New Plan of Attack in Cancer Fight: Two-Drug Combination, Under Certain Circumstances, Can Eliminate Disease

New research is laying out a road map to one of the holy grails of modern medicine: a cure for cancer. (Credit: © Ivelin Radkov / Fotolia)

July 19, 2013 — New research conducted by Harvard scientists is laying out a road map to one of the holy grails of modern medicine: a cure for cancer.

As described in a paper recently published in eLife, Martin Nowak, a professor of mathematics and of biology and director of the Program for Evolutionary Dynamics, and co-author Ivana Bozic, a postdoctoral fellow in mathematics, show that, under certain conditions, using two drugs in a "targeted therapy" -- a treatment approach designed to interrupt cancer's ability to grow and spread -- could effectively cure nearly all cancers.

Though the research is not a cure for cancer, Nowak said it does offer hope to researchers and patients alike.

"In some sense this is like the mathematics that allows us to calculate how to send a rocket to the moon, but it doesn't tell you how to build a rocket that goes to the moon," Nowak said. "What we found is that if you have a single point mutation in the genome that can give rise to resistance to both drugs at the same time, the game is over. We need to have combinations such that there is zero overlap between the drugs."

Importantly, Nowak said, for the two-drug combination to work, both drugs must be given together -- an idea that runs counter to the way many clinicians treat cancer today.

"We actually have to work against the status quo somewhat," he said. "But we can show in our model that if you don't give the drugs simultaneously, it guarantees treatment failure."

In earlier studies, Nowak and colleagues showed the importance of using multiple drugs. Though temporarily effective, single-drug targeted therapy will fail, the researchers revealed, because the disease eventually develops resistance to the treatment.

To determine if a two-drug combination would work, Nowak and Bozic turned to an expansive data set supplied by clinicians at New York's Memorial Sloan-Kettering Cancer Center that showed how patients respond to single-drug therapy. With data in hand, they were able to create computer models of how multidrug treatments would work. Using that model, they then treated a series of "virtual patients" to determine how the disease would react to the multidrug therapy.

"For a single-drug therapy, we know there are between 10 and 100 places in the genome that, if mutated, can give rise to resistance," Nowak explained. "So the first parameter we use when we make our calculations is that the first drug can be defeated by those possible mutations. The second drug can also be defeated by 10 to 100 mutations.

"If any of those mutations are the same, then it's a disaster," he continued. "If there's even a single mutation that can defeat both drugs, that is usually good enough for the cancer -- it will become resistant, and treatment will fail. What this means is we have to develop drugs such that the cancer needs to make two independent steps -- if we can do that, we have a good chance to contain it."

How good a chance?

"You would expect to cure most patients with a two-drug combination," Bozic said. "In patients with a particularly large disease burden you might want to use a three-drug combination, but you would cure most with two drugs."

The trick now, Nowak and Bozic said, is to develop those drugs.

To avoid developing drugs that are not vulnerable to the same mutation, Bozic said, pharmaceutical companies have explored a number of strategies, including using different drugs to target different pathways in cancer's development.

"There are pharmaceutical companies here in Cambridge that are working to develop these drugs," Nowak said. "There may soon be as many as 100 therapies, which means there will be as many as 10,000 possible combinations, so we should have a good repertoire to choose from.

"I think we can be confident that, within 50 years, many cancer deaths will be prevented," Nowak added. "One hundred years ago, many people died from bacterial infections, and now they would be cured. Today, many people die from cancer, and we can't help them, but I think once we have these targeted therapies, we will be able to help many people -- maybe not everyone -- but many people."

Story Source:

The above story is reprinted from materials provided byHarvard University. The original article was written by Peter Reuell.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Ivana Bozic, Johannes G Reiter, Benjamin Allen, Tibor Antal, Krishnendu Chatterjee, Preya Shah, Yo Sup Moon, Amin Yaqubie, Nicole Kelly, Dung T Le, Evan J Lipson, Paul B Chapman, Luis A Diaz, Bert Vogelstein, Martin A Nowak.Evolutionary dynamics of cancer in response to targeted combination therapy. eLife, 2013 DOI:10.7554/eLife.00747.001

Snow in an Infant Solar System: A Frosty Landmark for Planet and Comet Formation

An artist's concept of the snow line in TW Hydrae showing water ice covered dust grains in the inner disc (4.5–30 astronomical units, blue) and carbon monoxide ice covered grains in the outer disc (>30 astronomical units, green). The transition from blue to green marks the carbon monoxide snow line. The snow helps grains of dust to adhere to each other by providing a sticky coating, which is essential to the formation of planets and comets. Due to the different freezing points of different chemical compounds, different snow lines can be found at various distances from the star. (Credit: B. Saxton & A. Angelich/NRAO/AUI/NSF/ALMA (ESO/NAOJ/NRAO))

July 18, 2013 — A snow line has been imaged in a far-off infant solar system for the very first time. The snow line, located in the disc around the Sun-like star TW Hydrae, promises to tell us more about the formation of planets and comets, the factors that decide their composition, and the history of the Solar System.

The results are published today inScience Express.

Astronomers using the Atacama Large Millimeter/submillimeter Array have taken the first ever image of the snow line in an infant solar system. On Earth, snow lines form at high altitudes where falling temperatures turn the moisture in the air into snow. This line is clearly visible on a mountain, where the snow-capped summit ends and the rocky face begins.

The snow lines around young stars form in a similar way, in the distant, colder reaches of the dusty discs from which solar systems form. Starting from the star and moving outwards, water (H₂O) is the first to freeze, forming the first snow line. Further out from the star, as temperatures drop, more exotic molecules can freeze and turn to snow, such as carbon dioxide (CO₂), methane (CH₄), and carbon monoxide (CO). These different snows give the dust grains a sticky outer coating and play an essential role in helping the grains to overcome their usual tendency to break up in collisions, allowing them to become the crucial building blocks of planets and comets. The snow also increases how much solid matter is available and may dramatically speed up the planetary formation process.

Each of these different snow lines -- for water, carbon dioxide, methane and carbon monoxide -- may be linked to the formation of particular kinds of planets [1]. Around a Sun-like star in a solar system like our own, the water snow line would correspond to a distance between the orbits of Mars and Jupiter, and the carbon monoxide snow line would correspond to the orbit of Neptune.

The snow line spotted by ALMA is the first glimpse of the carbon monoxide snow line, around TW Hydrae, a young star 175 light-years away from Earth. Astronomers believe this budding solar system shares many of the same characteristics of the Solar System when it was just a few million years old.

"ALMA has given us the first real picture of a snow line around a young star, which is extremely exciting because of what it tells us about the very early period in the history of the Solar System," said Chunhua "Charlie" Qi (Harvard-Smithsonian Center for Astrophysics, Cambridge, USA) one of the two lead authors of the paper. "We can now see previously hidden details about the frozen outer reaches of another solar system similar to our own."

But the presence of a carbon monoxide snow line could have greater consequences than just the formation of planets. Carbon monoxide ice is needed to form methanol, which is a building block of the more complex organic molecules that are essential for life. If comets ferried these molecules to newly forming Earth-like planets, these planets would then be equipped with the ingredients necessary for life.

Before now, snow lines had never been imaged directly because they always form in the relatively narrow central plane of a protoplanetary disc, so their precise location and extent could not be determined. Above and below the narrow region where snow lines exist, the star's radiation prevents ice formation. The dust and gas concentration in the central plane is necessary to insulate the area from the radiation so that carbon monoxide and other gases can cool and freeze.

This team of astronomers succeeded in peering inside this disc to where the snow has formed with the help of a clever trick. Instead of looking for the snow -- as it cannot be observed directly -- they searched for a molecule known as diazenylium (N2H+), which shines brightly in the millimetre portion of the spectrum, and so is a perfect target for a telescope such as ALMA. The fragile molecule is easily destroyed in the presence of carbon monoxide gas, so would only appear in detectable amounts in regions where carbon monoxide had become snow and could no longer destroy it. In essence, the key to finding carbon monoxide snow lies in finding diazenylium.

ALMA's unique sensitivity and resolution has allowed the astronomers to trace the presence and distribution of diazenylium and find a clearly defined boundary approximately 30 astronomical units from the star (30 times the distance between Earth and Sun). This gives, in effect, a negative image of the carbon monoxide snow in the disc surrounding TW Hydrae, which can be used to see the carbon monoxide snow line precisely where theory predicts it should be -- the inner rim of the diazenylium ring.

"For these observations we used only 26 of ALMA's eventual full complement of 66 antennas. Indications of snow lines around other stars are already showing up in other ALMA observations, and we are convinced that future observations with the full array will reveal many more of these and provide further, exciting insights into the formation and evolution of planets. Just wait and see," concludes Michiel Hogerheijde from Leiden Observatory, the Netherlands.

Story Source:

The above story is reprinted from materials provided byEuropean Southern Observatory - ESO.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Chunhua Qi, Karin I. Öberg, David J. Wilner, Paola d'Alessio, Edwin Bergin, Sean M. Andrews, Geoffrey A. Blake, Michiel R. Hogerheijde, and Ewine F. van Dishoeck. Imaging of the CO Snow Line in a Solar Nebula Analog. Science, 18 July 2013 DOI: 10.1126/science.1239560

How Mars' Atmosphere Got So Thin: Reports Detail Curiosity Clues to Atmosphere's Past

This picture shows a lab demonstration of the measurement chamber inside the Tunable Laser Spectrometer, an instrument that is part of the Sample Analysis at Mars investigation on NASA's Curiosity rover. (Credit: NASA/JPL-Caltech)

July 18, 2013 — A pair of new papers report measurements of the Martian atmosphere's composition by NASA's Curiosity rover, providing evidence about loss of much of Mars' original atmosphere.

Curiosity's Sample Analysis at Mars (SAM) suite of laboratory instruments inside the rover has measured the abundances of different gases and different isotopes in several samples of Martian atmosphere. Isotopes are variants of the same chemical element with different atomic weights due to having different numbers of neutrons, such as the most common carbon isotope, carbon-12, and a heavier stable isotope, carbon-13.

SAM checked ratios of heavier to lighter isotopes of carbon and oxygen in the carbon dioxide that makes up most of the planet's atmosphere. Heavy isotopes of carbon and oxygen are both enriched in today's thin Martian atmosphere compared with the proportions in the raw material that formed Mars, as deduced from proportions in the sun and other parts of the solar system. This provides not only supportive evidence for the loss of much of the planet's original atmosphere, but also a clue to how the loss occurred.

"As atmosphere was lost, the signature of the process was embedded in the isotopic ratio," said Paul Mahaffy of NASA Goddard Space Flight Center, Greenbelt, Md. He is the principal investigator for SAM and lead author of one of the two papers about Curiosity results in the July 19 issue of the journalScience.

Other factors also suggest Mars once had a much thicker atmosphere, such as evidence of persistent presence of liquid water on the planet's surface long ago even though the atmosphere is too scant for liquid water to persist on the surface now. The enrichment of heavier isotopes measured in the dominant carbon-dioxide gas points to a process of loss from the top of the atmosphere -- favoring loss of lighter isotopes -- rather than a process of the lower atmosphere interacting with the ground.

Curiosity measured the same pattern in isotopes of hydrogen, as well as carbon and oxygen, consistent with a loss of a substantial fraction of Mars' original atmosphere. Enrichment in heavier isotopes in the Martian atmosphere has previously been measured on Mars and in gas bubbles inside meteorites from Mars. Meteorite measurements indicate much of the atmospheric loss may have occurred during the first billion years of the planet's 4.6-billion-year history. The Curiosity measurements reported this week provide more precise measurements to compare with meteorite studies and with models of atmospheric loss.

The Curiosity measurements do not directly measure the current rate of atmospheric escape, but NASA's next mission to Mars, the Mars Atmosphere and Volatile Evolution Mission (MAVEN), will do so. "The current pace of the loss is exactly what the MAVEN mission now scheduled to launch in November of this year is designed to determine," Mahaffy said.

The new reports describe analysis of Martian atmosphere samples with two different SAM instruments during the initial 16 weeks of the rover's mission on Mars, which is now in its 50th week. SAM's mass spectrometer and tunable laser spectrometer independently measured virtually identical ratios of carbon-13 to carbon-12. SAM also includes a gas chromatograph and uses all three instruments to analyze rocks and soil, as well as atmosphere.

"Getting the same result with two very different techniques increased our confidence that there's no unknown systematic error underlying the measurements," said Chris Webster of NASA's Jet Propulsion Laboratory, Pasadena, Calif. He is the lead scientist for the tunable laser spectrometer and the lead author for one of the two papers. "The accuracy in these new measurements improves the basis for understanding the atmosphere's history."

Curiosity landed inside Mars' Gale Crater on Aug. 6, 2012 Universal Time (on Aug. 5 PDT). The rover this month began a drive of many months from an area where it found evidence for a past environment favorable for microbial life, toward a layered mound, Mount Sharp, where researchers will seek evidence about how the environment changed.

More information about Curiosity is online at:http://www.nasa.gov/msl and http://mars.jpl.nasa.gov/msl/ .

You can follow the mission on Facebook at:http://www.facebook.com/marscuriosity and on Twitter athttp://www.twitter.com/marscuriosity .

Story Source:

The above story is reprinted from materials provided byNASA.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal References:

1. C. R. Webster, P. R. Mahaffy, G. J. Flesch, P. B. Niles, J. H. Jones, L. A. Leshin, S. K. Atreya, J. C. Stern, L. E. Christensen, T. Owen, H. Franz, R. O. Pepin, A. Steele.Isotope Ratios of H, C, and O in CO₂ and H₂O of the Martian Atmosphere. Science, 2013; 341 (6143): 260 DOI:10.1126/science.1237961
2. Paul R. Mahaffy, Christopher R. Webster, Sushil K. Atreya, Heather Franz, Michael Wong, Pamela G. Conrad, Dan Harpold, John J. Jones, Laurie A. Leshin, Heidi Manning, Tobias Owen, Robert O. Pepin, Steven Squyres, Melissa Trainer, and MSL Science Team. Abundance and Isotopic Composition of Gases in the Martian Atmosphere from the Curiosity Rover. Science, 2013; 341 (6143): 263 DOI:10.1126/science.1237966