Prostate cancer is the most commonly diagnosed cancer in American men and the second leading cause of male cancer deaths in the U.S. Currently, there is no cure for locally advanced or metastatic prostate cancer, which have responded poorly to traditional chemotherapy.
Two of the DoD-funded projects at Children's will study the role of angiogenesis and anti-angiogenic therapy (attacking a tumor by cutting off its blood supply), extending work begun by Dr. Judah Folkman. The third DoD grant supports research on the interaction between the hormone androgen and cellular growth-factor signaling in suppressing or stimulating tumor growth. The awards are as follows:
-- Dr. George Naumov, a postdoctoral fellow in Dr. Judah Folkman's Vascular Biology laboratory at Children's Hospital, received a $97,928 postdoctoral traineeship award to study why some prostate tumors and tumor metastases remain small and dormant, while others resume growth unpredictably.
Folkman's lab has shown previously that a tumor contains both angiogenic and non-angiogenic (dormant) tumor cells. The dormant cells are inhibited in their ability to attract new blood vessel growth, or angiogenesis; they may remain dormant indefinitely, or they may switch to the angiogenic state and begin to grow aggressively.
Naumov will examine the metastatic potential of three lines of human prostate cancer cells (two dormant lines and one angiogenic line) injected into mice. His team will look for molecular differences and differences in gene expression that might explain tumor dormancy, and will also investigate the timing of the angiogenic switch. The ultimate goal is to devise treatment strategies that suppress metastases by prolonging the dormant, non-angiogenic state.
-- Dr. Michael Fannon, an instructor in the Department of Surgery who is also in the Vascular Biology Program, received a $363,529 New Investigator award to test a two-drug treatment for prostate cancer that would target both the tumor cell and the blood vessels that support it. The naturally occurring compound DBP-maf (vitamin D binding protein - macrophage activating factor) will be administered, either alone or coupled with vitamin D, to mice implanted with prostate tumor cells. Both vitamin D and DBP-maf have shown antitumor activity, and DBP-maf has also been shown to be a potent inhibitor of angiogenesis, attacking the tumor's blood supply. Because DBP-maf binds to vitamin D and targets growing blood vessels, it has the added advantage of delivering vitamin D directly to the tumor site, potentially allowing vitamin D to be given at lower, non-toxic doses.
"These two studies are important extensions of our research into angiogenesis as central to the development and growth of tumors," says Dr. Judah Folkman, director of the Vascular Biology Program at Children's Hospital Boston, who originated the idea that one could starve a cancer into submission by shutting off its blood supply. "Our lab is finding and testing a growing number of anti-angiogenic compounds, alone and in combination with other treatments, to provide non-toxic anticancer drugs. A major focus is to prevent cancers from ever making the 'switch' to the angiogenic state."
-- Dr. Bekir Cinar, a postdoctoral fellow in the genitourinary research lab of Dr. Michael Freeman, received a $97,804 grant to investigate the interaction between the male hormone androgen and growth factors released by cells in suppressing or promoting prostate tumor growth.
It has been known for years that androgens play a central role in the development and progression of prostate cancer. Yet advanced or recurrent tumors can often grow independently of androgen, for reasons that are unknown. The Freeman lab and others have shown that a growth factor signaling via a protein called Akt can stimulate tumor growth independently of androgen.
In the new DoD project, Cinar will test the hypothesis that Akt and a growth factor known as HB-EGF can inhibit signaling by androgen receptors, thereby promoting cancer progression to the androgen-independent form, and that androgen can reverse this process by down-regulating HB-EGF and Akt activity. The ultimate goal, as the signaling pathways and their interaction with androgens are better understood, is to develop new treatment strategies for prostate cancer.
"These studies represent a potentially new paradigm in our thinking about how prostate cancer progresses to the androgen-independent state," says Freeman. "In the conventional model, androgen is thought to be driving cancer progression, even when hormone levels are suppressed by therapy. Here, we are testing whether the androgen and androgen receptor system might actually be acting in opposition to a potent cancer-promoting pathway known to be activated in advanced cancers. The results from this project may reveal ways to more effectively treat cancer by modulating androgen levels and other signaling molecules pharmacologically."
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults for over 100 years. More than 500 scientists, including eight members of the National Academy of Sciences, nine members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today is a 300-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital visit:www.childrenshospital.org.