by Carrie Wells <[log in to unmask]>
The Baltimore Sun
June 16, 2017

Hasini Jayatilaka was a sophomore at the Johns 
Hopkins University working in a lab studying 
cancer cells when she noticed that when the cells 
become too densely packed, some would break off and start spreading.

She wasn't sure what to make of it, until she 
attended an academic conference and heard a 
speaker talking about bacterial cells behaving 
the same way. Yet when she went through the 
academic literature to see if anyone had written 
about similar behavior in cancer cells, she found nothing.

Seven years later, the theory Jayatilaka 
developed early in college is now a bona fide 
discovery that offers significant promise for cancer treatment.

Jayatilaka and a team at Johns Hopkins discovered 
the biochemical mechanism that tells cancer cells 
to break off from the primary tumor and spread 
throughout the body, a process called metastasis. 
Some 90 percent of cancer deaths are caused when 
cancer metastasizes. The team also found that two 
existing, FDA-approved drugs can slow metastasis significantly.

"A female patient with 
cancer doesn't succumb to the disease just 
because she has a mass on her breast; she 
succumbs to the disease because [when] it spreads 
either to the lungs, the liver, the brain, it 
becomes untreatable," said Jayatilaka, who earned 
her doctorate in chemical and biomolecular 
engineering this spring in addition to her 
earlier undergraduate degree at Hopkins.

"There are really no therapeutics out there right 
now that directly target the spread of cancer. So 
what we came up with through our studies was this 
drug cocktail that could potentially inhibit the spread of cancer."

The study was published online May 26 in the 
journal Nature Communications. The next step for 
the team is to test the effectiveness of the drugs in human subjects.

Typically, cancer research and treatment has 
focused on shrinking the primary tumor through 
chemotherapy or other methods. But, the team 
said, by attacking the deadly process of 
metastasis, more patients could survive.

"It's not this primary tumor that's going to kill 
you typically," said Denis Wirtz, Johns Hopkins' 
vice provost for research and director of its 
Physical Sciences-Oncology Center, who was a senior author on the paper.

Jayatilaka began by studying how cancer cells 
behave and communicate with each other, using a 
three-dimensional model that mimics human tissue 
rather than looking at them in a petri dish. Many 
researchers believe metastasis happens after the 
primary tumor reaches a certain size, but 
Jayatilaka found it was the tumor's density that 
determined when it would metastasize.

"If you look at the human population, once we 
become too dense in an area, we move out to the 
suburbs or wherever, and we decide to set up shop 
there," Jayatilaka said. "I think the cancer 
cells are doing the same 

When the tumor reaches a certain density, the 
study found, it releases two proteins called 
Interleukin 6 and Interleukin 8, signaling to 
cancer cells that things had grown too crowded 
and it was time to break off and head into other parts of the body.

Previously, Wirtz said, the act of a tumor 
growing and the act of cancer cells spreading 
were thought to be very separate activities, 
because that's how it appeared by studying cancer 
cells in a petri dish, rather than the 3-D model 
the Hopkins team used. Many researchers study 
only cancer cell growth or its spread, and don't 
communicate with each other often, he said.

Once the cancer cells start to sense the presence 
of too many other cancer cells around them, they 
start secreting the Interleukin proteins, Wirtz 
said. If those proteins are added to a tumor that 
hasn't yet metastasized, that process would begin, he said.

The team then tested two drugs known to work on 
the Interleukin receptors to see if they would 
block or slow metastasis in mice. They found that 
using the two drugs together would block the 
signals from the Interleukin proteins that told 
the cancer cells to break off and spread, slowing 
 though not completely stopping  metastasis.

The drugs the team used were Tocilizumab, a 
rheumatoid arthritis treatment, and Reparixin, 
which is being evaluated for cancer treatment.

The drugs bind to the Interleukin receptors and 
block their signals, slowing metastasis.

Though metastasis was not completely stopped, 
Jayatilaka said, the mice given the drug cocktail 
fared well and survived through the experiment. 
She said adding another, yet-to-be-determined 
drug or tweaking the dose might stop metastasis entirely.

Contrary to the hair loss, nausea and other 
negative side effects patients undergoing 
chemotherapy suffer, Wirtz said the side effects 
from the drugs used in the study would be minimal.

Anirban Maitra, co-director of a pancreatic 
cancer research center at the MD Anderson Cancer 
Center at the University of Texas, cautioned that 
clinical trials in humans are needed to prove the theory.

"There's a risk that something that looks so 
great in an animal model won't pan out in a human," he said.

But Maitra said the study looked promising, in 
particular because the researchers had used drugs 
already on the market. It can take a decade to 
identify a drug that would perform similarly and 
get it approved, and many similar observations 
don't advance because of the time and expense it 
can take to get drug approval, he said.

Muhammad Zaman, a professor and cancer expert at 
Boston University, called the Hopkins discovery "exciting."

"This paper gives you a very specific target to 
design drugs against," he said. "That's really 
quite spectacular from the point of view of drug 
design and creating therapies."

Zaman said it was important for cancer 
researchers to use engineering to better 
understand cancer, as the Hopkins team did.

"This really brings cancer and engineering 
together in a very unique way, and it really 
takes an approach that is quantitative and 
rigorous," he said. "We have to think of cancer 
as a complex system, not just a disease."

Wirtz predicted a future where cancer would be 
fought with a mix of chemotherapy to shrink the 
primary tumor and drug cocktails like the one the 
Hopkins team developed to ensure it would not 
metastasize. He compared such a treatment to how HIV/AIDS is treated today.

"We're not going to cure cancer with one therapy 
or even two therapies; it's going to be drug 
cocktails," Wirtz said. "That's what saved the day with HIV/AIDS."

Immunotherapy, which uses the body's immune 
system to fight cancer, also could play a role in 
a combined method, Wirtz added.

"We're, in research, sometimes incentivized to 
look at one pathway at a time, one type of cancer 
at a time," Wirtz said. "I think oncology has 
started realizing we're going to need more than one approach."