The cancer fighters: A look at research at the UF Health Cancer Center

For most people, crystals, computers and platinum do not readily trigger the mind to think “cancer.” However, UF Health Cancer Center scientists are using these and other tools in their innovative approaches to combating cancer. In this issue, we take you inside the labs of several of UF Health’s innovative cancer researchers.

A CRYSTAL CLEAR APPROACH TO DRUG DISCOVERY

When one sees the enlarged images of protein molecules gliding across a computer screen, it is hard to believe that the structural information came from a small, beautiful crystal — a crystal that could be the key to improving an individual’s quality of life.

The UF Health Cancer Center Drug Discovery Program is using X-ray crystallography to develop a new, personalized method to boost immune responses in cancer patients.

Ostrov“There are many researchers considering personalized approaches, but ours is absolutely unique,” said David Ostrov, Ph.D., who leads the program. “Our strategy is more personalized than any other current approach because the targets of our drugs are the proteins that are most different between us. We are purposely selecting safe drugs based on the structures of immune response proteins that define our individuality.”

X-ray crystallography is a technique in which researchers grow crystals of proteins and expose them to an X-ray beam. When the X-rays pass through the crystal, some will diffract and form a pattern of spots. From that pattern of spots, researchers can use the computer to deduce the 3-D structure and literally see the location of the atoms that make up the protein.

“We take the structural information of the proteins that we obtain through X-ray crystallography, and then use the computer to help us select drug candidates that will interact with any protein we are interested in targeting,” Ostrov said.

Identifying drugs that will bind with the keyproteins involved in immune responses may be “a safe and effective personalized approach” for enhancing immune response against cancer, he said. The immune response protein that his group is targeting is called HLA-B (Human Leukocyte Antigen-B). This protein is distinctive in different individuals because it is encoded by the most diverse gene in the entire human genome.

“Cancer patients frequently have suppressed immune systems that are not able to effectively combat growing cancer cells,” Ostrov said. “By identifying which HLA-B molecules of these you
are expressing, we can then pick out drugs that bind specifically to your molecules and boost your immune system.”

Researchers investigated a large set of drug candidates for their abilities to interact with more than 2,800 HLA-B molecules, representing all known forms found in humans. With the assistance of the UF HiPerGator (the state’s most powerful supercomputer), the list of candidate compounds was narrowed down from approximately 140,000 to a list of 40 that are being tested in the lab. Selected drugs known to be safe are ready for accelerated clinical trials because information on dosage and toxicities are already available.

“We are trying to accelerate the efforts of researchers at UF in bringing their discoveries from the laboratory into the clinic,” Ostrov said.

SCANNING FOR A CURE

UF researchers have developed a new, more consistent way to detect very small tumors using computer technology.ODell

“We can go through and find very, very small tumors that sometimes the radiologist might miss, and we can actually calculate pretty accurately how fast they’re growing,” said Walter O’Dell, Ph.D., a biomedical engineer and an assistant professor in the College of Medicine department of radiation oncology.

O’Dell said when tumors are small, a smaller radiation field is used, less damage is caused to healthy tissue and the chances of killing the tumor are better.

As part of a trial, breast cancer patients who are at high risk of metastasis — the cancer spreading beyond the original tumor — undergo CT scans every six months with the purpose of trying to find tumors as soon as they show up.

“The current clinical guidelines, no matter what risk you have, are to wait and see,” O’Dell said. “Hospitals don’t do a lot of expensive things like preemptive CT scans of the chest. They will wait until you develop some type of secondary clinical symptoms, and then they’ll do a scan to see if cancer spread is really the cause. Usually by that time it has spread and becomes untreatable.”

Preliminary data suggest that patients will live longer if they are treated earlier, O’Dell said. As far as he knows, this is the only trial looking at this early detection approach. The funding for this novel research comes from private donors, including the nonprofit organization The Ocala Royal Dames for Cancer Research.

“Currently once you get a metastasis, your prognosis is very poor, but if we can find them and treat them early, then we believe that your prognosis is very much improved,” O’Dell said.

WATERMELONS AND GRAPES

DangWith roughly 60 different types of lymphoma in existence, Nam H. Dang, M.D., Ph.D., said the subtypes of this cancer are no more similar than watermelons and grapes. However, Dang wants to rid patients of them all.

A professor and deputy chief of the division of hematology and oncology, Dang is conducting several clinical trials looking at novel medications for different subtypes of lymphoma.

“Many of these drugs will actually become approved in the future, so by getting on the clinical trial now, many of our patients have early access to drugs that will help them,” said Dang, director of the UF Health Cancer Center clinical trials office. “I have multiple examples of patients whose lives have been prolonged because they were able to get on these trials before the drugs were approved.”

Dang said what makes this research unique is the use of various drugs that target different aspects of the disease and the knowledge to choose appropriate combinations of drugs to treat the disease.

“Up until now, we did not understand the molecular profile of the disease,” he said. “We can now develop medications that break up what drives the cancer.”

HELPING WOMEN SURVIVE BELOW THE BELT

As program leader for the UF Health Gynecologic Oncology Program, Merry-Jennifer Markham, M.D., focuses on bringing clinical trials to UF for women with gynecologic cancers.

Markham“Traditionally, gynecologic cancers have been understudied, especially compared to other cancers with historically more funding, such as breast cancer,” said Markham, who is also an assistant professor of medicine. “I feel that part of my job is to help raise awareness for women’s cancers — those below the belt — and to develop research studies that will allow those patients to have more treatment options.”

One current clinical trial available at UF with promising preliminary data offers an investigational drug for women with platinum-resistant, recurrent ovarian cancer, or those whose cancer returned within six months of finishing chemotherapy with a platinum chemotherapy agent. The survival rate for platinum-resistant patients is cut nearly in half
compared with platinum-sensitive patients.

“If we can find novel agents that can make a woman’s cancer sensitive to a platinum agent again, this would not only provide additional treatment options but would hopefully improve survival,” she said. “We know that once a woman has recurrent ovarian cancer, the cancer is no longer curable. Our treatment goals then focus on controlling disease, extending life expectancy, and improving quality of life. If we can get ovarian cancer to be more of a chronic disease when it reoccurs, and not an immediate death sentence, I think that will make a huge impact in many women’s lives.” — Emily Miller

UF Health has more than 100 ongoing cancer studies. In 2013, funding for cancer research at UF Health totaled $36 million.

 

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