Nav: Home

NIH, Cincinnati Children's scientists develop possible strategy for cancer drug resistance

September 04, 2019

Scientists from the National Institutes of Health and Cincinnati Children's Hospital Medical Center have devised a potential treatment against a common type of leukemia that could have implications for many other types of cancer. The new approach takes aim at a way that cancer cells evade the effects of drugs, a process called adaptive resistance.

The researchers, in a range of studies, identified a cellular pathway that allows a form of acute myeloid leukemia (AML), a deadly blood and bone marrow cancer, to elude the activity of a promising class of drugs. They then engineered a compound that appears to launch a two-pronged attack against the cancer. In several experiments, the compound blocked a mutant protein that causes the AML. At the same time, it halted the cancer cells' ability to sidestep the compound's effects. The results, reported Sept. 4 in Science Translational Medicine, could lead to the development of new therapies against AML and cancers that act in similar ways.

Co-corresponding authors Daniel Starczynowski, Ph.D., at Cincinnati Children's, Craig Thomas, Ph.D., at NIH's National Center for Advancing Translational Sciences (NCATS) and their colleagues wanted to better understand drug resistance in a form of AML caused by a mutant protein called FLT3. This form of AML accounts for roughly 25% of all newly diagnosed AML cases, and patients often have a poor prognosis. A more thorough understanding of the drug resistance process could help them find ways to improve therapy options.

FLT3 belongs to a class of enzymes called kinases. Kinases are proteins that play a role in cell growth and proliferation. When kinases work overtime, they can cause some cancers. Drugs that block kinase activity have been effective in treating cancers. While many of these drugs work initially, often in combination with other therapies, cancer cells frequently find ways to bypass the drugs' effects and begin growing again. For many patients, this drug resistance can be deadly. FLT3 is always turned on in these cancer cells, sending chemical signals for the cells to grow and divide. Scientists have designed drugs to block FLT3 activity, but the AML cells eventually find ways to get the growth signals elsewhere.

To find out how this happens, Starczynowski's team treated FLT3-mutant cancer cells grown in the laboratory with an inhibitor drug. The drug initially killed many cancer cells. The scientists closely examined the AML cells that survived, including genes that were turned on and off in the resistant cells. They found that the leukemia cells were now getting chemical growth signals from different protein kinases through a system normally used by the immune system to respond to viruses and other invaders. Experiments on AML cells from patients treated with a FLT3 inhibitor showed similar results.

"We think that these leukemia cells were under stress from the FLT3 inhibitor drug because it was blocking the growth signals they badly wanted," Starczynowski said. "The cells found another way to get these signals through another route that compensated for this, a complex of the kinases IRAK1 and IRAK4, which are involved in the immune system."

To prove their theory, the scientists, in a series of experiments on leukemia cell models in the lab and cells from leukemia patients, showed that inhibiting FLT3 and IRAK1-IRAK4 activity at the same time was more toxic to cells relative to only inhibiting FLT3.

To prevent this drug resistance, the NCATS team worked to block the activity of FLT3 and the IRAK kinases with a single compound. Starting with an IRAK4 inhibitor, they developed a compound that was effective against all three protein kinases. These efforts led to a new compound, NCGC1481, that could effectively block the activity of the kinases in both human cancer cells in the lab and mouse models with cancer cells from patients. (NCGC is an acronym for the NCATS Chemical Genomics Center.)

"NCGC1481 not only stops the cancer cells' growth caused by the mutant protein, but also blocks the cancer's escape route," said first author Katelyn Melgar, Ph.D. "The result is a compound with superior activity in the models we tested."

The findings may be broadly applicable to many other cancers as well. "There is already evidence that this may be a general cancer resistance mechanism to protein kinase inhibitor drugs," Starczynowski said. "In theory, the use of drugs that affect many kinases at once, along with other kinds of cancer therapies, could be effective treatments."

For now, NCGC1481 is still a work in progress.

"Kinase inhibitor development aims to thread a needle between targets that are important, such as FLT3 and IRAK1-IRAK4, and targets that aren't," said Thomas. "We're still working on a final product that we hope can advance to clinical testing."
-end-
The research was funded by Cincinnati Children's Hospital Research Foundation, the Leukemia Lymphoma Society, CancerFree Kids, National Institutes of Health grants R35HL135787 (National Heart, Lung, and Blood Institute) and RO1DK113639 (National Institute of Diabetes and Digestive and Kidney Diseases), and the intramural research programs at NCATS and the National Cancer Institute. Support also came from National Institutes of Health Research Training and Career Development Grant F31CA217140.

About the National Center for Advancing Translational Sciences (NCATS): NCATS conducts and supports research on the science and operation of translation -- the process by which interventions to improve health are developed and implemented -- to allow more treatments to get to more patients more quickly. For more information about how NCATS is improving health through smarter science, visit https://ncats.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIH...Turning Discovery Into Health®

NCATS Communications Branch
ncatsinfo@mail.nih.gov
(301) 435-0888

NIH/National Center for Advancing Translational Sciences (NCATS)

Related Cancer Articles:

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.
Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
More Cancer News and Cancer Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#538 Nobels and Astrophysics
This week we start with this year's physics Nobel Prize awarded to Jim Peebles, Michel Mayor, and Didier Queloz and finish with a discussion of the Nobel Prizes as a way to award and highlight important science. Are they still relevant? When science breakthroughs are built on the backs of hundreds -- and sometimes thousands -- of people's hard work, how do you pick just three to highlight? Join host Rachelle Saunders and astrophysicist, author, and science communicator Ethan Siegel for their chat about astrophysics and Nobel Prizes.