student spotlight archives
Brett DiNatale: Researching novel solutions for treating breast cancer
Meet Brett DiNatale, a soft spoken Ph.D. candidate passionate about his research to discover a new targeted therapy for breast cancer – the leading form of cancer with the second highest incidence of cancer death in women in the U.S.
Brett is a Boston native who after receiving his undergraduate degree in biochemistry from Boston College worked for six years as a pharmaceutical market analyst and researcher specializing in oncology. Through this experience he gained insight into cancer and tumor diseases, modes of cancer progression, and how different cancers are treated by medical professionals. He was surprised by the lack of innovations in treatment therapies. It seemed that the same approach used for decades was still the main treatment available: administer various cocktails of chemotherapy drugs at the highest possible dose, despite their adverse effects, without killing the patient. Brett says, “The same chemotherapy regimen has been used for the past fifteen years – compounds that do a mass killing of cells – they damage the DNA of rapidly proliferating cells and cancer cells grow faster than normal cells so it kills more of them. But it kills other cells too – that is one of the side effects.”
Recent advances in monoclonal antibodies (biologically-engineered substances designed to target a specific part of a cancer cell to kill or turn off the cancer cell) caused him to ask whether targeted therapies could be identified that would benefit certain cancer patients and whether there was an underlying molecular process that could be pinpointed to treat larger populations. These questions fostered his desire to attend graduate school – he wanted to conduct research that would help further an understanding of what was actually happening in breast cancer research on a molecular level, and investigate how disease progression could be slowed or stopped with targeted treatment without causing undue damage to the patients themselves.
After an extensive search of graduate programs, Brett chose Penn State’s intercollege Molecular Medicine program. “I felt confident that the interdisciplinary nature of the program and opportunity for collaboration dovetailed perfectly with my varied background and interest in attacking problems from a number of angles. The design of the program is such that I am able to draw upon my undergraduate degree in biochemistry, the extensive background that I built in understanding neoplasia (abnormal proliferation of cells) and current modes of treatment, and my data analysis experience, as well.”
Brett’s advisor is Dr. Gary Perdew, distinguished professor of veterinary science; holder of the John T. and Paige S. Smith professorship in agricultural sciences; and director of the Center for Molecular Toxicology and Carcinogenesis (CMTC). Brett states that working with researchers in the CMTC fits well with his research objectives; “I have the opportunity to work closely with seasoned scientists who have a history of cutting edge molecular research with respect to breast cancer and carcinogenesis. The lab employs both cell cultures and mouse models, and researchers utilize a wide variety of experimental techniques to investigate topics such as cytokine (a class of molecules that help regulate the immune system) signaling and dioxin-induced carcinogenesis, and estrogen-based transcriptional control of oncogenes (genes that control cell growth but when mutated can cause cancer) following dioxin exposure. While I don’t expect that anyone will find a silver bullet to revolutionize cancer treatment, the interdisciplinary nature of the lab provides the opportunity to investigate the disease from different angles. It is not a narrow field – we should be looking at all of the factors. When you are looking at cancer, don’t just look at cancer cells – look at inflammation and the inflammatory symptoms and the immune system – all of these components are playing off of each other.”
Brett’s
research is very complex – let’s start with the basics. Most of us
have seen an illustration of DNA – the double stranded molecule that looks sort of like
a ladder – but what is DNA and how does it relate to cancer? Deoxyribonucleic acid, DNA
for short, encodes the complete human genome of more than 25,000 genes. Genes are particular
segments along the DNA strands and every cell in our body carries a full complement of our genetic
code in its DNA. The function of each cell in the human body is controlled by the genes that
are expressed or “turned on” allowing each cell, even though it contains identical
DNA, to function differently. This genetic regulation is what makes a skin cell function differently
than a kidney cell. Each gene also provides instructions to the cell on how to produce a specific
protein that performs a particular function in the cell. Of particular interest are the genes
that provide instructions on how and when a cell should divide and make a new copy of itself.
Cancer takes place when these genes become damaged and the normal growth and replication of
cells is disrupted, allowing cells to continually grow without any controls. This unregulated
growth of cells can form a mass of extra tissue, a tumor, which may spread throughout the body.
Certain types of environmental pollutants have been shown to cause genetic damage and these genetic mutations in turn can cause cancer. Research has increasingly shown connections between inflammatory immune responses and carcinogenesis and cancer progression. Previous research by the lab determined that inflammatory mediators (IL-1B) and environmental toxins, such as dioxins and polycyclic aromatic hydrocarbons (PAHs), that activate or “turn on” the aryl hydrocarbon receptor (Ah receptor or AHR) synergistically induce high IL-6 levels and enhance breast cancer tumor progression. Dioxins belong to a pervasive group of highly persistent environmental contaminants that bioaccumulate in the food chain.
Brett explains, “IL-1B, IL-6, IL-8,
there are a number of them, all are interleukins – basically
cell signals that cells put out to signal each other to determine whether they should start
an inflammatory response. The IL levels increase and decrease in response to different stimuli.
This is one of the ways that cells tell each other what is happening in their surroundings.
Dioxins and PAHs operate through the AHR. When the AHR binds to a pollutant and comes into the
cell’s nucleus (with the normally present IL-1B) there is a huge increase in IL-6 levels.”
“IL-6 has been shown to change the way cells act in many different types of cancer: it
has the potential to make already existing cancer cells more immune to death signals so they
don’t die as easily; it may cause cells to divide more rapidly or grow more quickly; or
it can make them potentially more invasive by changing their adhesive properties, which allows
cancer cells to break away and metastasize in other parts of the body. IL-6 has been shown to
cause these changes in various cancer cell lines. We are trying to figure out if it also is
causing them in breast cancer cells, and in cervical cancer cells as well. I can’t say
that IL-6 causes the cancer but it has the potential to exacerbate the cancer that is already
there.”
The underlying question is why when IL-1B and dioxin are both in the cell why they turn on the IL-6 gene and cause the increased IL-6 levels. According to Brett, “My job is to figure out what is so special about the IL-6 gene – what goes crazy and what does that do to the cancer cells around it.”
Brett anticipates that his degree will take five years, maybe more, to complete. That means he will be spending a lot of time in the lab. He does find some time for recreation though. He and his girlfriend do a lot of mountain biking and playing pool. After living and working in New York City he says “It’s not very much fun riding a bike in NYC – it’s a lot slower here.” He and his girlfriend Christy Lusiak, a lecturer in literature at Penn State Altoona, also play scrabble, where they go head to head on Science and English, and enjoy cooking together.
Brett DiNatale is a Ph.D. candidate in Penn State’s Molecular Medicine graduate program.
He can be contacted by email at bcd148@psu.edu.
Gary Perdew is a distinguished professor of veterinary
science; holder of the John T. and Paige S. Smith professorship in agricultural sciences; and
director of the Center for Molecular Toxicology and Carcinogenesis. He can be contacted by email
at ghp2@psu.edu.