Nav: Home

Protein decoy stymies lung cancer growth in mice, Stanford-UCSF study finds

November 07, 2019

Scientists at Stanford and UC-San Francisco have developed an experimental drug that targets a currently untreatable type of lung cancer responsible for generating roughly 500,000 newly diagnosed cases worldwide each year.

A paper to be published online Nov. 7 in Nature Medicine reports that the researchers slowed the spread of this cancer in mice by neutralizing a single protein that would otherwise set off a chain reaction, causing runaway growth

The paper is the result of a long-term collaboration between Stanford bioengineer Jennifer Cochran, PhD, and UCSF cancer researcher Alejandro Sweet-Cordero, MD.

The researchers discovered how a particular type of protein known as a ligand hooks up with three receptor proteins to create conditions favorable for this cancer's spread. The researchers then engineered a decoy version of one of these receptors and delivered it to the tumor site, where it interfered with the growth mechanism behind the cancer.

"This is the second time we've shown how to engineer an effective decoy protein and used it to inhibit tumor growth in animals," said Cochran, the Shriram Chair of the Department of Bioengineering at Stanford, whose group initially developed this strategy in earlier experiments aimed at ovarian and breast cancers.

It was that earlier work which caught the attention of Sweet-Cordero, then a cancer researcher at the Stanford School of Medicine. In 2012, he published a paper showing how a protein called CLCF1 initiated a chain of events that accelerated growth in one of the three main variants of nonsmall cell lung cancer.

"CLCF1 binds to and activates three proteins found on the surface of tumor cells, and together they work to promote the growth of lung cancer," said Sweet-Cordero, who sought out Cochran in 2013 to propose that they work together to thwart this process.

The interdisciplinary collaboration they established continued after Sweet-Cordero joined the UCSF faculty at the end of 2016. His research team performed additional work that helped provide a detailed understanding of the mechanism behind CLCF1's effect on tumor growth. In addition, extensive work on cancer models established that blocking the CLCF1 ligand could be an effective strategy for treating lung cancer.

For its part, Cochran and her team of bioengineers found that designing a receptor decoy for lung cancer was far more complex than its earlier work with ovarian and breast cancer. In those cases, only two proteins, a ligand and a receptor, had to interact to spread the cancer, and the bioengineers sought to shut down that process by designing a mutated version of the receptor.

'Squirting gasoline around the edge of a fire'

But as Sweet-Cordero's research showed, tumor growth was accelerated by the interaction of the CLCF1 ligand with three receptor proteins. The cancer begins in the lung's epithelial cells, which line the surface of the lungs. These cells are nested within supportive cells called fibroblasts. The cancerous epithelial cells induce the fibroblasts to release CLCF1, which recruits the three receptors in a specific order: first, CLCF1 hooks up with CNTFR, and then this duo attracts two other receptor proteins, gp130 and LIFR. Together, these four proteins provide additional fuel to the tumor. "Imagine squirting gasoline around the edge of a fire," Sweet-Cordero said.

Cochran's bioengineers sought to dampen the flames by creating a receptor decoy based on CNTFR, the second protein in the chain, but they had to do so carefully. If the decoy CNTFR paired with CLCF1, and these two proteins then recruited the other two receptors, the proposed remedy could unintentionally fuel cancer growth.

"We had to design a decoy that did two things at once," Cochran said. "It had to preferentially bind tightly to CLCF1, edging out any naturally occurring CNTFR, and once locked in place, it had to repel gp130 and LIFR."

Jun Kim, a PhD student in Cochran's lab, led the painstaking work of designing this dual-purpose decoy. Think of proteins as moving puzzle pieces that fit together to form the body's molecular machinery. Using a variety of bioengineering techniques, Kim made eight, subtle tweaks to CNTFR's shape to increase the decoy's propensity to bind to CLCF1 while warding off gp130 and LIFR.

Neutralizing tumor growth

Cesar Marquez, an MD-PhD student at Stanford who is completing his dissertation in the Sweet-Cordero lab, carried out a series of experiments to test this engineered receptor decoy in mice with lung cancer. The experiments established that the decoy significantly neutralized the growth instigated by CLCF1 and slowed the cancer's spread.

It could require several years of further drug development and animal studies before the researchers can begin testing this treatment in humans. Once at that stage, the researchers are confident they'll be able to identify patients with this particular form of lung cancer because it is associated with mutations in a gene called KRAS. The presence or absence of the KRAS biomarker may identify patients who are most likely to benefit from the receptor decoy drug.

Cochran said her work with Sweet-Cordero is part of a long-term effort to increase the number of tools for fighting cancer.

It's too early to tell whether the decoy treatment will prove effective in patients. But Cochran is optimistic that the drug will be safe for use in humans, given there was no evidence of toxic side effects in mice. She has her fingers crossed in this regard, as a decoy drug based on her earlier work with ovarian cancer has already shown promising results in early clinical trials.

"As these studies show, when we combine detailed knowledge of a particular disease mechanism with bioengineering prowess, we can achieve some pretty powerful results," she said.
-end-
Cochran is a faculty fellow with Stanford ChEM-H, as well as a member of Stanford Bio-X, the Stanford Cardiovascular Institute, the Stanford Maternal & Child Health Research Institute, the Stanford Cancer Institute and Wu Tsai Neurosciences Institute at Stanford.

Joseph Shrager, MD, professor of cardiothoracic surgery at Stanford, and researchers at UCSF, the Spanish National Cancer Research Center, the Universidad de Navarra and the Centro de Investigación Biomédica en Red de Cáncer also contributed to the study.

Funding for the research was provided by the Howard Hughes Medical Institute, the Ruth L. Kirschstein National Service Research Award, the National Cancer Institute (R01CA225103) the Stanford Medical Scientist Training Program, Stanford Bio-X, the Swiss National Science Foundation, the Lungevity Foundation and Upstage Lung Cancer, the Stanford Coulter Foundation Translational Partnership Award and the American Lung Association.

Stanford's Department of Bioengineering, which also supported the study, is jointly managed by the Stanford School of Medicine and Stanford School of Engineering.

The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med.stanford.edu/school.html. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med.stanford.edu.

Print media contact: Tom Abate at (650) 736-2245 (tabate@stanford.edu)

Broadcast media contact: Margarita Gallardo at (650) 723-7897 (mjgallardo@stanford.edu)

Stanford Medicine

Related Lung Cancer Articles:

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Lung transplant patients face elevated lung cancer risk
In an American Journal of Transplantation study, lung cancer risk was increased after lung transplantation, especially in the native (non-transplanted) lung of single lung transplant recipients.
Proposed cancer treatment may boost lung cancer stem cells, study warns
Epigenetic therapies -- targeting enzymes that alter what genes are turned on or off in a cell -- are of growing interest in the cancer field as a way of making a cancer less aggressive or less malignant.
Are you at risk for lung cancer?
This question isn't only for people who've smoked a lot.
Better equipped in the fight against lung cancer
Lung cancer is the third most common type of cancer in Germany and the disease affects both men and women.
New liquid biopsy-based cancer model reveals data on deadly lung cancer
Small cell lung cancer (SCLC) accounts for 14 percent of all lung cancers and is often rapidly resistant to chemotherapy resulting in poor clinical outcomes.
Cancer drug leads to 'drastic decrease' in HIV infection in lung cancer patient
Doctors in France have found the first evidence that a cancer drug may be able to eradicate HIV-infected cells in humans.
Air pollution is associated with cancer mortality beyond lung cancer
A large scale epidemiological study associates some air pollutants with kidney, bladder and colorectal cancer death.
Free lung-cancer screening in the Augusta area finds more than double the cancer rate of previous screenings
The first year of free lung cancer screening in the Augusta, Ga., area found more than double the rate seen in a previous large, national study as well as a Massachusetts-based screening for this No.
Lung cancer may go undetected in kidney cancer patients
Could lung cancer be hiding in kidney cancer patients? Researchers with the Harold C.
More Lung Cancer News and Lung Cancer Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Risk
Why do we revere risk-takers, even when their actions terrify us? Why are some better at taking risks than others? This hour, TED speakers explore the alluring, dangerous, and calculated sides of risk. Guests include professional rock climber Alex Honnold, economist Mariana Mazzucato, psychology researcher Kashfia Rahman, structural engineer and bridge designer Ian Firth, and risk intelligence expert Dylan Evans.
Now Playing: Science for the People

#540 Specialize? Or Generalize?
Ever been called a "jack of all trades, master of none"? The world loves to elevate specialists, people who drill deep into a single topic. Those people are great. But there's a place for generalists too, argues David Epstein. Jacks of all trades are often more successful than specialists. And he's got science to back it up. We talk with Epstein about his latest book, "Range: Why Generalists Triumph in a Specialized World".
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at Radiolab.org/donate.