Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scanning for cancer treatment

16.04.2019

Researchers combine CRISPR gene-editing technology with drug discovery to understand why treatment works (or doesn't)

11,000 people are predicted to die from acute myeloid leukemia (AML) in 2019, according to the American Cancer Society. The cancer starts in the bone marrow. There, mutated genes fail to prevent blood cells from replicating again and again and again, growing tumors.


Cancerous cells (dark purple) start to spread in a patient's bone marrow. Mutated genes often spark rampant AML cancer growth.

Credit: The Armed Forces Institute of Pathology (AFIP)

Chemotherapy helps two out of three patients achieve remission. And recently, drug developers designed a new attack, one intended to target the patient's malfunctioning genes, reclaim their hijacked cells, and halt growth. But this kind of drug development can result in more errors in trials, and can take years to get from lab to patient.

Now, in a paper published in Nature Chemical Biology, Harvard University Assistant Professor of Chemistry and Chemical Biology Brian Liau reveals why certain AML drugs only work some of the time. With his new technique, Liau and team expose more intimate details about the drug-body relationship and, in the process, disprove previous assumptions about how AML drugs work.

THE DRUG-BODY RELATIONSHIP

To test a new drug, developers manipulate their product's small molecules, shifting them to see how the changes impact the drug's efficacy.

To investigate how AML drugs work, the Liau group followed the same process. But, like a good mediator, they hunted down the other side of the story, too: What happens, they wanted to know, if we manipulate the protein target instead?

"As chemists, we have the ability to make nearly anything," Liau says. "Now, we have the unprecedented ability to systematically change protein structure directly in cells."

For their first mediation, the Liau group focused on a specific subtype of AML, whose mutated genes cause a shift in a blood cell's so-called epigenetic state. Epigenetic changes, in which chemical tags land on genes and turn them on or off, result from environmental triggers--what you eat, how much you exercise and sleep, and where you live, can all impact your epigenome.

In AML, the mutated genes are enough to trigger an epigenetic change and reprogram cells to grow uncontrollably. Since enzymes often regulate the conversation between the genes and their hostage cells, new drugs target these proteins, hoping to reverse their malfunction. For AML, this enzyme target is called LSD1 (lysine-specific histone demethylase 1).

So far, LDS1-targeting drugs only work sometimes. So, Liau and his team decided to uncover what makes the protein so slippery.

EXPLOITING WEAKNESS

Proteins, like bicycles, have both essential and non-essential parts (or domains). Without handlebars, the machine keeps moving; without wheels, it stops. So, the Liau group searched for LSD1's "wheels," which, once dismantled, would halt the protein and the disease.

To do so, the team used a technique called CRISPR-scanning. The gene-editing tool CRISPR can make precise cuts in the genetic code (DNA). So, the Liau group used the tool to execute systematic but random slices in many AML-relevant genes at once.

Then, when the cell steps in to repair the cut, tiny scars can form in the genome. These scars produce various kinds of mutant genes, and the mutant genes produce mutant proteins. One mutant loses handlebars, another pedals, and eventually, one loses its wheels. Even though the first two proteins lost some parts, their cancerous cells live on. But the last is immobilized; growth shuts down.

With their systematic approach, the Liau group can classify which LSD1 weaknesses drug developers can exploit. A well-designed drug can act like a pebble in a gear spoke: A small but effective way to impede the machine.

BUMPS AND HOLES

Some mutations can strengthen rather than weaken: The protein might acquire a new set of wheels that are impervious to drugs.

To determine which mutations might hinder drug efficacy, the Liau group examines how a drug interacts with each mutant (a technique called CRISPR-suppressor scanning). Once again, some mutants die while others persist to continue malignant growth. Developers can use this information to tweak their drug and subvert the protein's new defenses.

"Maybe I add something on the drug, like make it bigger or add a bump," Liau says. "Or maybe I add something to the protein, like a hole. If the bump-hole complement each other, we can tease this information apart with the methodology."

Using CRISPR-suppressor scanning, his group explored how bumps and holes might affect the relationship between the AML mutant LSD1 and drugs currently under development to treat the cancer. What they found surprised him.

Drugs that target LSD1 shut down the protein's enzymatic function. But, this function is not as critical to cancer growth as previously assumed. The Liau group discovered that the drugs can end up cutting off communication between LSD1 and a transcription factor (GFI1B).

Even though the drugs worked because they (sometimes) disrupted both actions, the Liau group's new technique showed that the LSD1-GFI1B relationship is the most critical for AML survival. Their discovery could also explain why certain AML subtypes rely so heavily on LSD1. Armed with this new information, drug developers can focus their work, hasten drug development, and produce more targeted treatment.

Next, Liau and his team plan to investigate more bumps and holes on LSD1, the protein's darkest corners, and other cancer-relevant proteins. Before, according to Liau, "It wasn't appreciated or understood why certain cancers were sensitive to LSD1 inhibitors." Now, his technique could reveal new and more potent sensitivities, leading to more effective and efficient treatments for cancer.

Media Contact

Caitlin McDermott-Murphy
cmcdermottmurphy@fas.harvard.edu
617-496-2618

 @HarvardResearch

http://www.harvard.edu 

Caitlin McDermott-Murphy | EurekAlert!
Further information:
https://chemistry.harvard.edu/news/scanning-cancer-treatment
http://dx.doi.org/10.1038/s41589-019-0263-0

More articles from Life Sciences:

nachricht A human liver cell atlas
15.07.2019 | Max Planck Institute of Immunobiology and Epigenetics

nachricht Researchers reveal mechanisms for regulating temperature sensitivity of soil organic matter decompos
15.07.2019 | Chinese Academy of Sciences Headquarters

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Artificial neural network resolves puzzles from condensed matter physics: Which is the perfect quantum theory?

For some phenomena in quantum many-body physics several competing theories exist. But which of them describes a quantum phenomenon best? A team of researchers from the Technical University of Munich (TUM) and Harvard University in the United States has now successfully deployed artificial neural networks for image analysis of quantum systems.

Is that a dog or a cat? Such a classification is a prime example of machine learning: artificial neural networks can be trained to analyze images by looking...

Im Focus: Extremely hard yet metallically conductive: Bayreuth researchers develop novel material with high-tech prospects

An international research group led by scientists from the University of Bayreuth has produced a previously unknown material: Rhenium nitride pernitride. Thanks to combining properties that were previously considered incompatible, it looks set to become highly attractive for technological applications. Indeed, it is a super-hard metallic conductor that can withstand extremely high pressures like a diamond. A process now developed in Bayreuth opens up the possibility of producing rhenium nitride pernitride and other technologically interesting materials in sufficiently large quantity for their properties characterisation. The new findings are presented in "Nature Communications".

The possibility of finding a compound that was metallically conductive, super-hard, and ultra-incompressible was long considered unlikely in science. It was...

Im Focus: Modelling leads to the optimum size for platinum fuel cell catalysts: Activity of fuel cell catalysts doubled

An interdisciplinary research team at the Technical University of Munich (TUM) has built platinum nanoparticles for catalysis in fuel cells: The new size-optimized catalysts are twice as good as the best process commercially available today.

Fuel cells may well replace batteries as the power source for electric cars. They consume hydrogen, a gas which could be produced for example using surplus...

Im Focus: The secret of mushroom colors

Mushrooms: Darker fruiting bodies in cold climates

The fly agaric with its red hat is perhaps the most evocative of the diverse and variously colored mushroom species. Hitherto, the purpose of these colors was...

Im Focus: First results of the new Alphatrap experiment

Physicists at the Max Planck Institute for Nuclear Physics in Heidelberg report the first result of the new Alphatrap experiment. They measured the bound-electron g-factor of highly charged (boron-like) argon ions with unprecedented precision of 9 digits. In comparison with a new highly accurate quantum electrodynamic calculation they found an excellent agreement on a level of 7 digits. This paves the way for sensitive tests of QED in strong fields like precision measurements of the fine structure constant α as well as the detection of possible signatures of new physics. [Physical Review Letters, 27 June 2019]

Quantum electrodynamics (QED) describes the interaction of charged particles with electromagnetic fields and is the most precisely tested physical theory. It...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on UV LED Technologies & Applications – ICULTA 2020 | Call for Abstracts

24.06.2019 | Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

 
Latest News

A human liver cell atlas

15.07.2019 | Life Sciences

No more trial-and-error when choosing an electrolyte for metal-air batteries

15.07.2019 | Power and Electrical Engineering

Possibilities of the biosimilar principle of learning are shown for a memristor-based neural network

15.07.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>