Research matters

News from the Harvard Medical School research community.

Oncology

Hormone therapy in addition to radiation increases curability of prostate cancer

Although androgen suppression therapy (AST) has been shown to increase the risk of cardiovascular events, the survival benefit it may offer to certain patients has been unclear. In a new study, researchers at Brigham and Women's Hospital (BWH) have found that the addition of 6 months of AST to radiation therapy (RT) increased the overall survival rate of older men with localized, unfavorable-risk prostate cancer. Details of this study were published in the January 23, 2008 print edition of the Journal of the American Medical Association.

"This research helps to further refine the category of men that should receive androgen suppression therapy in addition to radiation therapy to improve their chance of survival," says Anthony D'Amico, MD, PhD, a professor at Harvard Medical School, and lead author and chief of Genitourinary Radiation Oncology at Dana-Farber/Brigham and Women's Cancer Center.

Researchers evaluated men with a median age of 72 who had unfavorable localized prostate cancer and were randomized to receive either RT alone, or AST with RT. Researchers also subdivided the men into groups based on a comorbidity score that was determined by preexisting medical conditions and comorbidities before randomization of therapy.

They report that in men who are otherwise healthy, the combination of RT and 6 months of AST improves curability 4-fold. However, in men with significant health issues unrelated to cancer, especially heart disease, which was the most common comorbidity in these men, adding AST to RT could have a reverse effect, doubling the overall death rate.

"Moving forward, randomized studies should be designed to assess whether new treatments being tested are beneficial to men when other significant health issues are present. However for now, an individual man's health profile should be evaluated and addressed, especially when pre-existing heart disease is present, before prescribing a treatment plan involving AST," said D'Amico.

Epidemiology

Transparent fish to make human biology clearer

Zebrafish are genetically similar to humans and are good models for human biology and disease. Now, researchers at Children's Hospital Boston have created a zebrafish that is transparent throughout its life. The new fish allows scientists to directly view its internal organs, and observe processes like tumor metastasis and blood production after bone-marrow transplant in a living organism.

The fish, described in the February 7 issue of Cell Stem Cell, was created by Richard White, MD, PhD, a clinical fellow in the Stem Cell Program at Children's, with others in the laboratory of Leonard Zon, MD.

The classic method for studying human diseases in animals is to allow the animal to get the disease, kill and dissect the animal, then ask, "what happened?" But in cancer and other fast-changing processes that traverse the body, this method is bound to miss something. "It's like taking a photograph when you need a video," says White, also an instructor of medicine at the Dana-Farber Cancer Institute.

Zebrafish embryos have enabled researchers to study disease in live organisms, since they are transparent. But zebrafish adults are opaque. "Everything after four weeks has been invisible to us," says White.

White's first experiment on the zebrafish examined how a cancer spreads. "The process by which a tumor goes from being localized to widespread and ultimately fatal is the most vexing problem that oncologists face," says White. "We don't know why cancer cells decide to move away from their primary site to other parts in the body."

White created a fluorescent melanoma tumor in the transparent fish's abdominal cavity. Viewing the fish under a microscope, White saw the cancer cells begin to spread within five days. He even saw individual cells metastasize, something that has not been observed, so readily and in real-time, in a living organism.

The spreading melanoma cells appeared to "home" to the skin after leaving the abdominal cavity. "This told us that when tumor cells spread to other parts in the body, they don't do it randomly," says White. "They know where to go."

White plans to study tumor cell homing, then look for ways to modify the tumor cells or cells of the host so that the spreading cells never find their new location.

The fish may also answer questions about stem cell transplants. While transplants of blood-forming stem cells help cancer patients rebuild healthy blood, some transplants don't "take," for reasons that are unknown. Scientists have lacked a full understanding what steps blood stem cells must take to do their job, says White.

White showed the process is observable in the fish. He first irradiated a transparent fish's bone marrow, then transplanted fluorescent blood-forming stem cells from another zebrafish. By four weeks, the fluorescent stem cells had visibly migrated and grown in the fish's bone marrow, which is in the kidney. Even individual stem cells were visible, something researchers haven't easily observed in a living organism, White says.

By studying how the stem cells embed and build blood in the fish, scientists can look for ways to help patients rebuild their blood faster. Drugs and genes could be tested in the living fish, with direct observation of results, White says.

White created the transparent fish simply by mating two existing zebrafish breeds.

Zebrafish have three pigments in their skin--reflective, black, and yellow. White mated a breed that lacks reflective pigment, called "roy orbison," with one that lacks black pigment, called "nacre." The offspring had only yellow pigment in their skin, essentially looking clear. White named the new breed "Casper".

The fish's brain, heart, and digestive tract are also visible, allowing researchers to study genetic defects of these organs from early embryonic development through adulthood.