Although this finding emerges from the study of a single toxic molecule and the protein that it transports, Whitehead Member David Sabatini says this phenomenon could be leveraged more broadly.
"Our work suggests a different strategy for cancer therapy that takes advantage of the capacity of a cancer cell to take up something toxic that a normal cell does not," says Sabatini, who is also a professor of biology at MIT and a Howard Hughes Medical Institute (HHMI) investigator. "As a result, that toxic molecule would kill the cancer cell. By identifying transporters on the surface of cancer cells, you might be able to find a molecule that a specific transporter would carry into the cell, and that molecule would be toxic to that cell. You really could have something that's much more selective to cancer cells."
The Sabatini lab's research is published online today in the journal Nature Genetics.
Kivanc Birsoy, a postdoctoral researcher in Sabatini's lab and first author of the Nature Genetics paper, used a special line of haploid cells developed by former Whitehead Fellow Thijn Brummelkamp to screen for genes that assist cellular entry of 3-bromopyruvate's (3-BrPA), a potential cancer drug in clinical development. 3-BrPA is thought to work by inhibiting glycolysis, a cellular process that releases energy by splitting glucose molecules. Because many cancer cells are heavily dependent on the upregulation of glycolysis, drugs that interrupt this pathway may be effective in targeting these glycolytic cancer cells.
From the screen and massively parallel sequencing, Birsoy identified the gene that codes for the protein monocarboxylate transporter 1 (MCT1), which is necessary and sufficient for 3-BrPA's transport into cells, where the toxic molecule ultimately kills them. In fact, the level of MCT1 on the surface of glycolytic tumor cells is a predictor of those cells' sensitivity to 3-BrPA—the higher the cells' expression of MCT1, the more sensitive they are to 3-BrPA. This holds true in in vitro and in vivo models across multiple lines of human cancer cells.
The correlation between MCT1 concentration and 3-BrPA sensitivity could be used to help determine how certain malignant tumors are treated.
"This study makes MCT1 a biomarker for 3-BrPA," says Birsoy. "So in the future, if 3-BrPA is approved as a drug, presumably you could predict if a patient's cancer tumor is going to be sensitive by looking at the levels of this molecule. No tumor without MCT1 would respond to treatment with 3-BrPA."
This work was supported by the National Institutes of Health (CA103866), the David H. Koch Institute for Integrative Cancer Research, the Jane Coffin Childs Memorial Fund, and the National Science Foundation (NSF).
Written by Nicole Giese Rura
David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.
"MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors"
Nature Genetics, December 2, 2012, online.
Kivanc Birsoy (1,2), Tim Wang (1), Richard Possemato (1,2), Omer H Yilmaz (1,2), Catherine E Koch (1,2), Walter W Chen (1,2), Amanda W Hutchins (1,2), Yetis Gultekin (1,2), Tim R Peterson (1,2), Jan E Carette (1,6), Thijn R Brummelkamp (1,6), Clary B Clish (3) and David M Sabatini (1).
1. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.2. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
Nicole Rura | EurekAlert!
Could this protein protect people against coronary artery disease?
17.11.2017 | University of North Carolina Health Care
Microbial resident enables beetles to feed on a leafy diet
17.11.2017 | Max-Planck-Institut für chemische Ökologie
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
17.11.2017 | Physics and Astronomy
17.11.2017 | Health and Medicine
17.11.2017 | Studies and Analyses