Meet the Investigator: Dr. Srinivasan Yegnasubramanian
 Regulating gene activity may allow scientists to turn on good genes and stop bad ones when it comes to controlling cancer. PCF-funded researcher, Dr. Srinivasan Yegnasubramanian, performs innovative research in the field of epigenetics, focusing on regulation of gene activity that may lead to new biomarkers and treatments.
Epigenetics is the study of gene control by mechanisms other than changes in gene sequence (genetic changes). This relatively new area of study has generated important discoveries linking gene expression to the development of cancer, and has proven to be vital to prostate cancer research. At the forefront of these complex investigations is PCF-funded researcher and Competitive Research Award recipient, Srinivasan Yegnasubramanian, MD, PhD of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.
In partnership with fellow PCF-funded researchers William Nelson, MD, PhD, and Angelo DeMarzo, MD, PhD, Dr. Yegnasubramanian and his team of skilled scientists are currently evaluating various key epigenetic changes seen in the development and progression of prostate cancer. Dr. Yegnasubramanian’s main objective is to determine whether epigenetic alterations can be used to create biomarkers for disease progression and treatment response for prostate cancer patients.
 “The collaborative environment in which I work lends itself to exciting findings in prostate cancer research,” said Dr. Yegnasubramanian. “With each of us being experts in diverse scientific disciplines, we are able to tackle this disease from many different angles.”
What is Epigenetics?
In contrast to irreversible genetic mutations, which actually change DNA code sequences, the term epigenetics refers to small variations in DNA structure that modify gene activity, without altering the actual genetic code. Epigenetic alterations in cancer cells can be compared to reading a novel out of order by skipping around its chapters. The words (i.e. genetic code) in the book remain unaffected, but the story has changed.
Epigenetic changes can inappropriately silence (turn off) or over-activate (turn on) genes through a biochemical process called methylation. Dr. Yegnasubramanian’s research has shown that prostate cancer cells epigenetically regulate genetic activity that normally would curb cancer tumor growth. Simultaneously as these epigenetic regulations fail, expressions of other genes may actually cause tumor development, a lethal combination.
“In all cells there’s a pattern of methylation that is normally present, but in cancer cells there are abnormal increases or decreases in this methylation process,” explains Dr. Yegnasubramanian.
 “When this happens, the cancer cell can escape the rules that typically govern normal cells, allowing them to survive or grow even when they have signals to stop doing so. However, the exciting thing about the epigenetic process is that it’s reversible. Ultimately what this means is that we may be able to create drugs that reverse these epigenetic changes to more closely resemble the pattern found in normal cells. In fact, certain new medications that affect epigenetic alterations are being clinically tested today in prostate and many other human cancers.”
New Discoveries
Investigations by Dr. Nelson’s group, and subsequently studied by Dr. Yegnasubramanian’s group, have led to the discovery of one gene in particular, called GSTPi. GSTPi has been shown to provide a defense mechanism against prostate cancer. This “good gene” is turned off by the process of DNA methylation in nearly all men with prostate cancer, leading to the use of this epigenetic change as a prostate cancer biomarker.
 Dr. Yegnasubramanian’s group has been able to show that GSTPi methylation is one part of a large scale “epigenetic catastrophe” that occurs very early in prostate cancer development – causing the silencing of dozens to hundreds of genes simultaneously. Other DNA methylation changes, such loss of DNA methylation at various genes, occur later in the disease progression tracking more with lethal metastatic disease. Interestingly, these large scale epigenetic alterations may make prostate cancer cells susceptible to new therapies.
Dr. Yegnasubramanian and colleagues recently discovered that lack of DNA methylation at some genes can turn these genes on and that various strategies, such as immunotherapies, could be used to target these newly turned-on genes to kill the prostate cancer cells. One such example is the gene NY-ESO1, which is turned on by loss of DNA methylation in many men with metastatic prostate cancer.
Developments on the Horizon
Within the next four to five years, Dr. Yegnasubramanian envisions that a new generation of anti-cancer drugs will be developed for reversing the epigenetic changes that feed prostate cancer growth and block existing therapies from effectively treating patients.
“There are already in development clinical trails to evaluate immunotherapies and vaccine strategies that will target some subset of these genes, like the NY-ESO1 gene for instance,” said Dr. Yegnasubramanain. “There are other drugs that are a few years off. In my lab, in collaboration with Dr. Nelson’s group, we are finding novel small-molecule drugs that can reverse the epigenetic process.”
As part of a continued effort towards supporting the discovery of promising medications that will improve the lives of men with prostate cancer, the PCF looks forward to providing further funding for research in the field of epigenetics.
 “We anticipate that Dr. Yegnasubramanian’s expert investigations and future work in the area of epigenetics will prove very useful for discovering new medications for treating prostate cancer patients,” said Howard Soule, PhD, Chief Science Officer for the PCF.
“Dr. Yegnasubramanian exemplifies translational research. His laboratory work has the potential to bring near-term benefits to patients with advanced prostate cancer. For PCF, this is an ideal program to invest our precious research funds.”
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