Cancer Research

Biologists’ new peptide could fight many cancers

MIT Cancer Research RSS - Mon, 01/15/2018 - 09:00

MIT biologists have designed a new peptide that can disrupt a key protein that many types of cancers, including some forms of lymphoma, leukemia, and breast cancer, need to survive.

The new peptide targets a protein called Mcl-1, which helps cancer cells avoid the cellular suicide that is usually induced by DNA damage. By blocking Mcl-1, the peptide can force cancer cells to undergo programmed cell death.

“Some cancer cells are very dependent on Mcl-1, which is the last line of defense keeping the cell from dying. It’s a very attractive target,” says Amy Keating, an MIT professor of biology and one of the senior authors of the study.

Peptides, or small protein fragments, are often too unstable to use as drugs, but in this study, the researchers also developed a way to stabilize the molecules and help them get into target cells.

Loren Walensky, a professor of pediatrics at Harvard Medical School and a physician at Dana-Farber Cancer Institute, is also a senior author of the study, which appears in the Proceedings of the National Academy of Sciences the week of Jan. 15. Researchers in the lab of Anthony Letai, an associate professor of medicine at Harvard Medical School and Dana-Farber, were also involved in the study, and the paper’s lead author is MIT postdoc Raheleh Rezaei Araghi.

A promising target

Mcl-1 belongs to a family of five proteins that play roles in controlling programmed cell death, or apoptosis. Each of these proteins has been found to be overactive in different types of cancer. These proteins form what is called an “apoptotic blockade,” meaning that cells cannot undergo apoptosis, even when they experience DNA damage that would normally trigger cell death. This allows cancer cells to survive and proliferate unchecked, and appears to be an important way that cells become resistant to chemotherapy drugs that damage DNA.

“Cancer cells have many strategies to stay alive, and Mcl-1 is an important factor for a lot of acute myeloid leukemias and lymphomas and some solid tissue cancers like breast cancers. Expression of Mcl-1 is upregulated in many cancers, and it was seen to be upregulated as a resistance factor to chemotherapies,” Keating says.

Many pharmaceutical companies have tried to develop drugs that target Mcl-1, but this has been difficult because the interaction between Mcl-1 and its target protein occurs in a long stretch of 20 to 25 amino acids, which is difficult to block with the small molecules typically used as drugs.

Peptide drugs, on the other hand, can be designed to bind tightly with Mcl-1, preventing it from interacting with its natural binding partner in the cell. Keating’s lab spent many years designing peptides that would bind to the section of Mcl-1 involved in this interaction — but not to other members of the protein family.

Once they came up with some promising candidates, they encountered another obstacle, which is the difficulty of getting peptides to enter cells.

“We were exploring ways of developing peptides that bind selectively, and we were very successful at that, but then we confronted the problem that our short, 23-residue peptides are not promising therapeutic candidates primarily because they cannot get into cells,” Keating says.

To try to overcome this, she teamed up with Walensky’s lab, which had previously shown that “stapling” these small peptides can make them more stable and help them get into cells. These staples, which consist of hydrocarbons that form crosslinks within the peptides, can induce normally floppy proteins to assume a more stable helical structure.

Keating and colleagues created about 40 variants of their Mcl-1-blocking peptides, with staples in different positions. By testing all of these, they identified one location in the peptide where putting a staple not only improves the molecule’s stability and helps it get into cells, but also makes it bind even more tightly to Mcl-1.

“The original goal of the staple was to get the peptide into the cell, but it turns out the staple can also enhance the binding and enhance the specificity,” Keating says. “We weren’t expecting that.”

Killing cancer cells

The researchers tested their top two Mcl-1 inhibitors in cancer cells that are dependent on Mcl-1 for survival. They found that the inhibitors were able to kill these cancer cells on their own, without any additional drugs. They also found that the Mcl-1 inhibitors were very selective and did not kill cells that rely on other members of the protein family.

Keating says that more testing is needed to determine how effective the drugs might be in combating specific cancers, whether the drugs would be most effective in combination with others or on their own, and whether they should be used as first-line drugs or when cancers become resistant to other drugs.

“Our goal has been to do enough proof-of-principle that people will accept that stapled peptides can get into cells and act on important targets. The question now is whether there might be any animal studies done with our peptide that would provide further validation,” she says.

Joshua Kritzer, an associate professor of chemistry at Tufts University, says the study offers evidence that the stapled peptide approach is worth pursuing and could lead to new drugs that interfere with specific protein interactions.

“There have been a lot of biologists and biochemists studying essential interactions of proteins, with the justification that with more understanding of them, we would be able to develop drugs that inhibit them. This work now shows a direct line from biochemical and biophysical understanding of protein interactions to an inhibitor,” says Kritzer, who was not involved in the research.

Keating’s lab is also designing peptides that could interfere with other relatives of Mcl-1, including one called Bfl-1, which has been less studied than the other members of the family but is also involved in blocking apoptosis.

The research was funded by the Koch Institute Dana-Farber Bridge Project and the National Institutes of Health.

Categories: Cancer Research

The need to know

MIT Cancer Research RSS - Mon, 12/18/2017 - 17:59

The name of Ryan Kohn’s son, Jayden, is tattooed in Hindi on his left outer forearm. Other tattoos on his inner arms declare “Respect” and “Loyalty.” A Latin phrase balances the tableau on his right outer forearm: “Many fear their reputation. Few their conscience.”

Kohn may stand out in the corporate milieu of Kendall Square, but he feels home at MIT. No one has ever judged me,” he says. “For as rigorous scientifically and academically as MIT is, it can be such a laid-back place. I’ve always felt included, if I wanted to be.”

Kohn, now a PhD candidate in the Jacks Lab at MIT’s Koch Institute for Integrative Cancer Research, has overcome a challenging adolescence, colored by economic difficulties and punctuated by personal loss. These hardships developed in him a resilient curiosity that made an unexpected cultural match between MIT and Kohn, a father and former mechanic from Boyertown, Pennsylvania.

Compelled to seek answers

After being placed in an alternative high school outside of Philadelphia for insubordination, Kohn graduated with a 1.8 GPA. His son was born three years later, while Kohn worked for six and a half years as a mechanic and manager at a Dodge dealership. After losing his job during the Great Recession, he decided to go back to school, attending his local community college on a premed track before transferring to Kutztown University after two years.

Kohn attributes some of his troubled youth to early tragedy. His older sister, Nicole, died from sepsis when she was a senior in college, just 10 days after 9/11; on the morning of her funeral, Kohn’s grandfather passed away from colon cancer. Kohn felt compelled to understand why and how these illnesses happened to his loved ones, and found himself spending his time googling the immune system, the inflammatory response, and cancer.

This habit remained with him. Kohn recalls scouring the internet again and again to understand illness when it arose near him, from his own son’s immunoglobulin A deficiency to the early-onset multiple sclerosis of a friend. Though he admits he did not yet have the core scientific knowledge to fully grasp what he read at the time, Kohn says he needed, deeply, to try.

At Kutztown University, Kohn met his undergraduate mentor Angelika Antoni, a professor who taught both oncology and immunology. According to Kohn, Antoni constantly encouraged him to pursue his curiosity despite the college’s lack of laboratory resources. In fact, Antoni paid for laboratory reagents with her own credit card, while Kohn wrote his own grants and subscribed to well-known biology journals out of his own pocket because journal access was not available through Kutztown.

These challenges shaped Kohn as an experimental biologist, requiring him to precisely understand the mechanisms of experimental techniques in order to reconstruct them in the most creative and inexpensive ways possible. Perhaps most importantly, this small-college experience cultivated Kohn’s persistent curiosity.

Diving into cancer research

In his current position at the Jacks Lab, Kohn studies cancer immunotherapy, the use of a cancer patient’s own immune system to fight cancer cells. To do this, Kohn uses a mouse model of lung cancer that mimics the natural development of human cancer: Mutations identical to those found in many human cancers are triggered in the mouse, causing a tumor to arise that originates from the mouse’s own cells. These mice, like human cancer patients, have an immune system that can recognize the cancer as aberrant. Kohn’s work focuses modifying mouse immune cells to identify and attack a tumor.

Kohn is excited by the translational potential of his work, but also eagerly defends basic research at MIT when he encounters skepticism about its practicality in his conservative hometown.

Kohn often draws on metaphors in these types of conversations. He may leverage car talk, for example, to explain why there will never be a single cure for cancer: “So your ‘check engine’ light always presents the same way … but there’s literally a multitude of different things that can [cause] it. It could be a loose gas cap for the evaporative emissions system that set it off, it could be a misfire because of a bad spark plug, it could be a catalytic converter.”

Likewise, cancer can be caused by many possible biological errors that lead to an overgrowth of cells, Kohn explains. “So just like there will never be a cure for ‘check engine light,’ there will never be a [single] cure for cancer.”

Perhaps unsurprisingly, Kohn embraces the scientific freedom of the research in his lab. His advisor, Tyler Jacks, director of the Koch Institute, an HHMI investigator, and a David H. Koch Professor of Biology at MIT, is frequently in high demand, but Kohn says he has felt fully supported in his work — including in the bold ideas and unconventional projects he undertakes in his free time.

Jacks remains accessible despite his busy schedule, according to Kohn, and his emphasis on mentorship has inspired the postdocs in the lab to mentor the graduate students. The Jacks Lab also enjoys a thriving social environment. Kohn regularly attends casual weekend parties held by his labmates, and every other year Jacks organizes a cross-campus themed scavenger hunt for which the whole lab dresses in elaborate costumes.

“Real conversations about ideas”

Outside of lab, Kohn calls himself a homebody and prefers to relax after a full day, often with a beer and a movie. He spends much of this down time with his partner Ruthlyn, whether they are exploring the Boston area or talking with friends and colleagues at local pubs.

Kohn speaks about these conversations with genuine excitement: “You meet so many different people, every religion, every gender identity, every country, every language, and you just meet these people and you get to have these cool conversations … these real conversations about ideas. Because that’s really what you want, right?”

He enthusiastically notes that, in contrast to his largely homogenous hometown, more than 200 countries are represented at MIT. Kohn says the diversity and ideals of MIT reflect his own worldview.

Despite his deep sense of belonging on campus, leaving home did lay an exceptional burden on Kohn: Twelve-year-old Jayden remains in Pennsylvania with his mother, over 300 miles away.

Kohn speaks about his son with immense pride, describing Jayden as not only an extremely talented baseball player, but as a positive, energetic, and deeply mature young person. Kohn recounts with admiration, and a trace of relief, that despite the difficulty of the distance, Jayden said his father’s coming to MIT was the right thing to do.

As for his own parents, Kohn finally feels that all the headaches he has given them over the years have been worthwhile. His intense desire for knowledge has driven him through many obstacles, connected him with like minds from all over the world, and still shows no signs of waning.

Kohn has a reputation in his lab for asking questions, big and small. Asked if he’s ever afraid to admit what he doesn’t know, he says no: “I want to know … and that’s really what it comes down to.”

Categories: Cancer Research

Over the river and do some good

MIT Cancer Research RSS - Wed, 11/22/2017 - 06:10

Boston is home to two National Cancer Institute-designated cancer centers: MIT’s Koch Institute for Integrative Cancer Research and the Dana-Farber/Harvard Cancer Center (DF/HCC). Each works to advance the fight against cancer in its own unique way.

The latter draws on the collective resources of Dana-Farber Cancer Institute (DFCI), Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Massachusetts General Hospital (MGH), Harvard Medical School (HMS), and Harvard T.H Chan School of Public Health. The Koch Institute (KI) integrates life sciences researchers with cancer-oriented engineers to develop new insights, tools, and technologies to detect, monitor, and treat the disease.

The work of the KI builds on that of its predecessor, the MIT Center for Cancer Research, which made seminal contributions to the understanding of cancer biology in its three-plus decades as MIT’s hub of cancer research. Clinical collaborations have been an important component of this enterprise for years — but never on the scale of the Bridge Project.  

The Bridge Project was launched in 2012 to provide seed funding for collaborative research teams comprised of investigators from both MIT and Harvard University. Its goal is to foster interdisciplinary studies that combine innovative tools and methods with the translational expertise of clinical oncologists to solve today’s most challenging problems in cancer research and care. It is a simple idea, uniquely suited to this community.

“In Boston, we are blessed with differently focused, world-class cancer researchers on both sides of the Charles River,” says founding donor Arthur Gelb ScD ’61, who is an emeritus trustee of DFCI and an emeritus MIT Corporation member. “The Bridge Project’s operating presumption is that spanning the gap between them — to enable truly joint research at the intersection of their disciplines — is destined to produce new, highly original, and powerful approaches to defeating cancer. The early history of the Bridge Project suggests that is exactly the case.”

MIT President Emerita Susan Hockfield says Gelb “had advocated collaboration between MIT and DF/HCC for a long time.”

“He presented the idea to me in one of our very first conversations, shortly after I became president,” Hockfield explains. “But we didn’t have a vehicle to make it happen until the KI.”

When the Koch Institute opened its interdisciplinary doors in 2011, the Bridge Project was one of the first initiatives to walk through them.

Fast-moving research

The first funding cycle was modest, yet aspirational. Four grants were awarded to target two of the most deadly, hard-to-treat cancer types — brain and pancreatic. In subsequent cycles, the Bridge Project expanded to include several additional high-need disease areas, including advanced breast cancer, aggressive lung cancer, and notoriously hard-to-detect ovarian cancer, and brought the total number of projects funded to 15 within the first four years of the program.

Among these efforts was a project by KI member Angela Belcher, the James Mason Crafts Professor and professor of biological engineering and materials science and engineering at MIT, who teamed up with oncologists Michael Birrer, then the director of medical gynecologic oncology at MGH, and professor of medicine at HMS, and Marcela del Carmen, an associate professor of gynecologic oncology at MGH and professor of obstetrics, gynecology, and reproductive biology at HMS, to adapt and refine the Belcher laboratory’s highly sensitive optical imaging system harnessing genetically-engineered, nanoscale fluorescent probes for early detection, real-time imaging, and monitoring of ovarian cancers. The team initially piloted the technology as a tool for image-guided surgery, and is now using it in advanced pre-clinical investigations for diagnostics and therapy of early-stage tumors.

Another early-funded project, led by MIT associate professor of bology and KI member Matthew Vander Heiden and fellow physician-scientists William Kaelin Jr., a professor of medicine at DFCI and HMS, and Daniel Cahill, an assistant professor of neurosurgery at HMS and MGH, was focused on the development of a new imaging modality for tumors known as IDH-mutant gliomas. Their approach is being tested as a way to monitor drug response in patients with these tumors. The project also supported the discovery of novel approaches to target these cancers.

Projects like these were just the beginning, says Tyler Jacks, director of the Koch Institute and co-leader of the Bridge Project. “As the Bridge Project gained momentum, so did the possibilities. The standards are very high — we are looking for true collaborations, rooted in real clinical need and fueled by truly innovative approaches. In exchange, we are able to catalyze progress and bring real advances to patients, very quickly.”

What is it about these projects that makes them so promising? “There’s a continuum of discovery,” explains Jacks’ co-leader David Livingston, deputy director of DF/HCC, in an interview with Bloomberg Radio. “[It] begins in basic research laboratories, goes to patients in clinics and hospitals, and then comes back, and turns into new therapeutics or new diagnostics or a new ability to figure out how [a] tumor is going to behave.”

This quick-paced cycle of discovery and innovation, coupled with clinical application, is why investors and others find the Bridge Project so appealing.

In 2015, the Bridge Project received a $20 million challenge grant from the Commonwealth Foundation for Cancer Research to further expand the program; this doubled the number of projects to be funded and introduced new Footbridge grants, for proof-of-concept studies, and Expansion Bridge grants to rapidly launch clinical trials. One of the first expansion projects is moving a new MIT-developed vaccine technology into clinical trials for lung cancer at DFCI. A second, a collaboration between KI member Michael Hemann, an associate professor of Biology at MIT; David Weinstock, an associate professor of medicine at DFCI and HMS; and Ann LaCasce, an assistant professor in medicine at HMS and instructor in medical oncology at DFCI, is already seeing promising results in active Phase 1 trials for lymphoma-targeting combination therapy. Other projects, new and continuing, will spring into action as additional funds are raised toward this challenge.

An additional research focus on pediatric brain cancer, initiated in 2016, spawned three new off-cycle projects, including the first-ever Bridge Project super-team, consisting of eight laboratories across Harvard and MIT, combining expertise in genomics, cell signaling, immunology, microfluidics, and nanotechnology, to develop non-invasive diagnostics and combination therapeutics to target aggressive gliomas in young patients.

Thanks to continuing support from philanthropic donors, and the tireless work of researchers, administrators, and reviewers, the Bridge Project has processed 160 applications and funded 37 projects led by researchers from 78 laboratories at MIT and DF/HCC. Each project includes researchers from both sides of the Charles River: 92 percent of past Bridge Project teams have joint publications, and 11 invention disclosures have been filed. The program, which is entirely supported by philanthropy, has raised more than $30 million, but there is more work to be done, especially in regard to the challenge grant.

Investing in success

Bridge Project research is poised to directly improve patient outcomes. A collaboration between Weinstock and KI member Scott Manalis, the Andrew and Erna Viterbi Professor and professor of biological and mechanical engineering, has seen startling success.

Their initial proposal to use a novel microfluidic device to measure the drug sensitivity of tumor cells has proven successful across a variety of cancer types. With published results in studying both acute lymphoblastic leukemia and glioblastoma multiforme, the MIT team’s cell-weighing technology is now being evaluated in a clinical laboratory at DFCI in which live cells from an individual patient can be exposed to different drugs to measure sensitivity, with the ultimate goal of determining if the technology can identify the best course of treatment for that patient. Their approach has seen particular success in mirroring how patients with multiple myeloma respond to different therapies.

The KI/DFCI collaboration also earned a prestigious U54 grant from the National Cancer Institute, amplifying the effect of the Bridge Project work through federal funding and multi-institutional support. The technology is being further developed by Travera, the team’s newly-launched startup.

Indeed, entrepreneurship offers yet another path to clinical translation. MIT spinoff PanTher Therapeutics, focused on improving therapeutic solutions to inoperable solid tumors, grew directly out of a Bridge Project grant.

“The Bridge Project gave us the money to do the science,” says CEO Laura Indolfi, a former postdoc in the laboratory of KI member Elazer Edelman, the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology. “Once we saw the results — a 12 times improvement in response rate for pancreatic cancer — we were able to take that proof-of-concept to business validation as a finalist in the MIT $100K Entrepreneurship Competition, and incubate it.”

With support from MIT’s Deshpande Center for Technological Innovation, Indolfi and her team were able to de-risk the project and scale it up, launching PanTher in 2015. The team then won a “golden ticket” to LabCentral from Bristol-Myers Squibb in 2016, providing the company with lab space to further develop their technology. They are currently transitioning from seed funding to Series A and hope to begin clinical trials in 2019; conversations with the U.S. Food and Drug Administration (FDA) are already underway.

Such clinical impact is usually a long way off for university researchers. The typical “bench to bedside” trajectory is on the order of a decade or more; to have so many projects in pre-clinical studies, pursuing FDA approval for clinical trials in such a short period of time is a testament to the Bridge Project’s goal of meeting the most urgent, unmet needs of cancer care.

Beyond the bridge

The Bridge Project has yielded unexpected benefits for researchers. Following the review of their collaborative Bridge Project application, KI member Darrell Irvine, a professor of biological engineering and materials science and engineering at MIT, and two DFCI immunologists, Michael Goldberg, an assistant professor of cancer immunology and virology at DFCI and assistant professor of microbiology and immunobiology at HMS, and Kai Wucherpfennig, director of DFCI’s Center for Cancer Immunotherapy Research and a professor of microbiology and immunobiology at HMS, decided to apply together for outside funding to support their proposed work. In 2014, they received a prominent Team Science Award from the Melanoma Research Association to improve the use of immunotherapy in cancer treatment through targeted nanoparticle delivery of small molecule drugs.

There are also instances of Bridge Project research changing the course of investigators’ career paths. Indolfi, for example, took on the drug delivery work of her advisor’s Bridge Project award as a side project, never imagining that it would be spun out and lead her into entrepreneurship.

Former MIT Department of Biology graduate student Mark Stevens, on the other hand, was positive that he was industry-bound when he joined the Manalis Lab. However, as he was starting to wrap up his initial thesis work using the lab’s microfluidic device to measure the masses of cells to learn about their metabolic properties, he became attracted to his advisor’s nascent collaboration with DFCI, which was just taking off. He was drawn to the project’s potential for patient-centric development, and using cell lines, mouse models, and patient samples from the collaborating labs at DFCI, ultimately added a component focused on testing for tumor drug susceptibility to his thesis. 

Two years past his PhD thesis defense, Stevens now holds a joint appointment between MIT and DFCI, driven by the Bridge Project’s support, where aforementioned clinical studies with the cell-weighing technology are ongoing. He describes this new position as an opportunity to provide much-needed translation, in every sense of the word, between academic and clinical settings.

“There is a lot of lip service paid to interdisciplinary research, which can have less familiar, or well-defined metrics for success,” Stevens says. “This uncertainty leads to an environment where what is actually supported is relatively subject-specific, niche expertise. Programs like the Bridge Project provide a context where interdisciplinary boundaries can really be pushed.”

As a result, Stevens finds himself in what he calls a “nexus” position: working to make connections between fundamental biology research and clinical need, and pushing research forward on a much faster timescale than he had originally anticipated.

Such accelerated trajectories were exactly what Gelb had in mind when he first approached the institutional leaders about the potential partnership. The collaborative nature of the work, Gelb says, provides “viewpoints, tools, and methods that would not necessarily occur to researchers focused only on the underlying biology, important as that may be.” This multidisciplinary perspective is, with every new project, reshaping the way cancer researchers talk to and learn from each other.

Of course, one can argue that many of these conversations would or could have happened without an official agreement, but like so many scientific endeavors, making connections is key — among researchers and investors alike.

“The Bridge Project got off the ground through philanthropic funding,” says Hockfield. “It would have been impossible for us to make those clinically relevant projects work if we had had to wait for the standard grant mechanisms.”

These initial investments in the Bridge Project are paying off, in the clinic, in the marketplace, and in an increasingly resource-challenged research environment. In September, the Bridge Project was honored by Boston’s life sciences and biotech community, having been chosen by a panel of judges as the winning “Big Idea” at the Xconomy inaugural awards ceremony. Additionally, the collaboration has been credited by some for contributing to the high scores that both partnering institutions received on their respective Cancer Center Support Grant reviews by the National Cancer Institute in 2014.

Still, the research will not rest on these laurels, nor will the people behind it. The Bridge Project is, at its heart, about people — patients, researchers, physicians, and all those who keep its momentum moving forward. The Bridge Project is about rapid acceleration of progress. The ideas and technologies being developed in research laboratories have the potential to affect the cancer patients of today and tomorrow, but it is the investigators themselves, together with their philanthropic partners, who are, at an unprecedented rate, bridging the gaps between bench and bedside.

Categories: Cancer Research

Cell-weighing method could help doctors choose cancer drugs

MIT Cancer Research RSS - Sun, 11/19/2017 - 23:00

Doctors have many drugs available to treat multiple myeloma, a type of blood cancer. However, there is no way to predict, by genetic markers or other means, how a patient will respond to a particular drug. This can lead to months of treatment with a drug that isn’t working.

Researchers at MIT have now shown that they can use a new type of measurement to predict how drugs will affect cancer cells taken from multiple-myeloma patients. Furthermore, they showed that their predictions correlated with how those patients actually fared when treated with those drugs.

This type of testing could help doctors predict drug responses based on measurements of cancer cell growth rates after drug exposure, says Scott Manalis, the Andrew and Erna Viterbi Professor in the MIT departments of Biological Engineering and Mechanical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research.

“For infectious diseases, antibiotic susceptibility testing based on cell proliferation has been extremely effective for many decades,” Manalis says. “Unlike bacteria, analogous tests for tumor cells have been challenging, in part because the cells don’t always proliferate upon removal from the patient. The measurement we developed doesn’t require proliferation.”

Manalis is the senior author of the study, which appears in the Nov. 20 issue of Nature Communications. The paper’s lead authors are Mark Stevens, a visiting scientist at the Koch Institute and research scientist at Dana-Farber Cancer Institute, and Arif Cetin, a former MIT postdoc.

An animation of how a serial suspended micro channel resonator functions with cells flowing through the device. Cells pass over 10 cantilever mass sensors to have their mass weighed over a 15 minute interval, with measurements spaced by delay channels. Multiple measurements allow the researchers to capture changes in mass over time, a metric called mass accumulation rate (MAR).

Predicting response

The researchers’ new strategy is based on technology that Manalis and others in his lab have developed over the past several years to weigh cells. Their device, known as a suspended microchannel resonator (SMR), can measure cell masses 10 to 100 times more accurately than any other technique, allowing the researchers to precisely calculate growth rates of single cells over short periods of time.

The latest version of the device, which can measure 50 to 100 cells per hour, consists of a series of SMR sensors that weigh cells as they flow through tiny channels. Over a 20-minute period, each cell is weighed 10 times, which is enough to get an accurate MAR measurement.

A few years ago, Manalis and colleagues set out to adapt this technique to predict how cancer drugs affect tumor cell growth. They showed last year that the mass accumulation rate (MAR), a measurement of the rate at which the cells gain mass, can reveal drug susceptibility. A decrease in MAR following drug treatment means the cells are sensitive to the drug, but if they are resistant, there is no change in MAR.

In the new study, the researchers teamed up with Nikhil Munshi at Dana-Farber Cancer Institute to test a variety of drugs on tumor cells from multiple-myeloma patients. They then compared the results to what happened when the patients were treated with those drugs. For each patient, they tracked the cells’ response to three different drugs, plus several combinations of those drugs. They found that in all nine cases, their data matched the outcomes seen in patients, as measured by clinical protein biomarkers found in the bloodstream, which are used by doctors to determine whether a drug is killing the tumor cells.

“When the clinical biomarkers showed that the patients should be sensitive to a drug, we also saw sensitivity by our measurement. Whereas in cases where the patients were resistant, we saw that in the clinical biomarkers as well as our measurement,” Stevens says.

Personalized medicine

One of the difficulties in treating multiple myeloma is choosing among the many drugs available. Patients usually respond well to the first round of treatment but eventually relapse, at which point doctors must choose another drug. However, there is no way to predict which drug would be best for that particular patient at that time.

In one scenario, the researchers envision that their sensor would be used at the time of disease relapse, when the tumor may have developed resistance to specific therapies.

“At this time of relapse, we would take a bone marrow biopsy from a patient, and we would test each therapy individually or in combinations that are typically used in the clinic. At that point we’d be able to inform the clinician as to which therapy or combinations of therapies this patient seems to be most sensitive or most resistant to,” Stevens says.

The new test holds “great promise” to screen myeloma cells for drug susceptibility, says Kenneth Anderson, a professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, who was not involved in the research.

“This assay may fast-forward personalized medical care and the choice of effective therapies for myeloma both at diagnosis and at relapse,” Anderson says. “It may also be useful to profile susceptibility of minimal residual disease in order to further inform therapy and improve patient outcome.”

Bone marrow biopsies often produce limited numbers of tumor cells to test — as few as 50,000 tumor cells in this study — but for this technique that is enough to test many different drugs and drug combinations. The MIT researchers have started a company to begin a larger clinical study for validating this approach, and they plan to investigate the possibility of using this technology for other types of cancer.

The research was funded by the National Institutes of Health, the Koch Institute’s Cancer Center Support (core) Grant from the National Cancer Institute, the Department of Veterans Affairs, a Koch Institute Quinquennial Cancer Research Fellowship, and the Bridge Project of the Koch Institute and Dana-Farber/Harvard Cancer Center.

Categories: Cancer Research

Mary Clare Beytagh: Finding poetry in medicine

MIT Cancer Research RSS - Sun, 11/12/2017 - 17:59

When MIT senior Mary Clare Beytagh isn’t performing research at the Koch Institute for Integrative Cancer Research or writing poetry, she can be found in ballet class at the Harvard Dance Center, continuing her 15 years of intensive dance training.

For Beytagh, ballet provides a reprieve from the hustle and bustle of academics and research. Her twice-a-week classes are “a nice way to de-stress and think about things,” including flashbacks to exciting moments on stage as a preprofessional ballerina, and fond memories with friends.

On days without dance class, Beytagh goes running. The two activities are “sort of antithetical to each other,” she notes. However, she makes it work. Beytagh is majoring in biology and literature at MIT — two fields that, like running and ballet, rarely intersect. But Beytagh aims to change that.

Running start on research

The summer before Beytagh’s senior year in high school, her teachers encouraged her to apply to a research program at the University of Texas Southwestern Medical Center.

The eight-week program took Beytagh out of the the classroom and into to the lab of Kathryn O’Donnell-Mendell, a cancer researcher studying B-cell lymphoma. The program was Beytagh’s first experience with scientific and medical research, and she was hooked.

She continued the research into her senior year of high school and submitted a paper to the prestigious Siemens Competition in Math, Science, and Technology.

While working in the lab, she met an MD-PhD student who opened Beytagh’s eyes to the possibility of pursuing medicine and cancer research simultaneously. When Beytagh applied to college, she looked for schools that emphasized undergraduate research. MIT topped her list.

“MIT rises above everyone else in that aspect,” she says. During an on-campus visit, she took part in a tour that allowed her to learn about the different types of research performed at the Institute. By the end of the tour, Beytagh knew MIT was the right fit. “These are my people,” she recalls thinking.

Upon the advice of her research advisor at UT Southwestern, after Beytagh arrived at MIT she sought out Tyler Jacks, professor of biology and director of the Koch Institute.

Beytagh has worked in the Jacks Lab since her second semester at the Institute. She and the other researchers are developing mouse models for cancer that recapitulate more aspects of the human disease. One goal, for example, is to have the tumors grow in the same locations in the animals as they do in humans.

Last year, Beytagh was invited to speak at the American Association for Cancer Research meeting. There, she presented her research alongside postdocs and early-career cancer biologists.

“That was a cool experience,” she says, “But then, it was back to the lab immediately!”

Documenting experiences

Outside of the lab, Beytagh enjoys expressing herself through her writing as a literature major.

During her sophomore Independent Activities Period (IAP), she traveled to Madrid to study Spanish literature. Her class was taught by MIT professors Stephen Tapscott and Margery Resnick. It examined post-Spanish Civil War novels and poetry — and captivated Beytagh.

After IAP ended, Beytagh continued studying poetry in Tapscott’s course 21L.487 (Modern Poetry). During the class, distinguished American poet Martha Collins visited and performed a poetry reading.

The visit had such an impact on Beytagh that she embarked upon an exercise inspired by one of Collins’ poetry series. The experiment lasted 21 days, during which Beytagh wrote poetic snapshots of each day within a set of predetermined rules.

“I’m a person who likes rules, but within those rules finds creativity,” Beytagh says.

On the 21st day, poetry morphed from hobby to emotional necessity. She found out her good friend had been diagnosed with Hodgkin’s lymphoma. At that moment, her poetry “became catharsis.”

She decided to declare literature as her second major.

“I had been flirting with the idea, but I had never committed,” she says, “Then, at the end of [sophomore] year, I committed.”

“This is it,” she says, recounting her reasoning, “These professors are amazing. I’m having a great time. It’s enriching me as a person.”

Bringing backstories to the forefront

Beytagh often integrates her research and other undergraduate experiences into her writing.

During her junior year IAP, she did an externship in the Yale School of Medicine’s emergency medicine department, with Charles Wira, III. She worked on developing a new risk score system for patients experiencing sepsis, but it was what she witnessed while shadowing in the emergency room that transformed her outlook.

“The most timely and impactful thing I saw there was the nature of the opioid epidemic,” she says, “You can read all you want in The New York Times and look at graphs — but that’s just statistics.”

That winter, she witnessed two to three patients coming into the emergency room for opioid overdoses each day she was there.

“What you don’t get in a graph,” she points out, “are the backstories of all these people.”

After that experience, she began to write about patients she saw and interacted with, in her poetry. In the long term, Beytagh hopes to become a science writer as well as a physician-scientist, telling stories that humanize patients and focus on the social and economic determinants of health.

Though she plans to study cancer biology in an MD-PhD program, she hopes to end up at an institution that allows her to take on other projects such as epidemiological research on opioid addiction.

Facilitating leadership

After a recommendation from her roomates freshman year, Beytagh joined the Leadership Training Institute, an organization which provides leadership training and mentorship to underprivileged Boston area high school students. The institute runs a 12-week program for 50 students each spring.

As the director of the program, Beytagh aims to reach students who are shy but passionate about community service and leadership, and works to provide them with transformative experiences.

“It’s always very gratifying when the students [graduate from the program],” she says. “They say, ‘You guys have made me realize that I not only want to keep service as a part of high school, but as a part of my career and onward.’”

“That gives you chills,” Beytagh says. “If you can spark that in someone and make them realize having an others-focused heart is the way to live life, it can only be good for our world.”

Categories: Cancer Research

Fighting a giant foe at a tiny scale

MIT Cancer Research RSS - Tue, 11/07/2017 - 09:55

Paula Hammond’s research focuses on using nanoscale biomaterials to attack cancer, which she calls “a supervillain with incredible superpowers.” Using targeted nanoparticles, she is attempting to turn off the natural defenses of mutant genes and deliver a deadly punch to the cancer cell. Her work will soon be translated into clinical practice through partnerships with pharmaceutical companies, entrepreneurial partners, and startups in health care.

Long interested in reading and the arts, Hammond ’84, PhD ’93 considered writing children’s novels before she decided to study chemical engineering as an undergraduate at MIT. After working at Motorola for two years, she earned her master’s degree at Georgia Tech and then returned to MIT for a new PhD program in polymer science. In 1995 Hammond joined the MIT faculty, where she is now the David H. Koch Professor of Engineering and head of the Department of Chemical Engineering.

During her 2003 sabbatical, she began to focus on biomaterials. As someone entering that field in mid-career, she says, “I brought a new perspective, with a materials design approach.”

Since then, she has merged design and polymer engineering to create breakthroughs in drug delivery technology. By layering negatively and positively charged molecules, Hammond and her team can create coated meshes and wound dressings that gradually release combinations of an antibiotic and a growth factor to help the wound heal, support bone regeneration, or control the scarring that can result from a burn or tissue injury.

This same layering concept is used to treat cancer, says Hammond. By taking a nanoparticle core loaded with drugs that kill cancer cells, surrounding that core with layers that contain silencing RNA to turn off the genes that promote cancer survival, and adding a final outer layer that helps the nanoparticle reach the tumor, it is possible to target drug-resistant cancer cells.

During her 2015 presentation for the live show "TED Talks: Science and Wonder," Hammond said that, using molecular engineering, “we can actually design a superweapon that can travel through the bloodstream. It has to be tiny enough to get through the bloodstream, it has got to be small enough to penetrate the tumor tissue, and it’s got to be tiny enough to be taken up inside the cancer cell. To do this job well, it has to be about one one-thousandth the size of a human hair.”

Hammond was elected to the National Academy of Engineering in 2017 and the National Academy of Medicine in 2016. She is also a member of the American Academy of Arts and Sciences

This story originally appeared in the September/October 2017 issue of MIT Technology Review magazine.

Categories: Cancer Research

New techniques give blood biopsies greater promise

MIT Cancer Research RSS - Sun, 11/05/2017 - 23:00

Researchers at the Broad Institute of MIT and Harvard, the Koch Institute for Integrative Cancer Research at MIT, Dana-Farber Cancer Institute, and Massachusetts General Hospital have developed an accurate, scalable approach for monitoring cancer DNA from blood samples.

Reporting in Nature Communications, the team demonstrates that nearly 90 percent of a tumor’s genetic features can be detected in blood samples using whole-exome sequencing, and that the method can be effectively applied in up to 49 percent of patients with advanced cancer — a number likely to increase as sequencing becomes cheaper. This less-invasive tumor sampling, which can provide a window into the cancer’s genome, has a range of potential applications.

“Our ultimate hope is to use blood biopsies to exhaustively search for and characterize even the smallest remnants of tumors,” explains Viktor Adalsteinsson, co-first author on the paper and group leader at the Broad Institute, where he leads the Blood Biopsy Team. “And, as tumors evolve in more advanced stages of cancer, developing resistance or becoming metastatic, we might access timepoints that could be pivotal in deciding which therapies are right for that patient.”

This ability to detect and analyze cancer DNA from a patient’s blood sample is emerging as a promising alternative to invasive surgical biopsies, which can be difficult, painful, and costly — especially when tumors have appeared in locations that are challenging to access.

Blood biopsies (also called liquid biopsies) are poised to overcome many of these issues. They have the potential to allow doctors to track the progress of disease and treatment in real-time and to help researchers understand how tumors resist treatment with far greater resolution.

Understanding cancer without invasive procedures

Cells in the body, including tumor cells, regularly expel fragments of DNA into the bloodstream when they die. With blood biopsies, clinicians collect this “cell-free” DNA from a blood draw and then detect and comprehensively profile the fragments originating from cancer cells. Tracking these data could make it possible to monitor cancer recurrence, a patient’s response to treatment, and other clinically important features, all from blood samples.

The research and development arena for blood biopsies is frequented by both academic and industry players, but with scalable whole-exome sequencing, a team led by Adalsteinsson and colleagues Gavin Ha, Sam Freeman, Matthew Meyerson, J. Christopher Love, and Gad Getz is taking the field in a new and innovative direction. Love is a Broad associate member, associate professor of chemical engineering at MIT, and a member of the Koch Institute for Integrative Cancer Research at MIT

Compiling a whole exome from DNA fragments currently requires at least 10 percent tumor DNA in a blood sample, but the fraction of tumor DNA in the blood can vary wildly from patient to patient. Because of this variation, the team first desired an unbiased approach for detecting and measuring levels of cancer DNA before attempting whole-exome sequencing.

Across the field, many blood biopsy methods detect tumor DNA by screening for mutations in known cancer-related genes, but this targeted sequencing misses cancers without those mutations.

Co-first author Ha, a postdoc at the Broad Institute and Dana-Farber Cancer Institute (DFCI), led the development of a tool called ichorCNA that can analyze DNA fragments for mutation patterns nearly universal in cancer genomes, and as a result capture cancers with both known and unknown mutations. Ha focused on detecting stretches of DNA that have either fewer or greater copies in cancer cells, in contrast to healthy cells.

The research team tested and refined ichorCNA on 1,439 blood samples collected prospectively from 520 metastatic breast or prostate cancer patients at DFCI (a significant effort championed by medical oncologists Atish Choudhury, Daniel Stover, Heather Parsons, Nikhil Wagle, and colleagues).

Using this approach, the researchers found that in 33 to 49 percent of the metastatic breast and prostate cancer patients, depending upon whether one or multiple blood samples were examined, tumor DNA made up greater than 10 percent of the cell-free DNA in their blood — enough to make whole-exome sequencing of cell-free DNA feasible.

Then, to determine whether this sequencing of cell-free tumor DNA could offer the same level of insight into cancer genetics as a tissue biopsy could, the team compared surgically obtained tumor biopsies to data collected from whole-exome sequencing of cell-free DNA from a group of 41 patients. The researchers found that genetic data from blood whole-exome sequencing and tissue biopsies matched significantly across a number of genetic features, such as clonal somatic mutations (88 percent match) and copy number alterations (80 percent match).

These results support cell-free DNA whole-exome sequencing, from blood samples, as a potential substitute for metastatic tumor biopsy sequencing for many patients.

“Our study has demonstrated that we can get a cancer whole exome reliably, from blood; that it reflects the matched tumor biopsy; and that it can be done for a significant fraction of patients with metastatic cancer,” says Adalsteinsson, who was a postdoc in Love’s lab before joining the Broad Institute. “This validation suggests that we can use blood biopsies for large-scale genomic characterization of disease in patients with metastatic cancer.”

“It unlocks the potential for a lot of studies that we couldn’t do before,” adds Getz, institute member and director of the Cancer Genome Computational Analysis group at Broad and associate professor of Pathology and director of Bioinformatics at the Massachusetts General Hospital Cancer Center and Department of Pathology. “The technology will allow us to track the dynamics of cancer and understand the evolution of drug resistance, or the development of the metastatic state, in a way that isn’t possible through surgical biopsies.”

The new study improves the analysis pipeline for blood biopsies and allows it to be performed at expanded scale. The researchers are actively applying their work to thousands of patients with metastatic cancer who may otherwise not have their tumors biopsied.

“With this work, we now have a framework for the precise measurement and quality control of tumor DNA in the plasma, enabling the genomic analysis of blood biopsies with high technical accuracy,” explains Meyerson, institute member at Broad and professor of pathology at DFCI and Harvard Medical School.

Method is already in use with patients for cancer research

On the back of the team’s success, ichorCNA and subsequent whole-exome sequencing of cell-free DNA have been incorporated into a collaboration with the Broad Institute Genomics Platform to enable comprehensive mapping of metastatic and drug-resistant tumors from blood samples at scale. This approach has also been integrated into direct-to-patient research efforts underway at Broad, including the Metastatic Breast Cancer (MBC) Project, a patient outreach effort that collects saliva and tissue samples — and now blood samples — donated from metastatic breast cancer patients for DNA sequencing to further therapeutic research. Similar efforts to incorporate blood biopsies are underway in the Angiosarcoma Project and upcoming Metastatic Prostate Cancer Project.

“We are excited about using blood biopsies to understand metastatic breast cancer, drug resistance, and tumor evolution, and to get a snapshot of the metastatic setting in patients who might not have available tissue from a metastatic biopsy,” says Nikhil Wagle, an associate member at the Broad Institute, deputy director of the Center for Cancer Precision Medicine at DFCI, and leader of the MBC Project. “With the Blood Biopsy Team’s latest results, it was clear that this technology had reached the right point for us to incorporate into the Metastatic Breast Cancer project.”

A means to perform large-scale blood biopsies could allow researchers and clinicians easy access to the cancer genome, with exciting implications for the way physicians monitor response to treatment, watch for recurrence, and more. The ability to frequently and noninvasively monitor cancer and its treatment could alter clinical trials, increase the resolution with which clinicians understand metastatic cancer, and potentially increase accessibility to quality precision medicine approaches.

“Using cell-free DNA to track cancer is not a new idea, but we’re developing the tools to understand how we can better qualify materials for those types of analyses, and we’re doing it in a way that allows us to look across the genome broadly,” says Love. “We’ve established quality metrics to make sure that this technology is cost-effective and scalable for thousands of patients and samples a year.”

This study was funded by the Gerstner Family Foundation, Janssen Pharmaceuticals, Inc., and a Koch Institute Support (core) grant from the National Cancer Institute.

Categories: Cancer Research

Gene circuit switches on inside cancer cells, triggers immune attack

MIT Cancer Research RSS - Thu, 10/19/2017 - 08:30

Researchers at MIT have developed a synthetic gene circuit that triggers the body’s immune system to attack cancers when it detects signs of the disease.

The circuit, which will only activate a therapeutic response when it detects two specific cancer markers, is described in a paper published today in the journal Cell.

Immunotherapy is widely seen as having considerable potential in the fight against a range of cancers. The approach has been demonstrated successfully in several recent clinical trials, according to Timothy Lu, associate professor of biological engineering and of electrical engineering and computer science at MIT and a member of MIT's Koch Institute for Integrative Cancer Research.

“There has been a lot of clinical data recently suggesting that if you can stimulate the immune system in the right way you can get it to recognize cancer,” says Lu, who is head of the Synthetic Biology Group in MIT’s Research Laboratory of Electronics. “Some of the best examples of this are what are called checkpoint inhibitors, where essentially cancers put up stop signs [that prevent] T-cells from killing them. There are antibodies that have been developed now that basically block those inhibitory signals and allow the immune system to act against the cancers.”

However, despite this success, the use of immunotherapy remains limited by the scarcity of tumor-specific antigens — substances that can trigger an immune system response to a particular type of cancer. The toxicity of some therapies, when delivered as a systemic treatment to the whole body, for example, is another obstacle.

What’s more, the treatments are not successful in all cases. Indeed, even in some of the most successful tests, only 30-40 percent of patients will respond to a given therapy, Lu says.

As a result, there is now a push to develop combination therapies, in which different but complementary treatments are used to boost the immune response. So, for example, if one type of immunotherapy is used to knock out an inhibitory signal produced by a cancer, and the tumor responds by upregulating a second signal, an additional therapy could then be used to target this one as well, Lu says.

“Our belief is that there is a need to develop much more specific, targeted immunotherapies that work locally at the tumor site, rather than trying to treat the entire body systemically,” he says. “Secondly, we want to produce multiple immunotherapies from a single package, and therefore be able to stimulate the immune system in multiple different ways.”

To do this, Lu and a team including MIT postdocs Lior Nissim and Ming-Ru Wu, have built a gene circuit encoded in DNA designed to distinguish cancer cells from noncancer cells.

The circuit, which can be customized to respond to different types of tumor, is based on the simple AND gates used in electronics. Such AND gates will only switch on a circuit when two inputs are present.

Cancer cells differ from normal cells in the profile of their gene expression. So the researchers developed synthetic promoters — DNA sequences designed to initiate gene expression but only in cancer cells.

The circuit is delivered to cells in the affected area of the body using a virus. The synthetic promotors are then designed to bind to certain proteins that are active in tumor cells, causing the promoters to turn on.

“Only when two of these cancer promoters are activated, does the circuit itself switch on,” Lu says.

This allows the circuit to target tumors more accurately than existing therapies, as it requires two cancer-specific signals to be present before it will respond.

Once activated, the circuit expresses proteins designed to direct the immune system to target the tumor cells, including surface T cell engagers, which direct T cells to kill the cells. The circuit also expresses a checkpoint inhibitor designed to lift the brakes on T cell activity.

When the researchers tested the circuit in vitro, they found that it was able to detect ovarian cancer cells from amongst other noncancerous ovarian cells and other cell types.

They then tested the circuit in mice implanted with ovarian cancer cells, and demonstrated that it could trigger T cells to seek out and kill the cancer cells without harming other cells around them.

Finally, the researchers showed that the circuit could be readily converted to target other cancer cells.

“We identified other promoters that were selective for breast cancer, and when these were encoded into the circuit, it would target breast cancer cells over other types of cell,” Lu says.

Ultimately, they hope they will also be able to use the system to target other diseases, such as rheumatoid arthritis, inflammatory bowel disease, and other autoimmune diseases.

This advance will open up a new front against cancer, says Martin Fussenegger, a professor of biotechnology and bioengineering at ETH Zurich in Switzerland, who was not involved in the research.

“First author Lior Nissim, who pioneered the very first genetic circuit targeting tumor cells, has now teamed up with Timothy Lu to design RNA-based immunomodulatory gene circuits that take cancer immunotherapy to a new level,” Fussenegger says. “The design of this highly complex tumor-killing gene circuit was made possible by meticulous optimization and integration of several components that target and program tumor cells to become a specific prey for the immune system — this is very smart technology.”

The researchers now plan to test the circuit more fully in a range of cancer models. They are also aiming to develop a delivery system for the circuit, which would be both flexible and simple to manufacture and use.

This work was supported by the National Institutes of Health, the Department of Defense, the Defense Advanced Research Projects Agency, the Koch Institute Frontier Research Program, and in part by the Koch Institute Support (core) Grant from the National Cancer Institute.

Categories: Cancer Research

Using artificial intelligence to improve early breast cancer detection

MIT Cancer Research RSS - Mon, 10/16/2017 - 16:59

Every year 40,000 women die from breast cancer in the U.S. alone. When cancers are found early, they can often be cured. Mammograms are the best test available, but they’re still imperfect and often result in false positive results that can lead to unnecessary biopsies and surgeries.

One common cause of false positives are so-called “high-risk” lesions that appear suspicious on mammograms and have abnormal cells when tested by needle biopsy. In this case, the patient typically undergoes surgery to have the lesion removed; however, the lesions turn out to be benign at surgery 90 percent of the time. This means that every year thousands of women go through painful, expensive, scar-inducing surgeries that weren’t even necessary.

How, then, can unnecessary surgeries be eliminated while still maintaining the important role of mammography in cancer detection? Researchers at MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts General Hospital, and Harvard Medical School believe that the answer is to turn to artificial intelligence (AI).

As a first project to apply AI to improving detection and diagnosis, the teams collaborated to develop an AI system that uses machine learning to predict if a high-risk lesion identified on needle biopsy after a mammogram will upgrade to cancer at surgery.

When tested on 335 high-risk lesions, the model correctly diagnosed 97 percent of the breast cancers as malignant and reduced the number of benign surgeries by more than 30 percent compared to existing approaches.

“Because diagnostic tools are so inexact, there is an understandable tendency for doctors to over-screen for breast cancer,” says Regina Barzilay, MIT’s Delta Electronics Professor of Electrical Engineering and Computer Science and a breast cancer survivor herself. “When there’s this much uncertainty in data, machine learning is exactly the tool that we need to improve detection and prevent over-treatment.”

Trained on information about more than 600 existing high-risk lesions, the model looks for patterns among many different data elements that include demographics, family history, past biopsies, and pathology reports.

“To our knowledge, this is the first study to apply machine learning to the task of distinguishing high-risk lesions that need surgery from those that don’t,” says collaborator Constance Lehman, professor at Harvard Medical School and chief of the Breast Imaging Division at MGH’s Department of Radiology. “We believe this could support women to make more informed decisions about their treatment, and that we could provide more targeted approaches to health care in general.”

A recent MacArthur “genius grant” recipient, Barzilay is a co-author of a new journal article describing the results, co-written with Lehman and Manisha Bahl of MGH, as well as CSAIL graduate students Nicholas Locascio, Adam Yedidia, and Lili Yu. The article was published today in the medical journal Radiology.

How it works

When a mammogram detects a suspicious lesion, a needle biopsy is performed to determine if it is cancer. Roughly 70 percent of the lesions are benign, 20 percent are malignant, and 10 percent are high-risk lesions.

Doctors manage high-risk lesions in different ways. Some do surgery in all cases, while others perform surgery only for lesions that have higher cancer rates, such as “atypical ductal hyperplasia” (ADH) or a “lobular carcinoma in situ” (LCIS).

The first approach requires that the patient undergo a painful, time-consuming, and expensive surgery that is usually unnecessary; the second approach is imprecise and could result in missing cancers in high-risk lesions other than ADH and LCIS.

“The vast majority of patients with high-risk lesions do not have cancer, and we’re trying to find the few that do,” says Bahl, a fellow doctor at MGH’s Department of Radiology. “In a scenario like this there’s always a risk that when you try to increase the number of cancers you can identify, you’ll also increase the number of false positives you find.”

Using a method known as a “random-forest classifier,” the team's model resulted in fewer unnecessary surgeries compared to the strategy of always doing surgery, while also being able to diagnose more cancerous lesions than the strategy of only doing surgery on traditional “high-risk lesions.” (Specifically, the new model diagnosed 97 percent of cancers compared to 79 percent.)

“This work highlights an example of using cutting-edge machine learning technology to avoid unnecessary surgery,” says Marc Kohli, director of clinical informatics in the Department of Radiology and Biomedical Imaging at the University of California at San Francisco. “This is the first step toward the medical community embracing machine learning as a way to identify patterns and trends that are otherwise invisible to humans.”

Lehman says that MGH radiologists will begin incorporating the model into their clinical practice over the next year.

“In the past we might have recommended that all high-risk lesions be surgically excised,” Lehman says. “But now, if the model determines that the lesion has a very low chance of being cancerous in a specific patient, we can have a more informed discussion with our patient about her options. It may be reasonable for some patients to have their lesions followed with imaging rather than surgically excised.”

The team says that they are still working to further hone the model.

“In future work we hope to incorporate the actual images from the mammograms and images of the pathology slides, as well as more extensive patient information from medical records,” says Bahl.

Moving forward, the model could also easily be tweaked to be applied to other kinds of cancer and even other diseases entirely.

“A model like this will work anytime you have lots of different factors that correlate with a specific outcome,” says Barzilay. “It hopefully will enable us to start to go beyond a one-size-fits-all approach to medical diagnosis.”

Categories: Cancer Research

New target for treating “undruggable” lung cancer

MIT Cancer Research RSS - Mon, 10/02/2017 - 04:40

Mutations in the KEAP1 gene could point the way to treating an aggressive form of lung cancer that is driven by “undruggable” mutations in the KRAS gene, according to a new study by MIT researchers.

KEAP1 mutations occur alongside KRAS mutations in about 17 percent of lung adenocarcinoma cases. Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and co-senior author of the study, and his colleagues found that cancer cells with nonfunctioning KEAP1 genes are hungry for glutamine, an amino acid essential for protein synthesis and energy use. Starving these cells of glutamine may thus offer a way to treat cancers with both KRAS and KEAP1 mutations.

Indeed, small-molecule-based inhibitors of glutaminase, an enzyme crucial to glutamine metabolism, slowed cancer cell growth and led to smaller tumors overall in human lung adenocarcinoma cell lines and in tumors in mice with KEAP1 mutations, the researchers found.

The study offers a way to identify lung cancer patients who might respond well to drugs that block the work of glutaminase, says MIT graduate student Rodrigo Romero, a first author on the paper that appears in the Oct. 2 online edition of Nature Medicine.

“All cell lines that we have currently tested that are KEAP1-mutant — independent of their KRAS status — appear to be exquisitely sensitive to glutaminase inhibitors,” says Romero, a graduate student in Jacks’ lab, who participated in the MIT Summer Research Program (MSRP) as an undergraduate.

Hyperactivating the antioxidant response

Lung adenocarcinoma accounts for about 40 percent of U.S. lung cancers, and 15 to 30 percent of those cases contain a KRAS mutation. KRAS has been “notoriously difficult to inhibit” because the usual ways of blocking the KRAS protein’s interactions or interfering with the protein’s targets have fallen short, says Romero.

Lung cancers containing KRAS mutations often harbor other mutations, including KEAP1, which is the third most frequently mutated gene in lung adenocarcinoma. To find out more about how these co-mutations affect lung cancer progression, the MIT research team created KEAP1 mutations in mouse models of lung adenocarcinoma, using the CRISPR/Cas9 gene-editing system to target the gene.

The KEAP1 protein normally represses another protein called NRF2, which controls the activation of an antioxidant response that removes toxic, reactive oxygen species from cells. When the researchers disabled KEAP1 with loss-of-function mutations, NRF2 was able to accumulate and contribute to a “hyperactivation” of the antioxidant response.

Lung adenocarcinomas bearing the KEAP1 mutation may “take advantage of this [hyper-activation] to promote cellular growth or detoxify intracellular damaging agents,” Romero says.

In fact, when the researchers examined genes targeted by NRF2 across a sample of human lung adenocarcinoma tumors, they concluded that the expression of these genes was greater in advanced stage IV tumors, and that patients with such “up-regulated” NRF2 tumors had significantly worse survival rates than other lung adenocarcinoma patients.

Tumors hungry for glutamine

Romero and colleagues used CRISPR/Cas9 to learn more about other genetic interactions with KEAP1 mutants. Their screening demonstrated that lung cancer cells with KRAS and KEAP1 loss-of function mutations were more dependent than other cells on increased amounts of glutamine.

To learn whether this glutamine hunger could be a therapeutic vulnerability, the researchers tested two glutaminase inhibitors against the cancer cells, including one compound called CB-839 that is in phase I clinical trials for KRAS-mutant lung cancer. CB-839 slowed growth and kept tumors smaller than normal in lung adenocarcinoma with KEAP1 mutations, the researchers found.

Phase I clinical trials that treat KEAP1-mutant lung adenocarcinoma patients with a combination of CB-839 and the cancer immunotherapy drug nivolumab (Opdivo) are also underway, says Romero, who notes the MIT study might help identify patients who would be good candidates for these trials.

“There are also many clinical trials testing the efficacy of glutaminase inhibition in a variety of cancer types, independent of KRAS status. However, the results from these studies are still unclear,” Romero says.

Jacks emphasizes that his laboratory has and will continue to study several mutations beyond KEAP1 that may cooperate with KRAS in their mouse models of human lung adenocarcinoma. “The complexity of human cancer can be quite daunting,” he notes. “The genetic tools that we have assembled allow us to create models of many individual subtypes of the disease and in this way begin to define the exploitable vulnerabilities of each. The observed sensitivity of KEAP1 mutant tumors to glutaminase inhibitors is an important example of this approach. There will be more.”

Co-authors on the Nature Medicine paper include former Koch Institute postdoc Thales Papagiannakopoulos, now at New York University, and MIT professor of biology Matthew Vander Heiden. The research was funded by the Laura and Isaac Perlmutter Cancer Support Grant, the National Institutes of Health, and the Koch Institute Support Grant from the National Cancer Institute.

Categories: Cancer Research

Early trip to the GP gives big boost to lung cancer patients

UK Cancer Research - Sun, 12/08/2013 - 13:01
 A powerful campaign urging people with a three week old cough to get checked out by their doctor has resulted in a dramatic rise in the numb…
Categories: Cancer Research

New tumour suppressor gene discovered

UK Cancer Research - Sun, 12/08/2013 - 07:01
  Cancer Research UK funded researchers have discovered a gene that is switched off in around one per cent of all cancers and could hold a vit…
Categories: Cancer Research

New EU legislation would halt research and put lives at risk, warns Cancer Research UK

UK Cancer Research - Wed, 12/04/2013 - 22:50
 Lives will be lost due to changes to European Union (EU) legislation that would put research in the UK under serious threat; in some cases m…
Categories: Cancer Research

Study highlights varying cancer survival rates across Europe

UK Cancer Research - Wed, 12/04/2013 - 06:46
  Cancer survival rates are continuing to improve in England, according to the results from a Europe-wide collaborative project.
Categories: Cancer Research

Prevent proteins folding and you may stop cancer growing

UK Cancer Research - Mon, 12/02/2013 - 00:00
 A molecule that helps cancer cells to keep dividing could be a promising target for new treatments, according to research published in the j…
Categories: Cancer Research

Targeting stem cell molecule blocks bowel cancer in mice

UK Cancer Research - Sun, 12/01/2013 - 07:01
  Blocking a molecule in tumour-fuelling stem cells could offer a new way to treat bowel cancer, a Canadian study has shown.
Categories: Cancer Research

Urine test could help detect aggressive bladder cancer

UK Cancer Research - Thu, 11/28/2013 - 13:01
 A simple urine test could distinguish between aggressive and less aggressive bladder cancers according to a new Cancer Research UK study pub…
Categories: Cancer Research

CRT, University of Manchester and Glaxosmithkline work together to generate new cancer drugs

UK Cancer Research - Thu, 11/28/2013 - 13:01
 Cancer Research Technology, the commercial arm of Cancer Research UK, and the University of Manchester today announced a research agreement …
Categories: Cancer Research

Cholesterol by-product linked to breast cancer in mice

UK Cancer Research - Thu, 11/28/2013 - 08:01
  A by-product of cholesterol breakdown could contribute to the growth and spread of breast cancer, a US study has revealed.
Categories: Cancer Research

Survey highlights 'worrying' lung cancer care delays

UK Cancer Research - Thu, 11/28/2013 - 04:54
  Nearly half of lung cancer patients say that they have experienced care delays at some point since their diagnosis, a new report suggests.
Categories: Cancer Research
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