Have you ever wondered why there is no “cure” for cancer? Conspiracy theories aside, a cure for cancer doesn’t exist because it is biologically impossible. The reason is simple: just as no two people are identical, no two cancers are the same. Each case of cancer may be genetically distinct, which means that the driver mutations that caused the cancer can differ from patient to patient. For this reason, different treatments are required for each type of cancer, making it unfeasible to think that there will someday be a “one-size-fits-all” cure for cancer.
Given such diversity among cancers, what is the best strategy for scientists to target specific driver mutations? Treatments that are tailored to a specific mutational subtype of a disease are called precision medicines. Precision medicines are designed with consideration of a patient’s genetics, lifestyle, and environment in order to more effectively treat individual cancer cases. In 2016, President Obama launched a $215 million Precision Medicine Initiative to fund advances in this area.
In order to develop precision medicines, scientists need an understanding of cancer genomics and cancer biology, but they also need to understand normal human biology. A critical first step in precision medicine development is identifying molecular targets, usually proteins, that can be inhibited to reduce features of cancer without harming non-cancerous cells.
In the Hollenhorst Lab here at IU, we study a specific subset of prostate cancer that is characterized by the abnormal presence of a protein called ERG. ERG is a protein that alters the expression of genes and is part of a large protein family that includes other cancer associated proteins. For example, a closely related protein called FLI1 is involved in Ewing’s sarcoma, a rare childhood cancer. Approximately 85% of Ewing’s sarcoma cases are driven by a mutation that fuses FLI1 to a non-related protein called EWS, forming a Frankenstein-like protein termed EWS-FLI1.
ERG-positive prostate cancer represents the largest subset of prostate cancer cases, accounting for more than 50% of cases. According to the National Institutes of Health, approximately 1.4 million men were living with ERG-positive prostate cancer as of 2013. Because there are currently no ERG targeting precision medicines, men with ERG-positive prostate cancer generally undergo prostatectomy (removal of the prostate), castration, and/or chemotherapy. These treatments are very invasive and take a large physical and psychological toll on the body.
It was clear that we needed a better understanding of the mechanism by which ERG transforms normal cells into cancerous cells, so that we could identify a molecular target for precision medicine development. In our recently published paper, we identified a surprising connection between ERG positive prostate cancer and Ewing’s sarcoma. This was striking because prostate cancer mainly affects men over the age of 50, while Ewing’s sarcoma occurs primarily in adolescent males.
We found that EWS (the protein fused to FLI1 in Ewing’s sarcoma) is a crucial interacting partner of ERG. The interaction between ERG and EWS is required for many features of prostate cancer, including tumor formation. This newly discovered molecular target will help us develop precision medicines that could help the many men affected by this subset of prostate cancer.
Kedage, V., N. Selvaraj, T. R. Nicholas, J. A. Budka, J. P. Plotnik, T. J. Jerde, and P. C. Hollenhorst. 2016. “An Interaction with Ewing’s Sarcoma Breakpoint Protein EWS Defines a Specific Oncogenic Mechanism of ETS Factors Rearranged in Prostate Cancer.” Cell Rep 17 (5):1289-1301. doi: 10.1016/j.celrep.2016.10.001.
“SEER Stat Fact Sheets: Prostate Cancer.” Surveillance, Epidemiology, and End Results Program. Accessed November 30, 2016. http://seer.cancer.gov/statfacts/html/prost.html.