UF selects areas of focus for creating a world-class cancer research program

Florida is the nation’s fourth most populous state but has the unenviable distinction of ranking second place on a variety of cancer statistical tables.

“To me, that’s a clarion call that Florida needs more cancer centers and more research into the root causes of cancer,” said Stratford May Jr., M.D., Ph.D., director of the University of Florida Shands Cancer Center.

“Effective cancer research requires a critical mass of people to develop the necessary collaborations,” May said. “On our campus — thanks to a proposal made by UF Genetics Institute Director Kenneth Berns back when he was dean of the College of Medicine — we soon will construct a building that provides an environment suited to teamwork among cancer, genetics and biotechnology researchers.

“Ultimately, the true cause of all cancers is both genetic and epigenetic — involving direct alterations or mutations of a gene’s DNA sequence to produce a cancer-causing oncogene, or malfunctions in gene expression that activate biochemical growth processes at the wrong time,” May added. “Genetics, epigenetics and biochemistry are critical frontiers in which to explore how a malignancy starts and how it grows and spreads.

“We have come to realize no magic bullet will end all cancers, but instead, various therapies targeting the genetic or epigenetic problems have to work in concert to effectively treat, cure or prevent different cancers. I believe it’s necessary to conduct research in a multidiscipinary manner to take advantage of how to best combine the various therapeutic approaches,” he said.

Initially, a corps of 35 to 40 scientists will move into the cancer segment of the new building and join collaborators from across the UF campus. Stephen Sugrue, Ph.D., associate director of basic science for the cancer center and chairman of the medical school’s department of anatomy and cell biology, explains the center is a matrix into which scientists already working in cancer-related areas are being enlisted, while new researchers are recruited.

Sugrue said the center plans to “go deep” and establish leadership in six key areas:

·Genetics of cancer cells — Alterations or mutations of the gene’s DNA sequence (the master molecule of heredity), which create an overactive or underactive gene product such as an oncogene or tumor suppressor gene.

·Epigenetics — Involving sporadic or inheritable changes in gene activities or expressions in tumors that appear to result from proteins and other factors outside the gene, which either modify the DNA or cause changes in chromatin, a set of proteins involved in packaging the DNA.

·Signaling and apoptosis — A natural process in which cells throughout the body decide at a certain time to stop dividing and undergo programmed death. Scientists seek to better define the factors, such as proteins, that signal apoptosis, and to find out how cancer cells override this process while continuing to divide and multiply.

·Stem cell biology — One of today’s hottest areas of medical research, aimed at defining how certain adult stem cells in the brain and other parts of the body “go bad” and form tumors or set the stage for malignant growth.

·Angiogenesis — The process by which blood vessels proliferate in and around tumors and nourish malignant growth. Blocking this unwanted vascular development is viewed as one promising step to robbing tumors of the blood vessels that nourish their growth.

·Studies of the cancer cell nucleus — To define factors that regulate the spatial positioning of the nucleus and define specific territories in it. Scientists have long recognized the nucleus of cancer cells is visibly different from that of non-cancer cells.

“Stem cell research is a very important initiative,” Sugrue said, “because the decisions stem cells make as to whether or not to divide and reproduce are the same decisions cancer cells make. The question many of us are now asking is whether cancer is a disease of stem cells gone awry.”

Sugrue said several UF scientists, whose recent discoveries regarding adult stem cells have been reported in top-tier journals, are actively engaged in the cancer center. Among them are molecular geneticist and microbiologist Edward Scott, Ph.D., who discovered that bone marrow stem cells in mice can build new blood vessels, and neuroscience Professor Dennis Steindler, who unexpectedly found evidence of a link between brain stem cells and gliomas (brain tumors).

“We also have a strong research program related to vascular genesis (blood vessel proliferation) and efforts to starve malignant tumors by cutting off their vascular supply — enanating in part from the pioneering animal studies by Judah Folkman at Harvard,” Sugrue said.

A tumor biology group, led by radiation oncology Professor Dietmar Siemann, Ph.D., has gained new insights into drugs that block new blood vessel formation (angiogenesis) and drugs that destroy existing blood vessels in actively growing tumors (vascular targeting agents). Through studies supported by the National Cancer Institute over the past five years, Siemann and colleagues have documented beneficial effects with all four drugs now under investigation and found ample rationale for further clinical testing.

Siemann said the latest findings show these new vascular targeting agents enhance the effectiveness of conventional radiation therapy and chemotherapy.

“We’ve found that combining these therapies improves total tumor response, and, in some animal studies, we documented the fact that combining vascular targeting drugs with radiation therapy improves cancer cure rates,” he said.

In recent studies in mice, Siemann reported “very promising” results from a combination of vascular targeting agents and antiangiogenic therapies, aimed at achieving the dual goal of knocking out existing tumor blood vessels and inhibiting new blood vessel development.

“With this new combination, we’ve achieved some long-term cures in mice with kidney tumors (which have excessive amounts of blood vessel proliferation), as well as in eradicating human tumors that were grown in mice whose immune systems had been weakened,” Siemann said. Details of this study are due to be reported in November at an international conference.

Siemann, author of a review article on vascular targeting agents in the November 2002 edition of Horizons in Cancer Therapeutics, cautioned that while the combination of vascular targeting drugs with antiangiogenic treatments has been shown to work well in animals, both involve new investigational drugs that must undergo extensive lab testing before use in people.

He added that a safe dosage of vascular targeting agents has been identified through phase 1 clinical trials at the Cleveland Clinic and the University of Pennsylvania, as well as at Mt. Vernon Hospital in England. These drugs will be further evaluated clinically in combination with radiation therapy and chemotherapy.

In the broader scope of investigations into the origins of cancer cell development and reproduction, Sugrue said UF has productive faculty in several key areas. He noted, for example, the epigenetics research under way by professors Michael Kilberg, Thomas Yang and Jorg Bungert, all Ph.D.s in biochemistry and molecular biology. In anatomy and cell biology, Diaquing Liao, Ph.D., and Sankar Swaminathin, M.D., are leading studies of how certain viruses are transformed into proteins that appear to cause healthy cells to become malignant.

The cell nucleus — the key site that pathologists scrutinize to detect cancer — also is the focal point of new explorations, which Sugrue believes will yield clues to the origins of cancer.

“We’re fortunate to have on our team Dr. Brian Burke, a world-renown expert on the molecular structure and regulation in the nucleus,” Sugrue said. “We also have recruited Dr. Alexander Ishov, who studies the regulation of nuclear spatial and thermal dynamics. In my own lab, I’m continuing to examine proteins in the nucleus that are related to the processing of messenger RNA and which appear to be disabled in certain cancerous tumors.”