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Quarterly Research Update
October 2009

Society Researchers Search for Ways to Identify and Treat Aggressive Prostate Cancers

Genes within our DNA tell our cells what to become and how to function. So, it is no surprise that the discovery of oncogenes, or genes capable of reprogramming a normal human cell into a cancerous cell, not only led former American Cancer Society grantee J. Michael Bishop, MD, and Society Professor Harold Varmus, MD, to receive the Nobel Prize, but also opened the door for other scientists to develop the idea of targeting genes to stop the spread of the disease.

Cancers do not develop as the result of just one diseased gene, but are the result of many abnormal changes to the cells. This aspect of cancer development has some scientists looking for other signs of disease development, namely biomarkers and signatures, much like blood cholesterol is a biomarker for heart disease risk.

Both biomarkers and signatures can be signals that a disease is in the process of developing, or can be used to determine how much the disease has progressed. The difference between the two is that a biomarker represents a change in a single gene, RNA molecule, or protein, whereas a signature, like a handwritten signature, is a unique pattern of changes in multiple genes, ribonucleic acid (RNA) molecules, or proteins. A biomarker can be thought of as a single patch in a quilt, and the signature, the quilt as a whole. And like a quilt, it is the subtle differences in the arrangements of biomarkers and signatures that can make each cancer unique.

The single patches of biomarkers and the versatile nature of the quilted design of signatures make these biological findings ideal candidates for ways to personalize medicine. Research funded by the American Cancer Society to identify biomarkers and signatures not only has advanced personalized care for breast cancer, such as through the development of herceptin and the identification of metastasis signatures, but is also moving us closer to effective personalized care for aggressive prostate cancer.

Genes going wild leads to aggressive cancers

A new genetic signature – a multi-gene pattern – has been identified that may lead to the detection of potentially aggressive prostate cancers. Former Society grantee E. Lynette Wilson, PhD, of New York University School of Medicine, recently used stem cells from the prostate to determine if the uncontrolled growth of adult stem cells contributes to the development of a subset of prostate cancers that may possibly be more aggressive.

Wilson and her colleagues discovered that certain genetic signatures responsible for rapid growth and self-renewal of the prostate are found in stem cells that are present during the development of the fetal prostate, called fetal prostate stem cells. Normally, stem cells that are present in the fully developed adult prostate, called adult prostate stem cells, do not use all of these fetal genetic signatures because their job is to remain inactive or “quiet” until they need to maintain and repair the adult prostate tissue. The researchers compared the genetic signatures of prostate tumors previously published by others and found that the genetic signature of prostate tumors had similar characteristics to those found in fetal prostate stem cells.

When looking at the individual genes that make up the signatures in fetal stem cells, the researchers uncovered a "seesaw effect." There were genes that were being “turned on,” making them more active, while others were being "turned off," making them less active. Some of the most active genes were those previously linked to prostate cancers that do not respond to hormone therapies and to decreased survival in patients with prostate cancer – genes indicative of an aggressive form of prostate cancer. Some of the genes with less activity within the signature were genes that keep stem cells inactive, preventing cells from increasing in number, thus inhibiting the development of tumors.

The seesaw disruption in the normal balance of genes that either promote or prevent cell growth in adult stem cells may eventually lead to the development of tumors from these otherwise “quiet” cells. This research may lead to the identification of a subset of aggressive tumors using genetic signatures and may serve as the framework for new therapeutic strategies for treating prostatic cancers.

Targeting the mechanisms of aggressive cancer growth

Current Society grantee Christopher A. Maher, PhD, and American Cancer Society Clinical Research Professor Arul M. Chinnaiyan, MD, PhD, of the University of Michigan Medical School in Ann Arbor, are among a group of scientists who recently reported that the loss of a specific type of RNA can lead to cancer progression and metastasis. RNA molecules typically function as the "middleman" in the process of making proteins from genes, but RNAs also play other roles – in particular controlling gene activity.

The EZH2 enzyme is a protein that normally prevents genes from being "turned on" by making external changes around (epigenetic) but not within the DNA. High levels of the EZH2 enzyme can lead to excess cell growth and metastasis. Efforts to unravel the mechanisms behind the link between high levels of the EZH2 enzyme and excess cell growth and metastasis focused the researchers' attention on small pieces of RNA called microRNAs.

MicroRNAs are known to have an important role in the development of several aggressive cancers, including aggressive solid tumors, almost all metastatic cancers of the prostate, and other cancers with high levels of EZH2, including breast, bladder, and gastric cancers. Maher states, "Overall, [this research] has significant implications for how we diagnose and treat cancers. We envision that by monitoring the level of microRNAs in solid tumors, we may be able to distinguish tumors likely to aggressively metastasize from those that would tend to remain localized."

With all of this information about the EZH2 enzyme and the role of microRNAs in aggressive cancers, particularly those with high levels of the EZH2 enzyme in hand, Maher, Chinnaiyan, and colleagues set out to determine if there were any direct links between the EZH2 enzyme, microRNAs, and the development of aggressive cancers. They discovered that the amounts of a particular microRNA regulated by the EZH2 enzyme, called microRNA-101 (miR-101), decreased as a tumor progresses to a metastatic cancer. "Once we have identified tumors that have lost miR-101, our study suggests that we could treat them by putting miR-101 back into the tumors and ultimately inhibit tumor progression," says Maher.

Problematic proteins promoting metastasis

The identification of a new biomarker for any cancer is exciting, especially if there is a chance that the biomarker can be used to develop new tests for detection or as a target for future therapies that prevent the spread of the disease (metastasis). A biomarker called galectin-3 was identified as having a role in prostate cancer by a group of researchers including American Cancer Society Clinical Research Professor Kenneth J. Pienta, MD, of the University of Michigan in Ann Arbor, and is now making headlines in prostate cancer research.

Galectin-3, a protein normally involved in cell growth and death, is “cut” (cleaved) as prostate cancer progresses from a localized tumor to a metastatic disease. Pienta and his colleagues found that simply reducing the amounts of the galectin-3 protein results in less metastasis because the cancer cells were no longer moving outside of the tumor and were no longer able to invade neighboring tissue. These findings suggest that galectin-3 levels may someday be useful in the diagnosis and treatment of prostate cancer.

Although the full story about cleaved galectin-3 protein is still in its early stages, Pienta says, "One of the most promising aspects is the potential to develop a urine test using this protein that will aid in the detection and staging of prostate cancer, since the presence of protein could correlate with how advanced the cancer is."

This is just one of Pienta's many projects dedicated to uncovering the causes of metastasis in prostate cancer. He is also developing new therapies for advanced prostate cancer that not only target the cancer cells, but also target cells that reside in the area in which the tumor may be developing. Pienta plans to conduct clinical trials to test the effect of chemicals that hamper specific components of the immune system in hopes of treating advanced prostate cancer, and possibly other solid tumors.

The American Cancer Society’s legacy for funding cutting-edge research is evident by these studies, as well as many other advances identifying biomarkers and signatures found in other types of cancer. As our grantees continue to explore causes and treatments for advanced prostate cancer, the Society moves closer toward a future with less cancer and more birthdays.

For more information on prostate cancer, click here.

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