Drug makes tumors more susceptible to chemo

One compound could help combat drug resistance.

Many chemotherapy drugs kill cancer cells by severely damaging their DNA.


However, some tumors can withstand this damage by relying on a DNA repair pathway that not only allows them to survive, but also introduces mutations that helps cells become resistant to future treatment.

Researchers at MIT and Duke University have now discovered a potential drug compound that can block this repair pathway. "This compound increased cell killing with cisplatin and prevented mutagenesis, which is was what we expected from blocking this pathway," says Graham Walker, the American Cancer Society Research Professor of Biology at MIT, a Howard Hughes Medical Institute Professor, and one of the senior authors of the study.

When they treated mice with this compound along with cisplatin, a DNA-damaging drug, tumors shrank much more than those treated with cisplatin alone. Tumors treated with this combination would be expected not to develop new mutations that could make them drug-resistant.

Cisplatin, which is used as the first treatment option for at least a dozen types of cancer, often successfully destroys tumors, but they frequently grow back following treatment. Drugs that target the mutagenic DNA repair pathway that contributes to this recurrence could help to improve the long-term effectiveness of not only cisplatin but also other chemotherapy drugs that damage DNA, the researchers say.

"We're trying to make the therapy work better, and we also want to make the tumor recurrently sensitive to therapy upon repeated doses," says Michael Hemann, an associate professor of biology, a member of MIT's Koch Institute for Integrative Cancer Research, and a senior author of the study.

Pei Zhou, a professor of biochemistry at Duke University, and Jiyong Hong, a professor of chemistry at Duke, are also senior authors of the paper, which appears in the June 6 issue of Cell. The lead authors of the paper are former Duke graduate student Jessica Wojtaszek, MIT postdoc Nimrat Chatterjee, and Duke research assistant Javaria Najeeb.

Overcoming resistance

Healthy cells have several repair pathways that can accurately remove DNA damage from cells. As cells become cancerous, they sometimes lose one of these accurate DNA repair systems, so they rely heavily on an alternative coping strategy known as translesion synthesis (TLS).

This process, which Walker has been studying in a variety of organisms for many years, relies on specialized TLS DNA polymerases. Unlike the normal DNA polymerases used to replicate DNA, these TLS DNA polymerases can essentially copy over damaged DNA, but the copying they perform is not very accurate. This enables cancer cells to survive treatment with a DNA-damaging agent such as cisplatin, and it leads them to acquire many additional mutations that can make them resistant to further treatment.

"Because these TLS DNA polymerases are really error-prone, they are accountable for nearly all of the mutation that is induced by drugs like cisplatin," Hemann says. "It's very well-established that with these frontline chemotherapies that we use, if they don't cure you, they make you worse."

One of the key TLS DNA polymerases required for translesion synthesis is Rev1, and its primary function is to recruit a second TLS DNA polymerase that consists of a complex of the Rev3 and Rev7 proteins. Walker and Hemann have been searching for ways to disrupt this interaction, in hopes of derailing the repair process.

In a pair of studies published in 2010, the researchers showed that if they used RNA interference to reduce the expression of Rev1, cisplatin treatment became much more effective against lymphoma and lung cancer in mice. While some of the tumors grew back, the new tumors were not resistant to cisplatin and could be killed again with a new round of treatment.

After showing that interfering with translesion synthesis could be beneficial, the researchers set out to find a small-molecule drug that could have the same effect. Led by Zhou, the researchers performed a screen of about 10,000 potential drug compounds and identified one that binds tightly to Rev1, preventing it from interacting with Rev3/Rev7 complex.

The interaction of Rev1 with the Rev7 component of the second TLS DNA polymerase had been considered "undruggable" because it occurs in a very shallow pocket of Rev1, with few features that would be easy for a drug to latch onto. However, to the researchers' surprise, they found a molecule that actually binds to two molecules of Rev1, one at each end, and brings them together to form a complex called a dimer. This dimerized form of Rev1 cannot bind to the Rev3/Rev7 TLS DNA polymerase, so translesion synthesis cannot occur.

Chatterjee tested the compound along with cisplatin in several types of human cancer cells and found that the combination killed many more cells than cisplatin on its own. And, the cells that survived had a greatly reduced ability to generate new mutations.

"Because this novel translesion synthesis inhibitor targets the mutagenic ability of cancer cells to resist therapy, it can potentially address the issue of cancer relapse, where cancers continue to evolve from new mutations and together pose a major challenge in cancer treatment," Chatterjee says.

A powerful combination

Chatterjee then tested the drug combination in mice with human melanoma tumors and found that the tumors shrank much more than tumors treated with cisplatin alone. They now hope that their findings will lead to further research on compounds that could act as translesion synthesis inhibitors to enhance the killing effects of existing chemotherapy drugs.

Zhou's lab at Duke is working on developing variants of the compound that could be developed for possible testing in human patients. Meanwhile, Walker and Hemann are further investigating how the drug compound works, which they believe could help to determine the best way to use it.

"That's a future major objective, to identify in which context this combination therapy is going to work particularly well," Hemann says. "We would hope that our understanding of how these are working and when they're working will coincide with the clinical development of these compounds, so by the time they're used, we'll understand which patients they should be given to."

The research was funded, in part, by an Outstanding Investigator Award from the National Institute of Environmental Health Sciences to Walker, and by grants from the National Cancer Institute, the Stewart Trust, and the Center for Precision Cancer Medicine at MIT.

Reprinted with permission of MIT News. Read the original article.


3D printing might save your life one day. It's transforming medicine and health care.

What can 3D printing do for medicine? The "sky is the limit," says Northwell Health researcher Dr. Todd Goldstein.

Northwell Health
Sponsored by Northwell Health
  • Medical professionals are currently using 3D printers to create prosthetics and patient-specific organ models that doctors can use to prepare for surgery.
  • Eventually, scientists hope to print patient-specific organs that can be transplanted safely into the human body.
  • Northwell Health, New York State's largest health care provider, is pioneering 3D printing in medicine in three key ways.
Keep reading Show less

Michio Kaku: Genetic and digital immortality are within reach

Technology may soon grant us immortality, in a sense. Here's how.

Videos
  • Through the Connectome Project we may soon be able to map the pathways of the entire human brain, including memories, and create computer programs that evoke the person the digitization is stemmed from.
  • We age because errors build up in our cells — mitochondria to be exact.
  • With CRISPR technology we may soon be able to edit out errors that build up as we age, and extend the human lifespan.
Keep reading Show less

Active ingredient in Roundup found in 95% of studied beers and wines

The controversial herbicide is everywhere, apparently.

(MsMaria/Shutterstock)
Surprising Science
  • U.S. PIRG tested 20 beers and wines, including organics, and found Roundup's active ingredient in almost all of them.
  • A jury on August 2018 awarded a non-Hodgkin's lymphoma victim $289 million in Roundup damages.
  • Bayer/Monsanto says Roundup is totally safe. Others disagree.
Keep reading Show less

Robot pizza delivery coming later this year from Domino's

The pizza giant Domino's partners with a Silicon Valley startup to start delivering pizza by robots.

Nuro
Technology & Innovation
  • Domino's partnered with the Silicon Valley startup Nuro to have robot cars deliver pizza.
  • The trial run will begin in Houston later this year.
  • The robots will be half a regular car and will need to be unlocked by a PIN code.

Would you have to tip robots? You might be answering that question sooner than you think as Domino's is about to start using robots for delivering pizza. Later this year a fleet of self-driving robotic vehicles will be spreading the joy of pizza throughout the Houston area for the famous pizza manufacturer, using delivery cars made by the Silicon Valley startup Nuro.

The startup, founded by Google veterans, raised $940 million in February and has already been delivering groceries for Kroger around Houston. Partnering with the pizza juggernaut Domino's, which delivers close to 3 million pizzas a day, is another logical step for the expanding drone car business.

Kevin Vasconi of Domino's explained in a press release that they see these specially-designed robots as "a valuable partner in our autonomous vehicle journey," adding "The opportunity to bring our customers the choice of an unmanned delivery experience, and our operators an additional delivery solution during a busy store rush, is an important part of our autonomous vehicle testing."

How will they work exactly? Nuro explained in its own press release that this "opportunity to use Nuro's autonomous delivery" will be available for some of the customers who order online. Once they opt in, they'll be able to track the car via an app. When the vehicle gets to them, the customers will use a special PIN code to unlock the pizza compartment.

Nuro and its competitors Udelv and Robomart have been focusing specifically on developing such "last-mile product delivery" machines, reports Arstechnica. Their specially-made R1 vehicle is about half the size of a regular passenger car and doesn't offer any room for a driver. This makes it safer and lighter too, with less potential to cause harm in case of an accident. It also sticks to a fairly low speed of under 25 miles an hour and slams on the breaks at the first sign of trouble.

What also helps such robot cars is "geofencing" technology which confines them to a limited area surrounding the store.

For now, the cars are still tracked around the neighborhoods by human-driven vehicles, with monitors to make sure nothing goes haywire. But these "chase cars" should be phased out eventually, an important milestone in the evolution of your robot pizza drivers.

Check out how Nuro's vehicles work: