Nav: Home

Study may explain why once-promising cancer drugs failed

January 24, 2019

DURHAM, N.C. -- Nearly two decades after a class of once-promising cancer drugs called MMP inhibitors mysteriously failed in clinical trials, scientists think they may have an explanation for what went wrong.

The findings in C. elegans worms could lead to better ways to prevent the first steps of metastasis, the spread of the disease responsible for 90 percent of cancer deaths.

MMP inhibitors were aimed at blocking a group of enzymes long thought key to cancer's spread. Called matrix metalloproteinases, the enzymes help dissolve the tough outer membrane that surrounds both tumors and healthy tissues, allowing cancer cells to escape from their original locations and set up shop in other organs.

Yet despite promising results in mice, MMP inhibitors didn't help people with cancer live longer and some patients developed serious side effects.

The new findings, from a team led by biology professor David Sherwood at Duke University, suggest that invasive cells switch to brute force and build a battering ram when their dissolving enzymes aren't available.

The study will appear online January 24 in the journal Developmental Cell.

To metastasize, a tumor cell must first penetrate a dense sheet-like mesh of proteins and other molecules called the basement membrane, which surrounds tissues like a Kevlar wrapper.

Sherwood and his team study a similar process in transparent 1-millimeter worms, which -- unlike human tumors -- allow researchers to watch invading cells in action.

Normal worm cells use their MMP enzymes to help cut through the matrix of proteins in the basement membrane like molecular scissors, the researchers say. But cells in "knockout" worms lacking the MMP enzymes instead build a large protrusion that pummels and smashes its way through with brute force, said research scientist Laura Kelley, who led the experiments.

Normally the invading cell pushes through a narrow hole, "kind of like the escape tunnel in 'The Shawshank Redemption,'" Sherwood said. "But in knockout worms it's more like the Kool-Aid Man when he busts through walls."

The researchers also found that the protrusion is filled with stiff networks of actin filaments for a harder-hitting punch. To fuel the blows, the cell also moves mitochondria -- the power plants of the cell -- to the site of the ram.

The team also developed a screening technique that enabled them to identify and target a mitochondrial gene that invasive cells rely on in the absence of MMPs, and were able to prevent the cells from breaking through.

The researchers hope their work in worms will identify drug targets that could one day be tested in combination with MMP inhibitors to better treat metastasis in humans.

If researchers can develop drugs that inhibit both MMP enzymes and the battering rams, they may be able to more effectively block cell invasion and keep cancer from spreading.
-end-
This research was funded by the American Cancer Society (129351-PF-16-024-01-CSM), the Leukemia and Lymphoma Society (3601-11/388-0036), the National Cancer Institute (4R00CA154870-03), the National Institutes of Health (F32GM103148, NIGMS R35, MIRA GM118049, R21HD084290), Foundation Association pour la Recherche sur le Cancer and the PSL Research University (ANR-10-IDEX-0001-02 PSL).

Other authors include Qiuyi Chi, Eric Hastie, Adam Schindler and Yue Jiang of Duke; Rodrigo Cáceres and Julie Plastino of the Curie Institute and Sorbonne University in Paris; and David Matus of Stony Brook University.

CITATION: "Adaptive F-actin Polymerization and Localized ATP Production Drive Basement Membrane Invasion in the Absence of MMPs," Laura Kelley, Qiuyi Chi, Rodrigo Cáceres, Eric Hastie, Adam Schindler, Yue Jiang, David Matus, Julie Plastino and David Sherwood. Developmental Cell, January 24, 2019. DOI: 10.1016/j.devcel.2018.12.018.

Duke University

Related Cancer Articles:

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
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.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.