Quests to outsmart cancer: 5 research projects underway at Upstate
BY AMBER SMITH
Of the 268,600 women who will be diagnosed with breast cancer in America this year, 90 percent will live for at least another five years. Breast cancer is survivable, especially when it’s caught early, but it remains the most common cancer in women, not counting skin cancers. The National Cancer Institute reports that 7 percent of all cancer deaths are from breast cancer.
Researchers are coming at the disease from multiple directions. They are designing new ways to target tumor cells, new methods of halting its spread, new approaches to drug resistance. With money from the Carol M. Baldwin Breast Cancer Research Fund, scientists at Upstate are on a quest to outsmart breast cancer. Here’s a look at five projects underway.
1. Putting the brakes on cancer
Using both chemistry and biology, Alaji Bah, PhD, is on a quest to improve breast cancer targets. He is searching for ways to keep cancer-suppressing genes “turned on” — research that may lead to new medications.
A biology-class refresher: Genes are sequences of nucleotides encoded within DNA. That same DNA is in every cell of our bodies, wrapping tightly around clusters of proteins. As they mature in our bodies, cells go through developmental changes to become skin cells, brain cells or other cells. Depending on how the cell develops, certain genes are turned on or off.
Bah’s laboratory is targeting one of the mechanisms by which genes are turned on or off: DNA methylation. When it is heavily present, tumor suppressor genes turn off and lose their ability to suppress cancer. They are the body’s cancer-braking system.
Many anti-cancer drugs prevent the global DNA methylation of genes, including tumor suppressors. Because of the lack of specificity of these drugs, other vital genes are also affected, resulting in unwanted side effects. The Bah lab focuses on five proteins that interpret DNA methylation to turn off the tumor suppressor genes.
Now for the chemistry class: Remember what happens if you put sugar in water? The sugar molecule dissolves, and the two substances mix and become inseparable. They bind, like a married couple.
What happens if you put oil and water together? They don’t mix. Chemists call this “phase separation.” Phase separation is like two random strangers standing near one another.
The proteins Bah studies appear to phase-separate like oil and water. “We believe that these proteins are not binding but phase-separating with the methylated DNA,” he says. “Some scientists think they are binding, but that’s not what our data is showing."
If his idea is proven, Bah says it could lead to new, better anti-cancer medications.
When chemotherapy drugs stop working, it is called chemoresistance. It is a major hurdle in the management of breast cancer. Identifying the genes involved in drug resistance, such as the work being done in the Bah lab, is a crucial step toward developing a way to overcome it.
2. Tackling drug resistance in breast cancer
Research in the Upstate pharmacology laboratory of Ying Huang, MD, PhD, has led to the identification of a protein called RBEL1A that appears to play an important role in breast cancer cell survival and drug resistance. Excessive levels of this protein are found in a majority of human breast cancers. Huang’s team has found that when breast cancer cells have higher levels of this protein, they become more resistant to certain anti-cancer drugs.Her team has also identified several small molecules that can be used to lower the levels of this protein. When levels of RBEL1A are lowered, Ying explains, cancer cell resistance should drop, and response to anti-cancer drugs should increase.
Studies in her laboratory are underway to see if these molecules can be combined with chemotherapy drugs to overcome chemoresistance, which is when the drugs stop working.
3. Potentially slowing the spread of cancer
Cells in the body are physically supported by a “scaffolding” called the extracellular matrix. Known as the ECM, this support structure is made of up of collagen and other fibrous proteins. Cancer develops when normal cells transform into tumor cells. When this occurs, fibroblasts — the cells that create the support structure — also activate. If they create a rigid and dense structure, cancer cells can use the fibers as “tracks” to more easily escape and spread through the body. A less dense structure, though, can make it more difficult for the cancer cells to migrate.
Cell and developmental biologist Christopher Turner, PhD, focuses his work on a protein called Hic5 found in these cancer-associated fibroblasts, or CAFs. The Hic5 protein promotes a rigid and dense matrix. In laboratory research in mice, he has shown a connection between the protein levels and tumor cell invasion, proliferation and metastasis. He believes Hic5 plays a role in certain aggressive breast cancers.
To test this idea, Turner has teamed with Upstate breast surgeon Lisa Lai, MD. Some of Lai’s patients are contributing to the research effort by donating tissue from their surgeries. Kyle Alpha, a student working toward a medical degree and a doctoral degree, splits his time between Lai’s operating room and Turner’s laboratory. He’s the one who has isolated CAFs from a dozen or so tissue samples from patients in the past year.
“We have just begun our analyses, but we have noticed that, similar to our animal studies,there are indeed differences in the levels of Hic5 in the CAFs from patient to patient,” Turner says. Their ongoing work will compare Hic5’s impact in aggressive breast cancers to that in slower-growing cancers and potentially identify Hic5 as a new therapeutic target for slowing cancer’s spread.
4. Halting cancer spread via a new target?
Microbiologist Christine King, PhD, is investigating a key molecule called STAT3 that allows breast cancer cells to grow, move and invade other cells. It’s active in more than half of all breast tumors. But it’s a molecule we need in order to survive, so getting rid of it entirely is not an option.
Her goal is to find a way for STAT3 to peacefully exist, without its ability to impact breast cancer cells. She has to find a way to keep the molecule from being activated.
Medications designed to inhibit STAT3 have not shown success.
So, King is working backward, unraveling a chain reaction and searching for a new target. She has discovered that another molecule influences STAT3. It’s called TRIM28.
When TRIM28 binds with STAT3, STAT3 behaves.
But if TRIM28 is phosphorylated, or altered, by an enzyme called MK2, TRIM28 cannot bind to STAT3, and the whole deal falls apart.
Scientists in King’s lab suspect that Trim28 is present in breast tissue, but they are trying to determine its phosphorylation state. That’s part of the work that is paid for by the Baldwin grant.
King envisions her work leading to a new target: MK2. If she can keep that enzyme away from TRIM28, then TRIM28 can bind to STAT3, and STAT3 would not be able to allow breast cancer cells to grow and spread and invade other cells.
“If this turns out to be true in breast cancer, then we have a new target,” King says, “a highly specific target.”
5. Paralyzing a protein that helps cancer cells
A protein called Hsp90 is a chaperone that looks after other proteins, making sure they work properly. However, cancer cells hijack the Hsp90 protein, so they too can survive and grow.
Several Hsp90 drugs are being tested in clinical trials. They are designed to selectively accumulate in tumor cells and paralyze Hsp90 so that it can no longer protect the tumor cells. “If you target the chaperone, you target the cancer cells,” describes Mehdi Mollapour, PhD, a professor of urology, biochemistry and molecular biology, and vice chair for translational research in the Department of Urology.
Mollapour and his research team study tissues from breast tumors and compare them with adjacent healthy breast tissues. He believes that chemical modifications of Hsp90 protein make them more attractive to the Hsp90 inhibitors, which would make the medications more potent.
While Hsp90 inhibitors hold promise, none will be a solution for every type of tumor, in every patient. So Mollapour wants to find a way to identify those tumors that respond better to the Hsp90 inhibitors. He’s looking for what scientists call a biomarker.
One of his projects focuses on FNIPs, which assist Hsp90 in chaperone duties. Mollapour knows that when FNIPs are “downregulated,” tumor cells are less sensitive to Hsp90 inhibitors. When they are “upregulated,” the inhibitors more readily bind to Hsp90 in tumor cells.
“Our findings suggest that FNIPs expression can potentially serve as a predictive indictor of tumor response to Hsp90 inhibitors,” he describes in an article in the journal Nature Communications.
This article appears in the summer 2019 issue of Cancer Care magazine.