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Researchers Discover Stem Cells That May Drive Aggressive Behavior in Glioblastoma

Source: Memorial Sloan Kettering - On Cancer
Date: 02/20/2020
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For the past several years, researchers have recognized that the brain tumor glioblastoma is powered by cancer cells called tumor stem cells. Figuring out how tumor stem cells function is important because their ability to survive likely explains why glioblastoma is so hard to treat.

A multicenter team led by scientists at Memorial Sloan Kettering recently reported discovering a likely identity for these tumor stem cells. The leading contenders are called radial glia cells. Radial glia cells play a key role in building fetal brains but were previously thought to disappear after birth. The findings were published January 30 in Stem Cell Reports.

“We can’t say with certainty that radial glia cells are the same as tumor stem cells, but they are now very high on the candidate list,” says physician-scientist Viviane Tabar, Chair of MSK’s Department of Neurosurgery, who was the study’s senior author. “The look and behavior of brain stem cells in the developing brain and the tumor stem cells that we have identified are so similar to each other. This is the first time we’ve seen these features in cells from a human tumor.”

An Unexpected Finding

The first clues about the identity of these tumor stem cells were uncovered by Rong Wang, a research associate in Dr. Tabar’s lab. Dr. Wang was studying tumor tissue that had been removed from patients. She was using the tissue to grow organoid-like structures in petri dishes. Organoids are miniature organs that look and behave very much like their full-size counterparts. They are an increasingly important tool across cancer research for studying tumor development as well as for testing drugs.

Dr. Wang noticed that some cells in the organoids had an unusual shape and exhibited unusual behavior. They had very long processes, or tails, and when they divided, their daughter cells had the same shape. Additionally, when these unusual cells divided, their nuclei jumped over long distances. Dr. Wang recognized that these features are also seen in radial glia.

Further analysis confirmed that these unusual cells also were present in the tissue taken from patients: The team studied samples from dozens of tumors.

“Radial glia cells previously were not thought to persist in adulthood,” Dr. Tabar explains. “If glioblastoma tumors arise from them, that may mean that humans retain some radial glia cells in our brains as adults. The other possibility is that the genetic changes in the cancer turn some of the brain cells back into cells that look very much like radial glia cells.”

A Valuable Collaboration

To learn more about these cells, the Tabar lab collaborated with Dana Pe’er, Chair of the Sloan Kettering Institute’s Computational and Systems Biology Program, as well as with computational biologists at the Wellcome Sanger Institute in the United Kingdom.

They performed studies called single-cell RNA sequencing to look at which genes were expressed, or turned on, in individual cells. The patterns of gene expression observed in the samples taken from patient tumors and those grown in the lab were very similar to what’s seen in radial glia cells from embryos.

“This was a very challenging study to pull together. We took advantage of MSK’s wide range of tumors and access to fresh surgical tissue, as well as the resources of the Computational and Systems Biology Program here,” Dr. Tabar says.

A Potential Explanation for a Cancer’s Aggressive Behavior

Additional research is needed to confirm whether these cells are indeed the same. Another focus of future work will be the role of inflammation. “Inflammation may help bring radial glia-like cancer cells out of dormancy,” Dr. Tabar explains. “This could explain why inflammation can sometimes lead to the worsening of brain tumors.”

Dr. Tabar hopes that the publication of the findings will encourage further analysis and that “as technology advances, there will be easier ways to identify and study these cells,” she concludes.

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What’s the Best Way to Screen for Breast Cancer? Abbreviated MRI Beats 3-D Mammography, but Research Is Ongoing

Source: Memorial Sloan Kettering - On Cancer
Date: 02/28/2020
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It’s well understood that women in certain age groups should undergo regular screenings to look for signs of breast cancer. But as technology has progressed, the methods used for screening have evolved.

Memorial Sloan Kettering radiologist Christopher Comstock published a study in the Journal of the American Medical Association (JAMA) on February 25 that shed light on this topic. The trial found that a new test called abbreviated MRI found far more cancers than 3-D mammography in women at average risk who have dense breasts. An abbreviated MRI reduces the length of a standard MRI scan from 45 to 10 minutes.

“About half of all women have dense breasts,” Dr. Comstock notes. Having dense breasts makes it more difficult for cancer to be detected because the dense tissue can obscure cancerous masses.

The most common method for screening women with dense breasts is 3-D mammography. This imaging test creates a three-dimensional view of the breast tissue. It is often combined with ultrasound. Also known as tomosynthesis, 3-D mammography is better than regular 2-D mammography at detecting masses in dense tissue. Abbreviated MRI, which uses fewer images than full MRI, is one of the new approaches being developed that could eventually replace current digital mammography techniques.

The study findings raise concerns that mammograms may not be the best way to screen for cancer among women who are of average risk and have dense breasts.

“Previous research done at MSK and elsewhere has shown that full-breast MRIs are the best imaging method for detecting cancer, but these tests are expensive, time-consuming, and not widely available,” Dr. Comstock explains. “This study was designed to look at the ability of abbreviated MRI to find breast cancer.” The trial also showed women tolerate the MRI with very few side effects and that the centers could perform the test in less than 10 minutes.

A Constantly Evolving Field

When doctors began screening for breast cancer in the 1960s and 1970s, they used standard X-rays. Eventually, they developed more-specialized techniques and equipment for doing mammograms. In the early 2000s, digital mammography, in which images are stored on computers, replaced films. In the past several years, 3-D mammography has replaced 2-D mammography as the standard screening method for women with dense breasts. Digital 2-D mammography is the standard for those who don’t have dense breasts.

More than 1,400 women, ages 40 to 75, participated in the JAMA study. All of them were found to have dense breasts on a prior mammogram, did not have any signs or symptoms of breast cancer, and were of average risk.

The women in the trial were screened with both 3-D mammography and abbreviated breast MRI at 48 centers in the United States and Germany.

In the first year of the study, 23 women were diagnosed with breast cancer. The abbreviated MRI detected 22 out of the 23 breast cancers, while the 3-D mammogram detected only nine out of the 23 cancers. Only one cancer was discovered with 3-D mammography that was not found with abbreviated MRI.

“The findings from this trial are significant,” Dr. Comstock notes. “The abbreviated MRI found about two and a half times more cancers than mammography alone, including ten that were invasive cancers.”

However, he notes that abbreviated MRI is still very new. Many breast-screening centers don’t have MRI machines — especially community hospitals and those in more rural areas. Experts at MSK are figuring out the best way to offer abbreviated MRI, which is not currently covered by insurance, to patients.

The Promise of Other Screening Technologies

Dr. Comstock points to another vascular-based technology that is similar to MRI, called contrast-enhanced digital mammography (CEDM), which he believes shows similar promise for becoming the new standard screening method for women with dense breasts. MSK already offers this test at the Evelyn H. Lauder Breast Centerin Manhattan as well as at all of its regional locations.

“CEDM is a significant improvement over standard 3-D mammography,” says MSK Senior Vice President Larry Norton, a medical oncologist who specializes in treating breast cancer. “One of the advantages of CEDM compared with MRI is that conventional mammography machines can be easily adapted to do CEDM, which means that more centers can offer it.”

“In the near term, CEDM is likely to be much more available and accessible to patients than MRI, and at a lower cost,” Dr. Comstock adds. “It uses a technology that’s already familiar to doctors, which makes it easier to provide.”

Research done at MSK has already shown the benefits of CEDM at detecting cancer in women with dense breasts, compared with conventional 3-D mammography: A study published in Radiology in October 2019 found that the newer technique detected nearly twice as many cancers. These early results suggest that CEDM, which has been offered at MSK since 2012, is a promising way to screen for breast cancer.

Looking Ahead

Dr. Comstock is currently planning a large multicenter trial to assess whether CEDM screening is more accurate in women with dense breasts compared with the combination of 3-D mammography and ultrasound. Called the Contrast-Enhanced Mammography Imaging Screening Trial (CMIST), it is expected to launch within the next few months. CMIST will be conducted at about a dozen centers around the world. “At MSK, we are exploring more-advanced techniques that detect cancers earlier to lead to better treatment,” says Elizabeth Morris, Chief of the Breast Imaging Service at MSK, who is also involved in planning CMIST. “The landscape of breast radiology is ever changing, and here at MSK, we are leading much of this research.”

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Deep Understanding of Immunotherapy Helps Patients Cope with Side Effects

Source: Memorial Sloan Kettering - On Cancer
Date: 04/16/2020
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Immunotherapy has changed the outlook for many people with cancer. It offers long-term control or even a cure for tumor types that don’t respond well to other treatments. But because immunotherapy works in a different way than more traditional cancer treatments, such as chemotherapy and radiation, it can lead to new kinds of side effects.

Memorial Sloan Kettering is a leader in developing immunotherapy approaches, including drugs called checkpoint inhibitors. These drugs work by taking the brakes off immune cells and allowing them to go after cancer. But sometimes the immune system becomes too active and attacks healthy tissue. This reaction, called an immune-related adverse event, occurs in about one-third of people taking these drugs. As pioneers in immunotherapy, MSK care providers have rich experience in managing and easing these side effects. This enables most people to complete their cancer treatment and increases the chances that it will ultimately be successful. 

The most common immune-related adverse events caused by checkpoint inhibitors are skin problems, such as rashes, and inflammation of the gastrointestinal tract, which causes problems like diarrhea. Less frequent but potentially serious side effects include inflammation in the heart, liver, kidneys, lungs, and endocrine glands. Overactive immune cells can also affect the joints. This can lead to a painful condition similar to rheumatoid arthritis.

A Leader in Clinical Trials

Some of the earliest clinical trials of checkpoint inhibitor drugs were headed by MSK physician-scientist Jedd Wolchok. From the beginning, Dr. Wolchok and his colleagues — including Alyona Weinstein, a nurse practitioner who works in Dr. Wolchok’s clinic — began seeing immune-system reactions in their patients that looked like autoimmune disorders.

“We’ve known for a long time how to manage the most common side effects from chemotherapy,” such as nausea and reduced blood counts, Ms. Weinstein says. But the side effects from checkpoint inhibitor drugs can be more wide-ranging and unpredictable. “The inflammation caused by an overactive immune system can happen in any part of the body,” she notes. “At MSK, we are careful to screen patients for these side effects early in their treatment so that we can manage them before they become serious.”

A Growing Community of Specialists

As more people have received checkpoint inhibitors, a cadre of experts in immune-related side effects has naturally grown within MSK’s Division of Subspecialty Medicine. Specialists include dermatologists, gastroenterologists, cardiologists, endocrinologists, and more. They focus on health problems other than cancer. But because they work at MSK, they exclusively treat these disorders in people with cancer.

“When patients see the list of potential side effects, they often get very worried,” Ms. Weinstein says. “But in many cases, the appearance of these side effects is an early indication that the drugs are working.” She adds that while some people have no side effects, others may experience more than one serious complication. 

“The management of side effects requires supportive services from many areas beyond medical oncology, and MSK has these specialists,” says Michael Postow, a medical oncologist who specializes in immunotherapy. “Our doctors see these problems a lot, and they’ve developed deep expertise within their areas of specialization.”

Focusing on Health and Quality of Life during and after Treatment

MSK dermatologist Mario Lacouture treats people with skin-related side effects from immunotherapy and other cancer treatments. He recently received a five-year grant from the National Institutes of Health to study the immune-system-related side effects of immunotherapy. The project is a collaboration with National Jewish Health in Denver, a leading center for immunological disorders.

“The big dilemma is that you want to suppress the side effects of immunotherapy enough that patients feel well but not enough that the cancer therapy is no longer active or that patients have additional side effects from immunosuppressive drugs,” Dr. Lacouture explains. “We plan to use the skin as a model to identify what causes these autoimmune reactions so we can develop better ways to treat side effects without reducing the effectiveness of the cancer treatment.”

Other MSK specialists who play a role in treating autoimmune side effects include gastroenterologist David Faleck, cardiologist Dipti Gupta, and endocrinologist Monica Girotra. MSK’s team also closely collaborates with specialists at other area hospitals. This includes rheumatologists at the Hospital for Special Surgery, who are studying arthritis caused by checkpoint inhibitors and treat many of MSK’s patients.

Physical and occupational therapists, as well as specialists in integrative medicine, can help patients cope with pain and mobility problems. Because the gastrointestinal side effects from checkpoint inhibitor drugs can be difficult to treat with medication alone, MSK also has nutritionists who can advise people about the best diets for reducing symptoms related to these complications.

“Our hope is that our patients live a long time, and we know that, unfortunately, autoimmune side effects can continue even after they finish their treatment,” Ms. Weinstein concludes. “We are focused on making sure our patients have a good quality of life in addition to successful treatment for their cancer.”

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Novel Tool Enables Study of Rare Acute Myeloid Leukemia Stem Cells

Source: Memorial Sloan Kettering - On Cancer
Date: 04/27/2020
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If you think of cells as factories for making proteins, and DNA as the instructions contained within those factories, RNA is the workforce that actually carries out the manufacturing. Understanding how RNA does its job is essential for figuring out what goes wrong in many diseases, including cancer.

To take the analogy one step further, RNA-binding proteins (RBPs) are tools that RNA uses in the production process. There are more than 1,500 RBPs in any given cell, which creates a challenge for scientists who want to study them on an individual basis. But researchers are looking for ways to overcome this hurdle because RBPs are an important target for the development of new drugs.

In a paper published April 24 in Nature Communications, Sloan Kettering Institute cancer biologist Michael Kharas, members of his laboratory, and collaborators in the lab of computational biologist Christina Leslie describe a new tool for studying RBPs. In addition to having broad applications for a range of cell types, the team reports that this tool has already uncovered details about one particular RBP, called Musashi-2. Musashi-2 helps stem cells in the blood become more-specialized cell types. It is known to be overly active in acute myeloid leukemia (AML) cells.

“This is an exciting study because it changes how we study RBPs,” Dr. Kharas says. “It also changes what we know about how they function in specific cells.”

Translating a Lab Technique from Flies to Mammals

The experimental technique used in the study is called HyperTRIBE. It was originally developed to study nerve cells from fruit flies. Dr. Kharas says this is the first published study demonstrating that HyperTRIBE can be used in mammalian cells. The cells they used were blood stem cells from mice and leukemia stem cells from mice and humans.

HyperTRIBE uses a technology that is different from current methods for studying RBPs. Other approaches require millions of cells. The biggest benefit of HyperTRIBE is that it works in rare cells that are available only in very small numbers.

“Our study shows that this technique can be used to study RBPs, not just in fruit fly cells but more broadly,” says Dr. Kharas, a member of SKI’s Molecular Pharmacology Program. “This will have global impact for anyone studying RBPs in rare cell populations, whether those are blood stem cells, neurons, germ cells, or other kinds of stem cells.”

New Clues about a Protein’s Role in Leukemia

In the Nature Communications paper, the investigators report that HyperTRIBE has already revealed important findings about Musashi-2 and how it contributes to AML. Dr. Kharas and the other researchers are developing drugs to treat AML that work by blocking Musashi-2, but they still have a lot to learn about how these drugs modify the function of RBPs.

Using this novel tool, Dr. Kharas’s lab learned that Musashi-2 behaves differently in leukemia cells than it does in regular blood stem cells. “We knew that leukemia cells seemed to be more addicted to Musashi-2 for their growth than normal cells,” Dr. Kharas says. “Now we know that’s because Musashi-2 increases its RNA-binding activity and changes how RNA gets translated into proteins in cancer cells compared to normal cells.”

The investigators plan to continue studying why this is the case. Dr. Kharas says it could aid the development of drugs that slow leukemia growth by affecting Musashi-2’s activity while avoiding side effects that could result if Musashi-2 changes the production of healthy cells. “Because HyperTRIBE doesn’t require a large number of cells, we’ll be able to do more experiments to test potential drugs under many different conditions,” he concludes.

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Mapping the routes to drug resistance in cancer

Source: Cell Press
Date: 04/11/16
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When a freeway shuts down because of an accident or construction, drivers find another road to take them where they’re going. Likewise, when a targeted therapy blocks a pathway that enables tumors to grow, the cells usually manage to get around that obstacle. The result is drug resistance. Researchers have now found a way to map those alternate routes by studying individual cancer cells, suggesting approaches for developing more effective combination therapies. The results are published April 11 in Cancer Cell.

“Because technology now allows us to see the alternate pathways that cancer cells use to drive growth, it will enable us to identify ways to cut off multiple roads at the same time,” says James Heath, one of the paper’s corresponding authors, at the NanoSystems Biology Cancer Center in the Division of Chemistry and Chemical Engineering at the California Institute of Technology.

In the study, the investigators primarily looked at glioblastoma, the most deadly form of brain cancer. Although therapies tailored based on genetic alterations in these tumors have been developed, their benefit is usually short-lived. Combination therapies, which target multiple alterations at the same time, may offer a better way to fight this disease.

“Figuring out why resistance to targeted therapies develops has been the focus of our research for a long time,” says Paul Mischel, the paper’s co-corresponding author, at the Ludwig Institute for Cancer Research at the University of California, San Diego. “In this study, we looked at a drug that should work and found out why it doesn’t.”

The technology the team used is called single-cell phosphoproteomics. This tool enables investigators to peer into the inner workings of individual cancer cells and see their signaling. Using patient tissues obtained directly from operating rooms, the researchers found that the cells began to adapt to and resist therapies that target the growth pathway called mTOR in as little as 48 hours. Analysis showed that these cells were remapping their routes and finding ways to evade the drug’s effect long before any changes could be detected at the clinical level.

The investigators say that this approach could eventually be used to find better combination therapies for glioblastoma, but obstacles remain. “Although the technology used to analyze the cells is relatively simple and inexpensive–just glass and plastic–trials will be difficult to design,” says Heath. “For this type of personalized treatment, we won’t know what drugs to give patients until after their tumors are analyzed. Every trial will essentially have a sample size of one.”

Mischel adds that there are additional challenges in developing drugs for glioblastoma because they must be able to cross the blood-brain barrier.

In the paper, the researchers also described that single-cell phosphoproteomics could be used to study how melanoma cells develop resistance to a class of drugs called BRAF inhibitors. The single-cell-analysis approach could likely be employed to develop personalized treatment for many other types of cancer as well.

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Study Uncovers Hidden Risk for Breast Cancer in Some Women

Source: Memorial Sloan Kettering blog, On Cancer
Date: 03/17/17
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The connection between obesity and some kinds of cancer, including breast cancer, is well established. Not only is obesity a risk factor for developing the disease, it’s also a poor prognostic indicator for people who are diagnosed — those who are obese tend to have worse outcomes than those who are not.A handful of recent studies have suggested that it’s possible to be physically lean but metabolically obese — meaning that certain conditions in your body may bring about the risks that come with obesity even if you have a normal body mass index (BMI).

Now, a new study led by teams from Memorial Sloan Kettering and Weill Cornell Medicine indicates for the first time that this so-called metabolic obesity in normal-weight women can increase the likelihood that they will develop breast cancer.

“We call these women the walking wounded. They’re currently not recognized as being unhealthy,” says MSK breast medical oncologist and researcher Neil Iyengar, the first author of the study, published in the journal Cancer Prevention Research.Andrew Dannenberg, senior author of the study and Associate Director of Cancer Prevention at the Meyer Cancer Center of Weill Cornell Medical College, adds, “Physicians currently cannot reliably detect which patients who have a normal BMI may have underlying metabolic obesity that could be putting them at risk for cancer.”

Linking Fat and Cancer

Drs. Iyengar and Dannenberg investigate the biological mechanisms by which obesity promotes cancer. Earlier studies from their group have looked at breast cancer and tongue cancer.

One of the things the team studies is inflammation in the fat tissue and how it may drive cancer. The condition can lead to the release of various substances including hormones and growth factors that stimulate the development of cancer cells. These factors also serve as fuel for the growth of existing cancer cells.

Several cancers have been linked to obesity, including uterine cancer, colorectal cancer, and prostate cancer, though breast cancer has one of the strongest connections. “The breast is an organ that could be particularly susceptible to fat tissue dysfunction because the tissue where breast cancer most commonly arises — the milk ducts — is surrounded by fat,” Dr. Iyengar notes.

“One observation that caught our attention in our initial studies was that there was a group of patients with breast cancer who were not considered obese by BMI, but who had the same biological changes in their tissues that we see in obese patients,” he adds.

He and his collaborators set out to determine how common this problem was.

A Surprising Discovery

The current study included 72 women with normal BMIs who were undergoing mastectomy at MSK. Most had breast cancer, but some were having preventive surgery. The women donated blood samples as well as their breast tissue, so the researchers could look for changes in their bodies at the time of surgery.

The investigators were surprised to find that 39% of these women had inflammation in the fat tissue of their breasts. They also had higher-than-normal levels of aromatase, the enzyme that makes estrogen, in their breast tissue. Increased levels of estrogen in the breast could directly stimulate the development of breast cancer, Dr. Iyengar says.

“Interestingly, when we looked at the blood, we found that these women with fat inflammation and elevated aromatase had insulin resistance, which can be thought of as a precursor to diabetes. They also had higher triglyceride levels and other inflammatory changes,” he adds. “These are the kinds of changes we normally see in obese patients.”

These findings suggest that the obesity epidemic is much greater than currently recognized and includes some women of normal weight. The investigators believe that a link is also likely to exist between metabolic obesity and cancer in men.

Developing a New Method of Diagnosis

So now the question is, how would a woman know if she falls into this category?

Currently, the only way to detect inflammation in fat tissue is by looking at tissue that comes from a biopsy or surgery, Dr. Iyengar explains, procedures that are invasive and not typically employed on a regular basis.

His team is currently undertaking new studies to look for other ways to diagnose metabolic obesity. These methods may include scans that could measure a person’s body composition or blood tests that could be conducted during a routine physical. He says these tests eventually could become a part of regular wellness checkups and health screenings, and not just for those with cancer.

The researchers feel a sense of urgency about developing these new tests. “Right now these patients go to the doctor, who looks at their normal BMI and says, ‘Keep up the good work,’” Dr. Dannenberg says. “But in fact they may have undetected metabolic obesity that could put them at risk not only for cancer but also for diabetes, high blood pressure, heart disease, and other kinds of diseases.”

Dr. Iyengar adds that a lack of physical activity or eating an unhealthy diet may contribute, but it’s too early to know for sure. “This is an active area of research and is reshaping the way we think about who is healthy and who is not,” he says.

“Once we can more easily and reliably detect who has metabolic obesity, our goal is to ultimately develop interventions — such as specific diets, exercise programs, or even medications — that are tailored to decrease the risk of cancer and other disorders related to obesity,” he concludes.