more effectively inhibit the epigenetic changes involved in cancer causation.
This SU2C Dream Team has tested a combination of epigenetic drugs in clinical trials and saw tumors shrink in a group of patients with non-small cell lung cancer, who had previously been treated, unsuccessfully, with three different chemotherapy regimens. More importantly, the team made the intriguing observation that multiple patients who were required to stop therapy after only two to four cycles have long survival periods and several are alive years after completion of these courses. These finding suggest that very short courses of the two epigenetic drugs used may have a lasting effect, and “prime” cancer cells to better respond to subsequent therapies such as cytotoxic chemotherapy, or immunotherapy. The Dream Team also reported success in a clinical trial testing a new generation of epigenetic drug in patients with leukemia, which prompted them to explore the possibility of conducting additional trials in solid tumors. The Dream Team is currently conducting clinical trials in breast, colon and lung cancers as well leukemia.
Steven A. Belinsky, PhD, director, Lung Cancer Program, Lovelace Respiratory Research Institute
Nancy E. Davidson, MD, director, University of Pittsburgh Cancer Institute and UPMC Cancer Centers
Jean-Pierre Issa, MD, director, Fels Institute for Cancer Research and Molecular Biology, Temple University