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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.
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.
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A Mercury-bound spacecraft's noisy flyby of our home planet.
- There is no sound in space, but if there was, this is what it might sound like passing by Earth.
- A spacecraft bound for Mercury recorded data while swinging around our planet, and that data was converted into sound.
- Yes, in space no one can hear you scream, but this is still some chill stuff.
First off, let's be clear what we mean by "hear" here. (Here, here!)
Sound, as we know it, requires air. What our ears capture is actually oscillating waves of fluctuating air pressure. Cilia, fibers in our ears, respond to these fluctuations by firing off corresponding clusters of tones at different pitches to our brains. This is what we perceive as sound.
All of which is to say, sound requires air, and space is notoriously void of that. So, in terms of human-perceivable sound, it's silent out there. Nonetheless, there can be cyclical events in space — such as oscillating values in streams of captured data — that can be mapped to pitches, and thus made audible.
Image source: European Space Agency
The European Space Agency's BepiColombo spacecraft took off from Kourou, French Guyana on October 20, 2019, on its way to Mercury. To reduce its speed for the proper trajectory to Mercury, BepiColombo executed a "gravity-assist flyby," slinging itself around the Earth before leaving home. Over the course of its 34-minute flyby, its two data recorders captured five data sets that Italy's National Institute for Astrophysics (INAF) enhanced and converted into sound waves.
Into and out of Earth's shadow
In April, BepiColombo began its closest approach to Earth, ranging from 256,393 kilometers (159,315 miles) to 129,488 kilometers (80,460 miles) away. The audio above starts as BepiColombo begins to sneak into the Earth's shadow facing away from the sun.
The data was captured by BepiColombo's Italian Spring Accelerometer (ISA) instrument. Says Carmelo Magnafico of the ISA team, "When the spacecraft enters the shadow and the force of the Sun disappears, we can hear a slight vibration. The solar panels, previously flexed by the Sun, then find a new balance. Upon exiting the shadow, we can hear the effect again."
In addition to making for some cool sounds, the phenomenon allowed the ISA team to confirm just how sensitive their instrument is. "This is an extraordinary situation," says Carmelo. "Since we started the cruise, we have only been in direct sunshine, so we did not have the possibility to check effectively whether our instrument is measuring the variations of the force of the sunlight."
When the craft arrives at Mercury, the ISA will be tasked with studying the planets gravity.
The second clip is derived from data captured by BepiColombo's MPO-MAG magnetometer, AKA MERMAG, as the craft traveled through Earth's magnetosphere, the area surrounding the planet that's determined by the its magnetic field.
BepiColombo eventually entered the hellish mangentosheath, the region battered by cosmic plasma from the sun before the craft passed into the relatively peaceful magentopause that marks the transition between the magnetosphere and Earth's own magnetic field.
MERMAG will map Mercury's magnetosphere, as well as the magnetic state of the planet's interior. As a secondary objective, it will assess the interaction of the solar wind, Mercury's magnetic field, and the planet, analyzing the dynamics of the magnetosphere and its interaction with Mercury.
Recording session over, BepiColombo is now slipping through space silently with its arrival at Mercury planned for 2025.
Erin Meyer explains the keeper test and how it can make or break a team.
- There are numerous strategies for building and maintaining a high-performing team, but unfortunately they are not plug-and-play. What works for some companies will not necessarily work for others. Erin Meyer, co-author of No Rules Rules: Netflix and the Culture of Reinvention, shares one alternative employed by one of the largest tech and media services companies in the world.
- Instead of the 'Rank and Yank' method once used by GE, Meyer explains how Netflix managers use the 'keeper test' to determine if employees are crucial pieces of the larger team and are worth fighting to keep.
- "An individual performance problem is a systemic problem that impacts the entire team," she says. This is a valuable lesson that could determine whether the team fails or whether an organization advances to the next level.