Starving Cancer

At the age of 10, Ruth Lupu, Ph.D., told her father she’d cure cancer.

“I probably didn’t know what cancer was,” laughs Dr. Lupu, a cancer researcher with Mayo Clinic’s Center for Biomedical Discovery. But if Dr. Lupu didn’t know cancer then, she certainly does now. After 20 years as a breast cancer researcher, and eight as a survivor of the disease, Dr. Lupu is a cancer veteran. Today, almost 40 percent of people in the United States will be diagnosed with cancer, according to the National Cancer Institute.

“I mean, think about this room and the amount of people here,” she says, as

we sit in a staff cafeteria bustling with physicians and researchers. “How many have had cancer or will have cancer is alarming.”

That unmet need, and a passion for science, drives Dr. Lupu and her Mayo colleagues to discover new cancer treatments. And across the nation, they are working on a promising concept: drugs that starve cancer.

Fueling the fire
In the human body, each cell is like a factory. It has pipelines of nutrients coming in, machines to process the raw materials, and pipelines going out with products the cell needs, such as energy. Most cells in the body divide or grow at a leisurely rate. They are perfectly happy with the nutrition provided by daily meals. But cancer cells are different. They need more pipelines to fuel their abnormal growth. And it’s this progression — the metabolic change before the development of cancer — that has intrigued Dr. Lupu for two decades.

Specifically, how cancer uses fat.

Fat used by the body is in the form of fatty acids. Fatty acids are long chains of carbon atoms that store energy. They’re built by enzymes, starting with fatty acid synthase. Fatty acid synthase is like a three-dimensional assembly line, connecting carbon after carbon into fatty acids. The more often this process takes place, the more energy and materials the cell has for growth and division.

For cancer cells, it’s the feast that fuels metastasis and growth.

To clarify the role of fatty acid synthase in cancer, Dr. Lupu and her team confirmed that most cancer tissues had elevated levels of the enzyme ─ not just breast cancer. They made a more ominous finding, as well.

“We determined tumors that express fatty acid synthase tend to be more aggressive,” says Dr. Lupu. “And because they are more aggressive, there is less overall survival.”

Starving the cancer
To examine the cause and effect of fatty acid synthase in the cancer cell, the researchers decided to block the enzyme’s action to see what changed in the cell. In their experiments, tumor growth and division slowed when fewer lipids were available for cellular activities. Eventually, the team determined that, without fast-paced fatty acid metabolism, the overall metabolism of the cancer cell is weakened in multiple ways that eventually activate the cell’s “controlled death” process. It also suggested further treatment opportunities to Dr. Lupu.

In breast cancer cells that produced the protein human epidermal growth factor receptor 2 (HER2) in high amounts, fatty acid synthase also was produced at high levels and, again, was linked to poor patient prognosis. HER2-positive breast cancer has an effective drug treatment. But, over time, tumor cells can become resistant, ramping up growth and division again. Dr. Lupu and her team knew that blocking fatty acid production weakened tumor cells. They now wondered if it might weaken the cancer cells enough to make them respond to the drug again. And it did. Blocking fatty acid synthase resensitized the tumor cells to the original treatment in cells, tissues and mice.

From discovery to clinical trials
Dr. Lupu and her team’s basic science research led to a drug development collaboration for a new fatty acid synthase inhibitor and a phase one clinical trial. While that trial is ongoing, Dr. Lupu, along with Tufia Haddad, M.D., a Mayo Clinic oncologist, have received phase two clinical trial funding to study the role of fatty acid synthase and possible treatment in breast cancer.

“At Mayo, the ability to work with patient samples and accessibility to others like clinicians, pathologists, statisticians and scientists who look at things completely differently creates the critical mass,” says Dr. Lupu. “It creates a research force that can go forward and think differently.”

And part of that force in Florida is exploring the same concept but from a different angle.

Starving kidney cancers
“I’ve always believed the answer is in the tumor,” says John Copland III, Ph.D., a cancer researcher at Mayo Clinic ‘s Florida campus.

Dr. Copland’s lab specializes in genetic profiling for patient tumor tissue. Using donated surgical and biopsy tissue, the lab sequences the genome of normal and cancerous tissue to suggest new therapies. The genes that are highly expressed in cancerous tissue but not in normal tissue provide an idea of what went wrong within the cell and perhaps what can be done to stop it. In the comparison of kidneys, the researchers tested the top 200 overexpressed genes to see which promoted tumor growth or cell proliferation. Of those, the 31 showed the most aggressive growth, making them good targets for drug development.

“SCD1 was one of those genes,” says Dr. Copland. “I knew nothing about it, but it’s these discovery processes that take us in new directions”

SCD1: Stearoyl-CoA deasaturase-1
The gene SCD translates into the enzyme stearoyl-CoA deasaturase-1 (SCD1). SCD1 plays its part just downstream from fatty acid synthase ─ the focus of Dr. Lupu’s research ─ and is part of the same cellular process that builds fatty acids. Just as Dr. Lupu did, Dr. Copland’s team looked for SCD1 in a number of aggressive cancers and they found the SCD gene turned on in most. Based on these findings, SCD1 seemed like a good bet for a drug. And SCD1-inhibitors had been developed for other treatments, such as diabetes, where SCD1 is elevated. So might the pharmaceutical companies be interested in collaborating?

Unfortunately, they were not. Dr. Copland didn’t find any company who wanted to resurrect their effort for cancer treatment. Fortunately, he had another option.

“We said, well, we’ll just make our own,” says Dr. Copland. “And we had the power to do that, because we have Tom Caulfield.”

Teamwork
Thomas Caulfield, Ph.D., is a computational chemist at Mayo Clinic. He consults with researchers to design new drugs using computational drug design, computational-based medical chemistry, and structural guided research.

To develop an SCD1-inhibitor, Dr. Caulfield created a computer program that learns from data and makes predictions about future options, called a machine learning algorithm.

“Beginning with 6 million compounds in the computer library, we reductively filter and reduce to a highly reliable set of pharmacophores, which can be imagined as Legos or Tetris,” Dr. Caulfield explains. “We’re popping in millions of different pieces until we get one that gives good physics in our equations.”

That means, Dr. Caulfield says, that, instead of testing thousands of compounds, they tested around 300.

Master builders find a match
Eventually, they came up with a new compound called “SCD1 specific inhibitor-4”, or SSI4. This compound blocks the enzyme created by the SCD1 gene, which prevents the cell from making monounsaturated fatty acids needed in the endoplasmic reticulum. When the cells sense this change, it starts the process of controlled cell death, or apoptosis.

“The endoplasmic reticulum is an area of the cell that, when cells get stressed, it tries to save the cell,” says Dr. Copland. “But if the stress becomes too much, it will actually trigger this apoptotic pathway and kill the cell.”

Currently, SSI4 has been tested in cell cultures. The next step, according to Dr. Copland, is to look for anti-tumor synergy with other drugs in tests using innovative animal models.

“We have those 31 targets [that are overexpressed in kidney cancer cells] that we can look at,” says Dr. Copland. “We can take them in different combinations and see which are the most effective.”

This ability to be nimble and provide a compound that will synergize with other drugs is key, explains Dr. Copland.

“You and I may be diagnosed with kidney cancer,” Dr. Copland says, “but your kidney cancer is going to be very different from mine even though it's in the same organ. Different gene pathways may be implicated in individual cancers, which is why patients have a varied response to treatment.”

But Dr. Copland is hopeful based on what he’s seen in cells. “We can stop the growth and kill the cells in the very aggressive tumors,” he says.

As Drs. Copland and Lupu’s new compounds make their way through the scientific process of discovery, translation to clinical trials and hopefully into the hands of clinicians, these enzyme inhibitors may provide a new way to cripple cancer cells, and a new hope for patients.

- Sara Tiner, September 2017