Grants Support Collaboration, Translational Work

When the National Cancer Institute (NCI) awards a SPORE grant (Specialized Program of Research Excellence), it tells a medical center, in essence, "We like the way your doctors and scientists are working together. We like the way you have people from different disciplines and maybe even different institutions tackling a common goal." The aim of a SPORE grant is "translational" research: Moving a novel idea — one that has the potential to improve detection, diagnosis and treatment of cancer, prevent cancer-caused deaths, prolong survival, and improve quality of life — from a scientist's brain to the laboratory to, eventually, patients in clinical trials.

A SPORE grant means, "We
like the way your doctors and
scientists are working together,
tackling a common goal."

As you may imagine, the NCI doesn't award too many SPORE grants; there are fewer than a dozen focused on prostate cancer. Hopkins recently had its SPORE grant renewed, with an excellent score. Better yet, says William G. Nelson, M.D., Ph.D., Director of the Sidney Kimmel Cancer Center, "in comparison with other Prostate Cancer SPOREs across the country, we have such a rich pipeline of discoveries headed toward the clinic that all of the projects described in the application were new since the previous submission five years ago.Even more impressively, each of our previously funded SPORE projects had reached its translational research milestone, moving on to later stage development supported by other types of funding."

Nelson recently co-chaired a 60-member Translational Research Working Group, charged by the NCI with coming up with strategies to streamline the journey from concept to laboratory to the patient's bedside. One of their results was a set of developmental pathways to prioritize, monitor, and manage translational research efforts at SPORE centers. "These pathways place a premium on newly discovered molecular targets for diagnostic and drug development," says Nelson. "For prostate cancer researchers at Johns Hopkins, whether supported by the SPORE Program, the Patrick C. Walsh Prostate Cancer Research Fund, or other sources, this focus is great news because this is one of our great strengths. Our research teams are the best in the world at bringing both a savvy for the behavior of prostate cancer as a disease and a deep knowledge of the molecular mechanisms that drive prostate cancer development and progression."

Four Brady scientists — Mohamad E. Allaf, M.D., Tamara Lotan, M.D., Jun Luo, Ph.D., and Prakash Kulkarni, Ph.D. — recently received funding as part of this SPORE program. Here's a brief look at some of their work:

The Next Best Thing to the Surgeon's Fingertips: Ultrasound Elastography

Over the last few years, robot-assisted laparoscopic radical prostatectomy has emerged as an exciting, minimally invasive alternative to the traditional open radical prostatectomy. There's just one drawback. "During open surgery, which remains the gold standard today, surgeons use tactile feedback to determine whether cancer extends outside of the prostate" says Mohamad E. Allaf, M.D., Director of Minimally Invasive and Robotic Surgery. If the surgeon feels anything suspicious, this could lead to removal of more tissue. "Robotic surgery does not offer this tactile feedback, and this has raised concerns regarding the surgeon's ability to appreciate differences in tissue texture or fi rmness along the prostate surface." The landscape immediately surrounding the prostate is treacherous for surgeons; for example, it is easy to cut or damage the tiny, delicate nerves on either side of the prostate that are responsible for erection (these are known as the neurovascular bundles of Walsh). "This sometimes means a dilemma for the surgeon," says Allaf. "Remove too much tissue needlessly and the patient loses erectile function. Remove too little, and risk leaving cancer behind." To address this, Allaf, along with Emad Boctor, Ph.D., an engineer in the division of Medical Imaging Physics, is working on a new means of imaging called elastography imaging. An advanced form of ultrasound, this technology helps the surgeon know where tissue is harder or more dense. "Elastography imaging is noninvasive, relatively inexpensive, and does not expose the patient to radiation," says Allaf.

Translational research is moving a
novel idea from a scientist's brain
to the laboratory to, eventually,
patients in clinical trials.

Better yet, it has "the potential to provide the surgeon with realtime information regarding the course of the neurovascular bundles. We know that there is variability in the location of these critical nerves, but to date there is no reliable way to image them during the operation." Their preliminary work, on resected prostate specimens, has been encouraging. "We were able to consistently identify cancerous and benign lesions," says Allaf.

Next, in animal studies, they were able to image the neurovascular bundles, as well. Now, they are working on integrating this technology into a robotic arm. "We hope that our work will provide surgeons with the best of both worlds," he adds, "the latest in technology and the irreplaceable ‘human touch.'"

Tubes and Prostate Cancer: Why Shape Matters

One telltale feature of prostate cancer that makes it easy for pathologists to spot under the microscope is that it makes tubes — simple little tubes of cells, which poke between normal prostate cells. As far as prostate cancer pathology goes, tubes are good. The vast majority of these tube-shaped cancers are confi ned to the prostate at radical prostatectomy, "and patient survival is generally excellent," says pathologist Tamara Lotan, M.D. But as the cancer cells advance, they lose this tube-making ability, and begin to grow in more complicated structures. "Then, the Gleason grade increases, and patients are more likely to develop recurrences, and possibly distant metastases."

Nobody knows why shape matters so much in prostate cancer, and why, when tumor cells stop growing in tubes, the cancer becomes more aggressive. Lotan and colleagues are working to answer these questions. Outside of cancer, she notes, the only other time that prostate cells grow in tubes is before birth, during embryonic development. "By first understanding the signaling pathways and proteins that drive normal prostate cells to grow as tubes, we will have a better idea of how disturbances in these pathways might lead to the inability of cancer cells to form these structures." The embryonic mouse is a perfect laboratory model for investigating how, very early on, normal prostate cells make these tubes and then, as part of normal life, stop making them, Lotan adds. "Using cutting-edge microscopic techniques, we can literally watch the embryonic mouse prostate tissue form tubes over two to four days, and watch what happens to the tubes when we alter specifi c proteins."

Lotan and colleagues are particularly interested in the role of a gene that is usually lost in prostate cancer cells, a tumor suppressor called PTEN. "PTEN is known to play an important role in the movement of immune cells and in tube formation in kidney cells," Lotan explains. "Also, it is most commonly lost in high Gleason-grade tumors — the very same tumors that fail to form tubes in human patients and are more likely to be associated with a poor clinical outcome." After the scientists have fi gured out the normal role of PTEN in prostate cells, they will study the effect of its loss in prostate cancer cells, to see how this affects the cancer's ability to spread.

New Clues May Help Predict Who Will Benefi t Most from Hormonal Therapy

Hormones are chemical signals, and they are picked up by specifi c proteins, called receptors — think of a baseball and a catcher's mitt. Male hormones, such as testosterone, are called androgens, and their designated "catcher's mitts" are called androgen receptors. But these receptors don't just catch the ball; instead, when they make contact with an androgen, they spring into action, issuing commands to cells to produce genes that, in turn, help the body's cells grow and function. This is known as the "androgenic signaling pathway," and since 1941, doctors have used it as a gateway to treat men with advanced prostate cancer.

Hormonal therapy means taking away the male hormones that nourish the prostate; it can also mean blocking the androgen receptor, to keep out the hormones' messages. For some men, hormonal therapy can keep cancer at bay for many years, but it comes at a steep price that includes loss of libido, personality changes, a higher risk of heart problems, osteoporosis, anemia, and a decline in cognitive function, among other side effects. It also doesn't work the same way in every man; some men receive the cancer-stalling benefi ts for only a few months.

"Because the clinical benefit is limited in time, and the side effects are additive with longer treatments," says scientist Jun Luo, Ph.D., "there is a pressing need to develop new tools to help determine whether and when to initiate hormone therapy."

Luo and colleagues believe they may have some good new tools in the making: They have discovered seven new androgen receptors that work differently from the "normal" androgen receptor, Luo explains. "One key feature of these variant androgen receptors is that they can activate the androgenic signaling pathway — even without androgens."

Which men will have the best
luck with hormonal therapy?

In work recently published in Cancer Research, Luo and colleagues found elevated levels of these variant androgen receptors in men who failed hormonal therapy. They also found higher levels in men who had not received hormone therapy, but had more advanced prostate cancer.

This work suggests that these new receptors may affect how well — or poorly — a man will do on hormonal therapy. Luo and colleagues are working to develop a test using these findings to help predict which men will have the best luck with hormonal therapy, and which men could be saved the side effects of a treatment that will not be of great long-term help.

Is It Aggressive Cancer? On the Trail of New Biomarkers to Help Find Out

What kind of prostate cancer is it? Everybody wants to know — men with prostate cancer, the doctors treating them, and scientists like Prakash Kulkarni, Ph.D., who are working to develop new molecular tests to answer this question. Is the cancer aggressive? If so, it needs to be treated right away. But if it's not, if it's lazy, slow-growing, not particularly ambitious, and poses no immediate threat, then a man can afford to delay treatment — sometimes, indefinitely.

New biomarkers may be able to
predict aggressive cancer that
has already metastasized.

Kulkarni is working with a group of proteins called Cancer/Testis Antigens (CTAs), and he believes he may be on the trail of new biomarkers for prostate cancer — especially for aggressive cancer, and even cancer that has already metastasized. Growing evidence, he says, suggests that these CTAs are linked to stem cells, and that in normal adult tissue, they're turned off. "However, genetic changes in cancer can cause them to reactivate," and the result is bad news — a more malignant cancer. "In addition to their role as cancer-specific antigens, several CTAs have also shown considerable promise in predicting the course of other malignancies, including neuroblastoma, gastrointestinal tumors, multiple myeloma and cervical carcinoma." Also, if several CTAs are active at once, this has been shown to make several kinds of cancer more resistant to treatment. "Using a variety of molecular biology, cell biology and immunochemical techniques, we hope to identify CTAs, and to develop novel biomarkers that may aid in accurate diagnosis, prognosis, and predicting response to therapy in men with prostate cancer."

Interested in Participating in a Clinical Trial?

One of the advantages of receiving care at a major academic medical center is that this is where the latest innovations are being studied. There are always clinical trials underway at Hopkins, for men at every stage of prostate cancer. This includes men getting ready for primary therapy (surgery or radiation treatment); men with a rising PSA after treatment; men with metastatic cancer, and men with metastatic disease who have already undergone chemotherapy. If you are interested, please see this page on the Brady website: http://urology. jhu.edu/research/trials.php, and talk to your doctor. Before you enroll, Brady staff and faculty will make sure that you know how it works; whether there are any potential side effects; and that you know that you are free to stop being in the study whenever you want. Participating in a study often means more than the opportunity to get an early chance at a new breakthrough. Many who volunteer to take part in a medical study do it because they feel they are helping a greater cause — that their participation will advance medical science and, ultimately, help other people. You can also find clinical trials by going to this website, run by the Sidney Kimmel Cancer Center at Hopkins: http://www.hopkinskimmelcancercenter.org/ index.cfm/cID/37

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