New findings published in Cancer Cell, a leading scientific journal

October 14, 2016 – A research team supported in part by SU2C has published findings that show how we may be able to kill cancerous cells more effectively by combining drugs that work together to significantly disrupt a cancer cell’s ability to survive DNA damage. These findings are the first to show this combination drug therapy as a novel approach for treating acute myeloid leukemia (AML) and potentially, many other cancers.

Why It’s Important

AML is a type of blood cancer characterized by the rapid growth of abnormal white blood cells. It is typically treated with chemotherapy and in some cases followed by a stem cell transplant. For patients who do not respond to chemotherapy, a group of compounds called DNA methyltransferase inhibitors (DNMTi) are frequently used. DNMTi block DNA methylation, a process that controls a cell’s DNA, acting as an “on” or “off” switch for genes that affect cancer cell growth.

Another target in cancerous cells is an enzyme called poly-ADP-ribose polymerase (PARP). This enzyme is very important to repair DNA damage, which is crucial for cell survival. By targeting PARP with PARP inhibitors (PARPi), we can block the activity of the enzyme and kill cancerous cells effectively. PARPi are primarily used to treat tumors that have known defects in BRCA genes, such as in breast or ovarian cancers, but they also are showing promise in other cancers.

The research team found that in addition to blocking PARP, PARPi also cause PARP to become trapped in the cancer cells’ DNA. This observation was greatly enhanced when they added DMNTi. Together, the two types of inhibitors lead to massive DNA damage that couldn’t be repaired (more so than when either inhibitor was used alone), causing cancer cells to self-destruct.
Feyruz V. Rassool, PhD, associate professor of radiation oncology at the University of Maryland School of Medicine, a researcher at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, and an investigator on the Van Andel Research Institute (VARI)-SU2C Cancer Epigenetics Dream Team, is the senior author of the Cancer Cell paper. Cancer Cell, published by Cell Press, covers all aspect of cancer research at the cellular level.

Stephen B. Baylin, MD, Virginia and D.K. Ludwig professor for cancer research, professor of oncology and medicine at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, is co-senior author of the paper. Baylin is co-leader of the VARI- SU2C Cancer Epigenetics Dream Team, along with Peter A. Jones, PhD, DSc, VARI chief scientific officer.
“Our preclinical data in AML cell lines, primary cells, and mouse models suggest the potential for enhancing the clinical effects of both DNA methyltransferase inhibitors and PARP inhibitors by combining low doses of both drugs to treat patients with AML,” Rassool said. A clinical trial has been

planned to test whether low doses of a DNMTi and a PARPi, talazoparib, can be safely combined and whether this therapy shows efficacy for AML patients, Rassool added. The trial is expected to open soon at the Greenebaum Comprehensive Cancer Center and several other sites.

SU2C’s Impact:

SU2C has supported cancer epigenetics research since the first Dream Teams were established in 2009. The epigenetic team’s research has contributed greatly to the understanding of how processes within the cell can be used to attack cancer. The team’s work continues under the SU2C umbrella through VARI in Grand Rapids, Michigan. The research described above was supported by SU2C’s inaugural Laura Ziskin Prize in Translational Research – a $250,000 grant awarded to Rassool and Baylin in 2012—and by the VARI-SU2C Cancer Epigenetics Dream Team.

For Further Reading

http://www.cell.com/cancer-cell/fulltext/S1535-61081630437-8

Muvarak et al., Enhancing the Cytotoxic Effects of PARP Inhibitors by DNA Demethylating Agents – A
Potential Therapy for Cancer, Cancer Cell, Volume 30, Issue 4, 637-650

AACR Oct. 13, 2016