Harper Cancer Research Institute
SIYUAN ZHANG, MD, PhD
Nancy Dee Associate Professor of Cancer Research
Associate Professor of Biological Sciences
Understanding tumor cell behavior – to cure and prevent cancer
What if there were an inexpensive, safe way for cancer survivors to prevent cancer from recurring?
Preventing cancer recurrence is one of many goals for Siyuan Zhang, the Nancy Dee Associate Professor of Cancer Research at the University of Notre Dame. He’s a member of the university’s prestigious Harper Cancer Research Institute.
Zhang’s work in understanding the development and recurrence of cancer has impressed the Walther Cancer Foundation, which has provided seed funding for many of his projects.
For Zhang, cancer biology is a series of puzzles. One fact in particular continues to fascinate him: Certain cancer cells have a mysterious way of leaving the primary site — like the breast, for example — and reappearing, usually years later, in the brain.
A drug to inhibit cancer recurrence
Working with chemical engineers at the University of Notre Dame, Zhang is trying to understand how cancer cells adapt to this new environment: the brain. In a project initially funded by the WCF, he worked with Jeremiah Zartman, associate professor of chemical and biomedical engineering, to study tumor progression using a fruit fly model, then mice, to trace the process. “Studying those models allowed us to narrow down the critical genes that drive the cancer cell’s adaptation to the brain,” he says.
It turns out that one of the genes that drives the cell’s adaptation to the brain is the Rab protein, a protein that also happens to drive the recirculation process in the tumor cell.
From cell biology, we know that cargo proteins continually recirculate up from within the cell to the surface when they’re needed, then cycle back into the cell again. It is on the cell surface that the proteins receive outside signals that instruct the cell to grow, or to die.
This is key, Zhang says, because if the mechanism that drives this cell recycling process, the Rab protein, goes awry, the cell doesn’t behave properly.
“For example, if you have a ‘super driver’ that tells cell proteins to all go to the cell surface, that makes the cell super aggressive,” he says. “Then they proliferate faster.”
Zhang says that initially he and his team were disappointed to find that there is no small-molecule inhibitor that directly targets Rab. “It is interesting to know the mechanism,” he explains, “but what we really wanted to find was a drug to cure metastases.”
Nevertheless, he persisted exploring the puzzle — to make a groundbreaking discovery. A thorough search of the literature revealed that people have already been using a drug to prevent the Rab activation pathway: The statin class of drugs. Drugs in this class have been used in millions of patients to treat elevated cholesterol.
Working to inhibit the signaling molecule “upstream,” or before the Rab proteins in the cell-signaling cascade, statins can effectively inhibit Rab along the whole pathway — and prevent undesirable proliferation.
Zhang and his team are excited because statins are generally safe drugs, and they have been proven to penetrate the blood-brain barrier.
“We’re talking about long-term use of a drug that can prevent metastases. Nobody wants to take chemo drugs for 10 years to prevent a future potential relapse. This makes us very excited.” A preprint of the work is available.
Better tissue models
In his various research efforts, Zhang has also been puzzled by a little-discussed gap between clinical treatments and research models. Although most cancers develop in humans over 50 years old, more than 99 percent of cancer mouse models are developed with young mice, mice between six and 10 weeks old. And a 10-week old mouse is equivalent to a 20-year-old human.
“You can imagine that the hormone regulation, the tissue structure, all of those tissue architectures, are very different in someone who is 50 or 60 years old,” he says.
But Zhang had an idea for a new approach — and the Walther foundation provided seed funding to explore it. With support from the WCF, he joined forces with Pinar Zorlutuna, associate professor of engineering at Notre Dame, and their team is devising a practical way to study cancer in aged-mouse tissue.
Although it’s difficult to screen hundreds of two-year-old mice, he’s found that it is quite possible to study aged mouse tissue and screen drugs — in the culture dish.
Focusing on breast cancer, Zhang and Zorlutuna’s team analyzed and compared aged breast tissue to young mouse tissue, then they worked to extract the essential components of that aged tissue. By mimicking and re-creating the aged mouse tissue microenvironment in the lab, he says, the team can create a practical, and more effective, technique to study cancer development — as well as the efficacy of cancer drugs.
With cultured tissue, the team can study a wide range of drugs for those that work best in aged tissue. “Then we take what appears to work best and move to the complete mouse-model work,” he says.
“Our goal is to re-create that intermediate, aged environment to study those cancer mechanisms,” he says. The work is in its early stages, but already they’ve accumulated promising preliminary results.
The Walther seed funding enabled the team to land $1 million in NIH funding for the next four years.
Zhang studies two sides of tumor development. One is at the beginning, understanding how tumors develop at the primary site, breast cancer for example, and how that tumor cell evolves over time. “The goal is really to figure out the trajectory of the tumor cells – where they are heading next,” he says, “so we can potentially design a drug proactively.”
At the other end of the tumor spectrum, he studies the metastasis of cancer tumors in the brain, which is quite far from the breast or lung tissue where the primary tumor initially occurred. He is fascinated by this biological phenomenon.
“We’re really aiming to do with therapeutics is to block that so-called adaptation process,” he says. “If we can delay that process in cancer patients, from 10 to even 30 years, then cancer recurrence is less of a health concern.”
Another of Zhang’s major research projects involves working with computer scientists to analyze the complexities of tumor growth patterns. Working with researchers in fields seemingly far afield from his own is the norm for him.
“We have a lot of interdisciplinary adventures,” Zhang laughs. Although he has clinical experience, having done postdoc work at the M.D. Anderson Cancer Center, he is grateful to be working in the academic setting at Notre Dame.
In the future, expect to read more about Zhang and the methods he’s devised for preventing and curing cancer.