Issue No. 2
Recruiting World Class Physicians
One of the hallmarks of Johns Hopkins is its ability to attract the best and the brightest. Three recent recruits to the breast cancer program—Roisin Connolly, Joshua Lauring, and Dipali Sharma— are representative of our strength in translational medicine. From innovative laboratory research to new
therapies for patients, these talented investigators are working to transfer discoveries about the biology of breast cancer to new, potentially more effective targeted therapies for patients.
Roisin Connolly, M.B., BCh, B.A.O., M.R.C.P.I., is leading a clinical trial for advanced stage breast cancer patients. Tapping into the promising field of epigenetics (alterations to genes that occur without mutating them), Connolly and colleagues are testing a new, two-drug approach based on research conducted in labs for the Breast Cancer Program at Johns Hopkins.
The approach involves two agents—5-azacitidine (5-aza) and an HDAC inhibitor entinostat. In cancer, investigators have found that critical tumor suppressor genes are frequently silenced by a chemical process known as hypermethylation.
The drug 5-aza was shown to reverse methylation and reactivate tumor suppressor genes. This research also revealed other epigenetic changes involving proteins known as histones that work in concert with abnormal methylation to support cancer cell growth. Histones play a key role in compressing DNA to fit
inside cells and provide a mechanism for controlling gene expression and copying DNA as cells divide. When cell DNA is over methylated, the investigators found that histones compress the DNA more tightly further interfering with tumor suppressor genes and keeping them in a constant state of non-expression. In the laboratory, when investigators used drugs, such as 5-aza, in conjunction with a histone-blocking HDAC inhibitor, some tumor suppressor gene function was restored. Silenced estrogen receptor proteins also regained expression, causing breast cancer cells that were resistant to
hormonal therapy to respond to treatment.
Now, Connolly and team are moving these findings to the clinic. The new breast cancer treatment combines the demethylating agent 5-aza with an HDAC inhibitor entinostat to target both abnormal methylation of genes and the alterations to DNA packaging that help give cancer cells their edge. Josh Lauring, M.D., Ph.D., and colleagues are building upon the pioneering cancer genetics research completed at the Kimmel Cancer Center that revealed the unique genetic blueprint of breast cancer. He is studying mutant genes and chromosomes in human breast cancer cells and cell lines to better understand how the alterations foster abnormal cell growth and the aggressiveness of tumors. These cell lines will serve as model systems to study drugs or other interventions for their ability to selectively inhibit the growth of breast cancers containing that specific mutant gene. Lauring and team are currently studying a number of altered genes related to the most common type of breast cancer, known as ER-positive or hormone receptor positive breast cancer.
This important research is helping to determine if these mutant genes contribute to sensitivity or resistance to widely used hormonal therapies, such as tamoxifen. He also has identified mutant genesto which certain types of cancer cells become “addicted;” that is, the tumor’s growth and survival is directly tied to these mutant genes. In some cases, these mutant genes are abnormally active and can be successfully targeted with therapy. A well-known example of this in breast cancer is the Her-2 gene. Her-2 is overexpressed in about 15 percent of breast cancers and found to play an important role in the progression of the cancer. As a result, a number of active drugs targeting the Her-2 protein have been developed and have dramatically improved survival for this type of breast cancer. Lauring is hoping to uncover other targets that may have similar potential for extending
Dipali Sharma, Ph.D., is pursuing a natural approach to hold breast cancer cells in check and keep them from spreading to distant sites in the body. The compound, derived from the magnolia plant species, is widely known for its potential in treating inflammation and blood clots, and, now possibly cancer. In
animal models, the compound activated tumor suppressor cells, and more importantly, blocked migration and invasion of breast cancer cells.
Sharma also is looking at the changes to proteins secreted by fat tissue, and particularly higher levels of the hormone leptin, are believed to play a major role in the growth and spread of breast cancer cells. However, the mechanisms of this biology are currently not well understood. Sharma and team have uncovered evidence that leptin is involved in a transformation of breast cancer cells that promotes cancer spread. They uncovered interactions between leptin, the MTA1 gene (metastasis-associated protein), and the Wnt pathway. Wnt is a common cell signaling pathway closely associated with breast cancer and proteins that are known to promote cancer cell growth. In laboratory models, Sharma and colleagues found that targeting the Wnt pathway with a drug that blocks these growthpromoting proteins also inhibits leptininitiated activity that leads to cancer cell growth and spread. This new understanding provides important clues about new ways to manage breast cancer and prevent the deadly spread of the disease.