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Unexpected Finding Reveals New Target for Aggressive Form of Lung Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 12/01/2020
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Targeted therapies are currently available for about one-third of people with lung adenocarcinoma, the most common kind of lung cancer. These drugs inhibit cancer cells by thwarting the molecular changes that drive them to grow while largely sparing healthy tissues. But for the other two-thirds of people with this type of cancer, there are fewer treatment options.

A team from Memorial Sloan Kettering is reporting new findings about a particularly aggressive subset of lung adenocarcinomas that are driven by two mutations that frequently occur together, in genes called KEAP1 and STK11. The molecular changes characteristic of these tumors were surprising to the investigators who discovered them: they block a type of cell death called ferroptosis. Cancers with these changes require this blockade to stay alive and grow. The study was published December 1, 2020, in Cell Reports.

Ferroptosis is a type of programmed cell death that is dependent on iron. Ferroptosis was discovered less than a decade ago, but it has already emerged as an important target for cancer therapies as well as drug treatments for other diseases. When ferroptosis fails to occur when it should, cells can grow uncontrollably. 

“We really didn’t know what particular vulnerabilities we would find in these cancer cells,” says MSK physician-scientist Charles Rudin, Chief of the Thoracic Oncology Service, Co-Director of the Fiona and Stanley Druckenmiller Center for Lung Cancer Research, and the paper’s senior author. “But all of the work we report in this study pointed toward ferroptosis as a key player.”

Two Mutations Working Together

The genetic change that allows the cancer cells to block ferroptosis is called a co-mutation: alterations in two genes called STK11 and KEAP1 work together to create an environment in which tumor cells are able to grow even when they are receiving signals that would otherwise induce cell death. The combination of mutations in these two genes is found in more than 10% of lung adenocarcinomas, so a drug that could successfully target this alteration would have a meaningful impact.

MSK biostatistician Ronglai Shen was the first to discover that the STK11/KEAP1 co-mutation is often found in lung adenocarcinomas that are very aggressive and hard to treat. She made the discovery when doing an analysis of lung cancer using data from MSK-IMPACTTM, a test that looks for hundreds of mutations in tumors at the same time. Dr. Shen is a co-author on the new study.

The connection to ferroptosis was unexpected. “Our findings suggest that targeting certain proteins that play a role in the regulation of ferroptosis could lead to new treatments for this cancer,” Dr. Rudin says.

CRISPR Helps Create Useful Lab Models

In the current study, first author Corrin Wohlhieter, a graduate student in the lab that’s co-led by Dr. Rudin and Triparna Sen, used the gene editing tool CRISPR — which allows researchers to make very specific changes to the genetic code — to create three types of cells: some of these cells had the gene STK11 knocked out, some had KEAP1 knocked out, and some had both genes knocked out. She then isolated each of the three cell types and studied them in the lab, including in mouse models. By analyzing the cells’ behaviors, she was able to figure out which other genes were activated when STK11 and KEAP1 were lost.

“Lung cancers tend to be very heterogeneous, so if you don’t do these kinds of controlled experiments it’s hard to isolate changes attributable to a particular gene or set of genes,” Dr. Rudin says. “By creating these knockouts, it allows us to really focus on cells with these mutations and to link any behaviors we observe to the presence or absence of these factors.”

The team’s observations helped them make the connection to ferroptosis. They found that cells with both the STK11 and KEAP1 mutations also had high levels of proteins already known to make cells resistant to ferroptosis. Dr. Rudin and his colleagues pinpointed one of these proteins, called SCD1, as a particularly good target for these tumors.

“Although the current SCD1 inhibitors that we have are not likely to make good drugs,” he explains, “there are many labs at MSK that are actively investigating strategies for targeting ferroptosis in cancer cells.”

Dr. Rudin says he plans to work with other researchers to learn more about these interactions and to look for compounds that could be developed into drugs. “We hope to find drugs that inhibit the pathways in these tumor cells, ultimately developing a targeted therapy strategy for these particularly difficult cancers,” he concludes.

Targeted therapies are currently available for about one-third of people with lung adenocarcinoma, the most common kind of lung cancer. These drugs inhibit cancer cells by thwarting the molecular changes that drive them to grow while largely sparing healthy tissues. But for the other two-thirds of people with this type of cancer, there are fewer treatment options.

Ferroptosis is a type of programmed cell death that is dependent on iron. Ferroptosis was discovered less than a decade ago, but it has already emerged as an important target for cancer therapies as well as drug treatments for other diseases. When ferroptosis fails to occur when it should, cells can grow uncontrollably. 

“We really didn’t know what particular vulnerabilities we would find in these cancer cells,” says MSK physician-scientist Charles Rudin, Chief of the Thoracic Oncology Service, Co-Director of the Fiona and Stanley Druckenmiller Center for Lung Cancer Research, and the paper’s senior author. “But all of the work we report in this study pointed toward ferroptosis as a key player.”

Two Mutations Working Together

The genetic change that allows the cancer cells to block ferroptosis is called a co-mutation: alterations in two genes called STK11 and KEAP1 work together to create an environment in which tumor cells are able to grow even when they are receiving signals that would otherwise induce cell death. The combination of mutations in these two genes is found in more than 10% of lung adenocarcinomas, so a drug that could successfully target this alteration would have a meaningful impact.

MSK biostatistician Ronglai Shen was the first to discover that the STK11/KEAP1 co-mutation is often found in lung adenocarcinomas that are very aggressive and hard to treat. She made the discovery when doing an analysis of lung cancer using data from MSK-IMPACTTM, a test that looks for hundreds of mutations in tumors at the same time. Dr. Shen is a co-author on the new study.

The connection to ferroptosis was unexpected. “Our findings suggest that targeting certain proteins that play a role in the regulation of ferroptosis could lead to new treatments for this cancer,” Dr. Rudin says.O

CRISPR Helps Create Useful Lab Models

In the current study, first author Corrin Wohlhieter, a graduate student in the lab that’s co-led by Dr. Rudin and Triparna Sen, used the gene editing tool CRISPR — which allows researchers to make very specific changes to the genetic code — to create three types of cells: some of these cells had the gene STK11 knocked out, some had KEAP1 knocked out, and some had both genes knocked out. She then isolated each of the three cell types and studied them in the lab, including in mouse models. By analyzing the cells’ behaviors, she was able to figure out which other genes were activated when STK11 and KEAP1 were lost.

“Lung cancers tend to be very heterogeneous, so if you don’t do these kinds of controlled experiments it’s hard to isolate changes attributable to a particular gene or set of genes,” Dr. Rudin says. “By creating these knockouts, it allows us to really focus on cells with these mutations and to link any behaviors we observe to the presence or absence of these factors.”

The team’s observations helped them make the connection to ferroptosis. They found that cells with both the STK11 and KEAP1 mutations also had high levels of proteins already known to make cells resistant to ferroptosis. Dr. Rudin and his colleagues pinpointed one of these proteins, called SCD1, as a particularly good target for these tumors.

“Although the current SCD1 inhibitors that we have are not likely to make good drugs,” he explains, “there are many labs at MSK that are actively investigating strategies for targeting ferroptosis in cancer cells.”

Dr. Rudin says he plans to work with other researchers to learn more about these interactions and to look for compounds that could be developed into drugs. “We hope to find drugs that inhibit the pathways in these tumor cells, ultimately developing a targeted therapy strategy for these particularly difficult cancers,” he concludes.

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Taking on New Challenges: 8 Questions with Gilles Salles

Source: Memorial Sloan Kettering - On Cancer
Date: 12/23/2020
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Gilles Salles recently joined Memorial Sloan Kettering as Chief of the Lymphoma Service within the Division of Hematologic Malignancies. Dr. Salles came to MSK after a long career at Claude Bernard University in Lyon, France.

In an interview conducted in early December just before the annual American Society of Hematology (ASH) meeting, where he presented updates from several studies he’s conducted, Dr. Salles spoke about his decision to join MSK, his research, and his plans for the Lymphoma Service.

Why did you decide to come to MSK?

MSK is a fantastic place in terms of clinical care, clinical research, and basic research. There are not many places in the world that have strengths in all three of these areas. There are so many opportunities here to bring talented scientists together with clinicians who can help them deliver their discoveries to patients.

I’ve been successful in my career, and I’ve been able to bring many improvements in lymphoma care to patients. I asked myself, “Should I just continue here in France and then retire in six or eight years, or should I take on a new challenge?” I decided that this kind of opportunity, to be able to interact more with basic scientists and to build upon translational research projects, doesn’t happen very often. That’s why I took the leap.

What was your relationship with MSK before you came here?

I already knew many members of the Lymphoma Service as well as people in other groups at MSK. I’ve been involved in collaborations with them over the years and have met them at conferences. They are a large part of the reason I decided to join MSK — it’s exciting to work with such talented people.

What was it like moving to a new continent in the middle of a pandemic?

It was strange. I moved to New York over the summer and started working at MSK in mid-August. I haven’t been in the same room with most of my new colleagues yet. We’ve all been meeting on Zoom.

I studied in the United States for my postdoc about 30 years ago in Boston. And I’ve been to New York and other parts of the United States many times since then, both for work and for vacations with my family. This is not the New York I was wishing to rediscover, but I’m hopeful that the pandemic will end soon.

What’s different about MSK’s Lymphoma Service?

We have the SPORE in Lymphoma [Specialized Programs of Research Excellence, a project funded by the National Cancer Institute to help move basic science findings into the clinic]. That was started by my predecessor, Anas Younes, and is now being led by Andrew Zelenetz, a leading physician in the field of B cell malignancies.  

MSK’s Lymphoma Service is quite large, with more than 20 faculty. Because there are so many of us, we can specialize not just in lymphoma but in particular types of lymphoma.

What types of lymphoma do you specialize in treating?

I was very fortunate 20 years ago to be part of the early development of the first monoclonal antibody drug for diffuse large B cell lymphoma (DLBCL), called rituximab. I’m continuing to work on developing new antibody drugs for DLBCL.

I also treat follicular lymphoma. This disease is unusual because some patients who are diagnosed with it don’t require treatment right away, only active surveillance. But it also doesn’t have a cure. Thanks to new treatments, we’ve been able to extend survival for this disease considerably, from an average of eight to ten years to an average of 15 to 20 years. But I think that with the addition of new treatments, especially different kinds of immunotherapy, we will soon be able to offer a cure for some patients.

What are some of the research collaborations you’re planning?

There are many projects I plan to pursue with people here at MSK.

I’m very excited to work with physician-scientist Santosh Vardhana, who recently started his own lab in the Human Oncology and Pathogenesis Program. He has so much knowledge about T cell biology, and we want to apply this to some of the clinical trials we are developing.

I’ve already had the opportunity to work on projects with hematopathologist Ahmet Dogan. To understand lymphoma, we have to really know what’s happening in the tumor, and pathology is the cornerstone of that.

Before I came here, I had met Sloan Kettering Institute cancer biologist Hans-Guido Wendel a few times, and I knew his work. I’ve joined his very innovative project looking at abnormal RNA translation in lymphoma to help bring his findings to the clinic.

In the past, I’ve participated in studies that looked at the ways a person’s genes influence how they respond to treatments for lymphoma. Through this work, I’ve been involved in some consortia with geneticist Vijai Joseph, who studies hereditary cancer. Now that we’re in the same place, we can find time to work more on this project.

What made you interested in pursuing science and medicine as a career — particularly cancer?

I got interested in medicine because I wanted to help people. Medicine is a profession where you bring something to others — health, one of the most precious things we have. I’m also a curious person, so that made science a natural fit.

When I finished medical school, and I had to choose where to focus, the field of oncology was attractive, in part because it was challenging. At that time, there weren’t many options for people with cancer, other than chemotherapy. We in the field were starting to learn more about the biology and immunology of the disease, and it felt like there were many opportunities to improve treatment for cancer patients.

What are you most looking forward to doing in New York once the pandemic is over?

My wife and I are both excited about getting into the jazz music scene. We sometimes hear musicians when we’re walking through Central Park, and it’s so good to hear live music.

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A new way of thinking about tau kinetics, an essential component of Alzheimer’s disease

Source: Cell Press
Date: 03/21/2018
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Alzheimer’s disease is most often characterized by two different pathologies in the brain: plaque deposits of a protein called beta-amyloid and tangles of another protein called tau. A paper appearing March 21 in the journal Neuron brings new insights into how tau proteins are processed in the human central nervous system. Researchers found that tau production and secretion from nerve cells appears to be an active process in the natural course of Alzheimer’s disease. This may explain why experimental treatments targeting tau have had disappointing results, as the current focus of these drugs assumes that the protein is primarily released from dying nerve cells.

“This study changes our way of thinking about tau in the context of neurodegenerative diseases,” says senior author, Randall Bateman, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine in St. Louis. “Contrary to the idea that tau is a product released by dying neurons, we have shown that the release of tau is an active and controlled activity that appears to be an important part of the disease process.”

In the study, the investigators used mass spectrometry and a method called stable isotope labeling kinetics to study tau in the cerebrospinal fluid (CSF) of people who were known to have Alzheimer’s and healthy controls. This enabled them to measure the tau turnover rate and its half-life in the human nervous system as well as to analyze the different forms of the protein. Their findings revealed that certain forms of tau have faster turnover rates than others, suggesting that they may have unique biological activities. In addition, they found that production rate of tau was higher in people with Alzheimer’s, suggesting a biological link between the presence of amyloid plaques and tau kinetics.

“We’ve known for a long time that CSF tau is increased in Alzheimer’s disease, but until this study, we didn’t know if tau production was increased or if clearance was decreased,” says Chihiro Sato, a member of the Bateman lab and one of the paper’s co-first authors. “Our results showing that tau production is increased suggest that we might want to target tau production therapeutically.”

The researchers also looked at tau production in human neurons made from induced pluripotent stem cells (iPSCs). “The research with the iPSCs was really valuable, because we were able to ask questions about human neurons that we wouldn’t be able to ask in living subjects,” says Celeste Karch, an Assistant Professor of Psychiatry at Washington University School of Medicine and one of the study’s co- authors. “We found that inside neurons some forms of tau are turned over more quickly than others. Interestingly, the forms of tau that are turned over more quickly are also those that are prone to misfold and aggregate in the context of Alzheimer’s disease and other tauopathies.”

“Using mass spectrometry, we found that tau is truncated in CSF in healthy people and Alzheimer’s patients,” says Nicolas Barthélemy, a member of the Bateman lab and the other co-first author. “Truncated tau is released differently from full-length tau, supporting our hypothesis that tau is actively processed under physiological and pathological conditions.”

The investigators say the knowledge gained from this study not only helps to understand more about Alzheimer’s disease, but other diseases characterized by the aggregation of tau as well. “We expect these findings will help us to distinguish between Alzheimer’s and other types of tauopathies in future,” Bateman says. The investigators plan to expand their research to patients with some of these other diseases, including progressive supranuclear palsy and corticobasal degeneration, to determine whether there are different forms of tau in the cerebrospinal fluid and different kinetics underlying the changes that are observed.

“It’s hard to do clinical research on tauopathies right now, because we don’t have good tests for diagnosing these other diseases, such as frontotemporal dementia,” Bateman adds. “Having an accurate diagnosis helps not only in the clinic but also in clinical trials, to ensure that we’ve included the right patients in our studies.”

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Mitochondria may metabolize ADP differently in aging muscle, despite exercise resistance

Source: Cell Press
Date: 03/13/2018
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Most adults reach their peak levels of muscle mass in their late 30s or early 40s. Even for those who exercise regularly, strength and function start to decline after that point. For those who don’t exercise, the drops can be dramatic. Now, a study of twenty men published March 13 in the journal Cell Reports provides new clues about the cellular mechanisms of aging muscles, showing a key role for how mitochondria, the powerhouses of the cell, process ADP, which provides energy to cells.

ADP, or adenosine diphosphate, plays a role in how our cells release and store energy. But previous lab models that have looked at the mechanisms of aging in human cells have not included ADP. When ADP is metabolized in the mitochondria, it stimulates cellular respiration and decreases reactive oxidative species (ROS; also known as free radicals). Higher ROS levels are linked to damage in different components of the cell, a process also called oxidative stress.

In the study, the investigators developed an in vitro system employing individual muscle fibers taken from muscle biopsies. The fibers were put into a system in which mitochondrial function and respiration could be measured across a range of ADP concentrations that are relevant to those found in the human body. “The way people normally measure ROS is in a system that has ADP removed,” says senior author Graham Holloway, an associate professor at the University of Guelph in Ontario. “But biologically, we always have ADP in the system. We started to think that maybe how we get ADP into the mitochondria is important for aging.”

In the first part of the paper, the researchers compared muscle from ten healthy men in their 20s with muscle from ten healthy men in their early 70s. They found that there was an 8- to 10-fold decrease in ADP sensitivity, and therefore, when ADP was added to the system, there was a 2- to 3-fold higher rate of ROS emission in the muscle taken from the older men. ROS levels were determined by measuring emissions of hydrogen peroxide, a byproduct of activity in the cell.

The findings suggested that mitochondrial ADP sensitivity was somehow impaired in the muscles of the older men and that increased levels of ROS were contributing to sarcopenia, or the degenerative loss of muscle mass. “The magnitude of change was quite striking to us,” Holloway explains. “For humans, it’s remarkable to have such a big difference.”

In the second part, the older men undertook a program of supervised resistance training, which included leg presses and upper-body exercises. But, after 12 weeks, there were no changes in the levels of hydrogen peroxide emitted, suggesting no improvements in age-associated cellular stress.

“This doesn’t mean there’s no hope for building strength in aging muscle,” Holloway says. “I actually think that endurance training would be potentially beneficial, because we know with that kind of training you get increases in mitochondrial content.” Endurance training includes aerobic exercise like cycling and swimming. “Moving forward, we plan to look at other types of exercise, to see if it can improve the dynamic response of mitochondria to ADP,” he adds.

Other future work will use rodent models to delve into the cause-and-effect relationships of the molecular mechanisms of ADP metabolism. The investigators also plan to extend their studies to looking at different types of exercise in aging women. Early research in healthy young people has indicated that there are differences in sensitivity to ADP between men and women.

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High-resolution brain imaging provides clues about memory loss in older adults

Source: Cell Press
Date: 03/07/2018
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As we get older, it’s not uncommon to experience “senior moments,” in which we forget where we parked our car or call our children by the wrong names. But currently there are no good ways to determine which memory lapses are normal parts of aging and which may signal the early stages of a severe disorder like Alzheimer’s disease. In a study appearing March 7 in the journal Neuron, researchers report that data from high-resolution functional brain imaging can be used to show some of the underlying causes for differences in memory proficiency between older and younger adults.

“At the fundamental level, we still understand very little about how aging affects the neural systems that give rise to memory,” says Zachariah Reagh, the study’s first author, who is now a postdoctoral fellow at the University of California, Davis.

The paper reports data from 20 young adults (ages 18 to 31) and 20 cognitively healthy older adults (ages 64 to 89). The participants were asked to perform two kinds of tasks in an fMRI scanner, an object memory task and a location memory task. Because fMRI looks at the dynamics of blood flow in the brain, it enables investigators to determine which parts of their brains the subjects are using in each task.

In the object task, participants learned pictures of everyday objects and were then asked to distinguish them from new pictures. “Some of the pictures were identical to ones they’ve seen before, some were brand new, and others were similar to what they’ve seen before–we may change the color or the size,” says Michael Yassa (@mike_yassa), Director of the Center for the Neurobiology of Learning and Memory at the University of California, Irvine, and the study’s senior author. “We call these tricky items the ‘lures.’ And we found that older adults struggle with these lures. They are much more likely than younger adults to think they’ve seen those lures before.”

The second task was very similar but required subjects to determine during test whether objects changed their location. For this type of memory task, older adults fared quite a bit better. “This suggests that not all memory changes equally with aging,” says Reagh. “Object memory is far more vulnerable than spatial memory, at least in the early stages.” Other studies have shown that problems with spatial memory and navigation do manifest as individuals go down the path to Alzheimer’s disease.

Importantly, by scanning the subjects’ brains while they underwent these tests, the researchers were able to establish a mechanism within the brain for that deficit in object memory.

They found that it was linked to a loss of signaling in the part of the brain called the anterolateral entorhinal cortex. This area was already known to mediate the communication between the hippocampus, where information is first encoded, and the rest of the neocortex, which plays a role in long-term storage. It is also an area that is known to be severely affected in people with Alzheimer’s disease.

“The loss of fMRI signal means there is less blood flow to the region, but we believe the underlying basis for this loss has to do with the fact that the structural integrity of that region of the brain is changing,” Yassa explains. “One of the things we know about Alzheimer’s disease is that this region of the brain is one of the very first to exhibit a key hallmark of the disease, deposition of neurofibrillary tangles.”

In contrast, the researchers did not find age-related differences in another area of the brain connected to memory, the posteromedial entorhinal cortex. They demonstrated that this region plays a role in spatial memory, which was also not significantly impaired in the older subjects. “These findings suggest that the brain aging process is selective,” Yassa adds. “Our findings are not a reflection of general brain aging, but rather specific neural changes that are linked to specific problems in object but not spatial memory.”

To determine whether this type of fMRI scan could eventually be used as a tool for early diagnosis, the researchers plan to expand their work to a sample of 150 older adults who will be followed over time. They will also be conducting PET scans to look for amyloid and tau pathology in their brains as they age.

“We hope this comprehensive imaging and cognitive testing will enable us to figure out whether the deficits we saw in the current study are indicative of what is later to come in some of these individuals,” Yassa says.

“Our results, as well as similar results from other labs, point to a need for carefully designed tasks and paradigms that can reveal different functions in key areas of the brain and different vulnerabilities to the aging process,” Reagh concludes.

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Artificial intelligence can diagnose and triage retinal diseases

Source: Cell Press
Date: 02/22/2018
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While we might trust virtual assistants to give us directions or recommend as spot for lunch, trusting artificial intelligence (AI) with something as important as a medical diagnosis is a step that many people are not yet willing to take. A team of scientists in the United States and China aim to change that. In the February 22 issue of Cell, they describe a platform that uses big data and AI not only to recognize two of the most common retinal diseases but also to rate their severity. It can also distinguish between bacterial and viral pneumonia in children based on chest X-ray images.

“Macular degeneration and diabetic macular edema are the two most common causes of irreversible blindness but are both very treatable if they are caught early,” says senior author Kang Zhang, a professor of ophthalmology at the University of California, San Diego’s Shiley Eye Institute. “Deciding how and when to treat patients has historically been handled by a small community of specialists who require years of training and are concentrated mostly in urban areas. In contrast, our AI tool can be used anywhere in the world, especially in the rural areas. This is important in places like China, India, and Africa, where there are relatively fewer medical resources.”

The platform looked at more than 200,000 optical coherence tomography (OCT) images collected with a noninvasive scan that uses light waves to image the layers of the retina. Earlier studies have used machine learning to study retinal images, but the authors of the new study say their platform goes a step further by using a technique called transfer learning. This is a type of machine learning in which general knowledge related to classification can be transferred from one disease area to another and can enable the AI system to learn effectively with a much smaller dataset than traditional methods. In addition to making a medical diagnosis, this AI platform also can make referral and treatment recommendations, which is another step that goes beyond previous studies.

The researchers also used occlusion testing, which allowed them to show areas of greatest importance when reviewing the scan images. “Machine learning is often like a black box, where we don’t know exactly what is happening,” Zhang explains. “With occlusion testing, the computer can tell us where it is looking in an image to arrive at a diagnosis, so we can figure out why the system got the result it did. This makes the system more transparent and increases our trust in the diagnosis.”

In the study, the researchers compared the diagnoses from the computer with those from five ophthalmologists who reviewed the scans. “With simple training, the machine could perform to the level of a well-trained ophthalmologist. It could generate a decision on whether or not the patient should be referred for treatment within 30 seconds and with more than 95% accuracy,” Zhang says.

He explains that diagnosing and treating retinal diseases normally involves visiting a general medical doctor or an optometrist, then a general ophthalmologist, and finally a retina specialist. This referral process can waste valuable time and resources for a disease in which prompt treatment can mean the difference between going blind or retaining sight. “Having an automated diagnosis could enable patients who would benefit from treatment to see a specialist and get that treatment much sooner and change outcomes,” he says.

Zhang estimates that the test will be only a fraction of the current cost. “In addition to economic benefit, there are significant non-economic benefits in increased personal and society productivity regarding a patient’s wait time spent to see a doctor and better access to care in remote areas,” he says.

The researchers also applied the tool to childhood pneumonia. By reviewing chest X-rays, the computer was able to determine the difference between viral and bacterial pneumonia with greater than 90% accuracy. Viral pneumonia is treated mainly with supportive care, whereas bacterial pneumonia requires swift initiation of antibiotic treatment. This showed that the tool is adaptable and can be used effectively with multiple types of medical images.

Zhang says this technology has many other potential applications, such as distinguishing between cancerous and noncancerous lesions on CT scans or MRIs, and his group has made their data and tools open source so that other groups can use it. “If we all work together as a community, we can develop better and better tests with higher computational power,” he says. “The future is more data, more computational power, and more experience of the people using this system, so that we can provide the best patient care possible, while still being cost effective.”

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Walking fish suggests locomotion control evolved much earlier than thought

Source: Cell Press
Date: 02/08/2018
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Cartoons that illustrate evolution depict early vertebrates generating primordial limbs as they move onto land for the first time. But new findings indicate that some of these first ambulatory creatures may have stayed under water, spawning descendants that today exhibit walking behavior on the ocean floor. The results appear February 8 in the journal Cell.

“It has generally been thought that the ability to walk is something that evolved as vertebrates transitioned from sea to land,” says senior author Jeremy Dasen (@JeremyDasen), a developmental neurobiologist in the Department of Neuroscience and Physiology at the New York University School of Medicine. “We were surprised to learn that certain species of fish also can walk. In addition, they use a neural and genetic developmental program that is almost identical to the one used by higher vertebrates, including humans.”

The researchers focused on the neural development of a type of fish called the little skate (Leucoraja erinacea). Related to sharks and rays, these cartilaginous fish are considered to be among the most primitive vertebrates, having changed little from their ancestors that lived hundreds of millions of years ago.

Little skates have two sets of fins: large pectoral fins, which they use for swimming, and smaller pelvic fins, which they use for walking along the ocean floor. Previous research had shown that these fish use alternating, left-right motions when they walk, similar to the motions used by animals that walk on land, making them a valuable model to study.

The investigators used a technology called RNA sequencing (RNA-seq) to assess the repertoire of genes that are expressed in the skate’s motor neurons. They found that many of these genes are conserved between skates and mammals. In addition, they discovered that the neuronal subtypes that are essential for controlling the muscles that regulate the bending and straightening of limbs are present in the motor neurons of the skate. “These findings suggest [that] the genetic program that determines the ability of the nerves in the spinal cord to articulate muscles actually originated millions of years earlier than we have assumed they appeared,” Dasen says. “This fin-based movement and walking movements use the same developmental program.”

The discovery went beyond the nerves that control muscles. The researchers also looked at a higher level of circuitry–the interneurons, which connect to motor neurons and tell them to activate the muscles. Interneurons assemble into circuits called central pattern generators (CPGs). CPGs determine the sequence in which different muscles are activated, thereby controlling locomotion. “We found that the interneurons, nearly a dozen types, are also highly conserved between skates and land mammals,” Dasen says.

Dasen’s team plans to use the little skates to study how motor neurons connect with other types of neurons and how they are regulated. “It’s hard to study the circuitry that controls walking in higher organisms like mice and chicks because there are so many more muscles and types of neurons that facilitate that behavior,” he says. “We think this species will serve as a useful model system to continue to work out the nerves that control walking and how they develop.”

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Building a Safer Opioid: MSK Research Seeks to Develop New Ways to Relieve Pain

Source: Memorial Sloan Kettering - On Cancer
Date: 01/04/2018
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The United States is in the midst of an opioid epidemic. According to the Centers for Disease Control and Prevention, 91 Americans die every day from opioid overdoses, and that figure is rising.

Researchers are working to combat this epidemic. Economics, psychology, and medicine all play a role. Chemistry also can be a factor by contributing to the development of safer opioid drugs that effectively treat pain but are less likely to lead to addiction or abuse.

Memorial Sloan Kettering medicinal chemist Susruta Majumdar has focused on this effort for more than a decade. He is part of a multicenter group of researchers publishing a paper in Cell that reports an inventive approach for developing safer opioid drugs. We spoke with Dr. Majumdar recently about this research.

Why are opioid drugs so likely to cause addiction and abuse?

All of the opioid drugs that are currently available target what is called the mu opioid receptor. These drugs include morphine, oxycodone, and fentanyl. When they bind to this receptor, which is found in nerve cells all over the body, they block the pathways that transmit pain signals to the brain.

But targeting the mu receptor has another effect on the nervous system. It gives you a feeling of euphoria, a high. It’s the same thing you feel when you have sex or eat chocolate or take some other drugs, like cocaine. One of the reasons people become addicted to opioids is because they’re constantly seeking that high.

How does your research address the issue of opioid addiction and abuse?

In addition to mu, there are two other opioid receptors that also block pain signals. They are called the kappa receptor and the delta receptor. In my research, we’re looking for ways to activate the kappa receptor. We think this approach has great potential. Drugs that target the kappa receptor can block pain signals without giving the feeling of euphoria that leads to abuse.

Unfortunately, kappa drugs that have been studied in the lab also have unwanted side effects, like frequent urination. But more importantly, they cause hallucinations and dysphoria, or feelings of unhappiness. Our goal is to design kappa drugs that will provide effective pain relief while avoiding these other effects.

How are you investigating this?

We’re using an approach called structure-based drug design. It’s built on the idea that once we know the shape of a protein, we can design a molecule that will fit into it exactly the way we want it to, like a key fitting into a lock.

In this case, that protein is the kappa opioid receptor. We have determined its shape, so now we can design drugs that bind to it in just the right way.

What does the new Cell study add to this area of research?

In 2015, our team at MSK reported that we had created a compound that binds very effectively to the kappa opioid receptor. We called the compound MP1104. We showed this molecule had the ability to reduce pain without the other negative effects associated with kappa opioids. We also showed that it blocked cocaine addiction in mice.

A team led by pharmacologist Bryan Roth at the University of North Carolina (UNC) at Chapel Hill then used our molecule to crystalize the kappa opioid receptor and determine its structure. Once they did that, our lab at MSK developed a library of other molecules that are related to MP1104 using structure-based drug design.

The new compounds were synthesized by MSK research scholar Rajendra Uprety and tested by postdoctoral researcher Tao Che at UNC. At least one of the molecules we made shows an ability to bind selectively to the kappa receptor over other opioid receptors.

To summarize our findings, MP1104 has made it possible to understand how kappa receptors are activated. In addition, having the crystal structure available will allow us and others to discover new kappa drugs that can relieve pain without causing the unhappy feelings that the current kappa drugs can cause.

What’s next for this research collaboration?

We now have several promising compounds that we can begin to test in animals in the lab. Our goal is to find the best candidates to eventually test in people.

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Remembering Jimmie Holland, a Founder of Psycho-Oncology

Source: Memorial Sloan Kettering - On Cancer
Date: 01/09/2018
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On Christmas Eve, Memorial Sloan Kettering and the wider cancer community lost a beloved and brilliant doctor, Jimmie Holland, who died of cardiovascular disease at 89. Dr. Holland was a tireless advocate for supporting the emotional and psychological needs of people with cancer. She also made huge strides in reducing the stigma surrounding the disease.

Dr. Holland was considered a founder of the field of psycho-oncology, which combines oncology and psychiatry. It is increasingly considered a vital part of comprehensive cancer care, largely thanks to her work.

In 1977, Dr. Holland joined MSK as the inaugural Chief of the Psychiatry Service, the first such service at a cancer center anywhere in the world. She was then named Chair of MSK’s Department of Psychiatry and Behavioral Sciences when it was created in 1996. The department was also the first of its kind, and Dr. Holland remained in her role there until 2003. At the time of her death, she held the Wayne E. Chapman Chair in Psychiatric Oncology.

“Jimmie’s death is a profound loss to us all,” says MSK Physician-in-Chief José Baselga. “Through her visionary work she has forever changed the landscape of cancer care.”

Changing World, Changing Needs

Dr. Holland grew up in a tiny town in north Texas, the only child of a cotton farmer and his wife, neither of whom had finished high school. When she earned her medical degree from Baylor College of Medicine in the early 1950s, “cancer”was a word that most people wouldn’t say out loud. Many newspapers and magazines wouldn’t print it, and patients often were not even told of their diagnosis.

That began to change in the 1970s. Better treatments became available and people with once-fatal cancers starting living longer and even being cured. As the wife of James Holland — a leading oncologist and one of the pioneers of chemotherapy combinations — Dr. Holland had a front-row seat from which to witness the medical revolution that was taking place. While her husband and his colleagues focused on curing people of their cancer, Dr. Holland asked a question that none of them were able to answer: How do the patients feel about it?

As a psychiatrist, she had long been interested in studying how people with otherwise good mental health responded emotionally and psychologically to life-threatening illnesses. She called this focus “psychological care of the medically ill.” She began encouraging oncologists who were conducting clinical trials to include questions about patients’ quality of life in their data collection and research.

The Science of Caring

But measuring things like anxiety, depression, and fatigue was not always straightforward. Dr. Holland met this challenge by developing ways to gauge what patients were feeling that went beyond what doctors and nurses could just observe. She worked to create objective scales to evaluate aspects of people’s experience that were once considered immeasurable. This in turn could validate whether psychological treatments were working. Her research brought the emerging field of psycho-oncology into the realm of evidence-based science, which allowed it to become a recognized subspecialty.

During her years at MSK, Dr. Holland created the nation’s largest training and research program in psycho-oncology. In 1984, she produced for MSK the first-ever syllabus on psycho-oncology. In 1989, she was senior editor of the first textbook on the subject. She also shared her knowledge with the world. She co-founded the International Psycho-Oncology Society in 1984 and founded the American Psychosocial Oncology Society in 1986. She is credited with putting psychosocial and behavioral research on the agenda of the American Cancer Society in the early 1980s. She was also a founder and co-editor-in-chief of the journal Psycho-Oncology.

Dr. Holland recognized that people’s psychological distress could linger even after they were considered cured of their cancer. To address this, she advocated for the formation of a program at MSK that today is called Resources for Life After Cancer. It became a model for other similar initiatives around the world.

“Jimmie was a cancer pioneer, a remarkable woman, and a once-in-a-generation influencer,” says William Breitbart, the current Chair of Psychiatry and Behavioral Sciences and the Jimmie C. Holland Chair. “Her death is a profound loss for all of oncology.”

The Sixth Vital Sign

Dr. Holland pushed to recognize patient distress as the sixth vital sign in medicine. (The others are temperature, pulse, blood pressure, respiration, and pain.) She played a key role in the development of the National Comprehensive Cancer Network’s distress thermometer. This enables people to report their levels of anxiety and depression on a scale of zero to ten, similar to the way they rate their pain.

Other topics that were important to her included survivor guilt, diminishing the stigma of a cancer diagnosis, and evaluating ways to lessen cancer side effects like depression, anxiety, and fatigue with medication and other treatments.

In her later years, she also became particularly interested in supporting the psychosocial needs of elderly patients. As part of that effort, she founded the Vintage Readers Book Club, an offshoot of a support group she led on aging and cancer. The participants talked about classic works by writers including Cicero and Benjamin Franklin, and used their discussions as a springboard for talking about wider-ranging topics that were important to them.

“Jimmie was an inspiration on multiple levels, not least of which was her appreciation of the fact that we are more than our careers,” says psychologist and author Mindy Greenstein, who first came to know Dr. Holland when she conducted her fellowship in MSK’s Department of Psychiatry and Behavioral Sciences. The two later worked together and coauthored the book Lighter as We Go: Virtues, Character Strengths, and Aging. “While raising her own family as well as comforting patients and their family members with her Texas warmth and sound insights, she still found the time to accomplish so much in her work. Hers was a life of unique and dedicated service.”

Dr. Holland, who died at home surrounded by family, was still seeing patients up until two days before she died. She is survived by her husband; six children; nine grandchildren; and countless friends, colleagues, and collaborators.

“Jimmie was a true pioneer in the field of psycho-oncology, and her passion for her patients and her research was evident,” says MSK President and CEO Craig Thompson. “She will be dearly missed by the MSK community and by the world.”

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MSK Opens New Clinic to Monitor People with a Genetic Risk for Developing Blood Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 01/23/18
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Most cancers arise by chance and, therefore, are hard to predict. But scientists and doctors are learning more about the genetic changes that cause cancer as well as those that signal a higher risk for it. Thanks to MSK-IMPACT™, Memorial Sloan Kettering’s diagnostic test that looks for genes associated with cancer, more people who carry cancer-related genes are being identified.

To take advantage of these new opportunities, MSK has launched the Precision Interception and Prevention Initiative. This program is focused not only on catching cancer very early but also on eventually preventing it from forming in the first place. One of the program’s components is a clinic for people with an age-related condition called clonal hematopoiesis (CH). MSK’s clinic, the first of its kind, is beginning to see people with CH this month.

“This initiative unites high-impact science and clinical medicine to actively identify and help a population of people who are either at a high risk of developing cancer or who already have cancer but don’t know it,” says Luis Diaz, head of MSK’s Division of Solid Tumor Oncology, who is leading this effort.

A person with clonal hematopoiesis has an increased number of blood cells that carry some of the same mutations that are found in blood cancers. CH occurs when hematopoietic stem cells (which give rise to all types of blood cells) form cells that are genetically distinct from the rest of the blood stem cells. Sometimes these distinct cells carry cancer-associated mutations.

“This is an exciting and quickly growing field, and it’s vital for us to learn as much about it as possible,” says physician-scientist Ross Levine, who will be heading the new clinic. “By launching this effort to monitor and care for people with CH, we will be able to advance our understanding about this important area of science.”

Clonal Hematopoiesis: A Common Phenomenon Linked to Aging

Dr. Levine was part of the research team that was the first to identify the genetic basis of CH and its connection to blood cancer. They first reported that relationship in 2012. Since then, many investigators have begun to study the condition and have shown that CH is very common. Researchers have found that it is linked to an increased risk of certain blood cancers, especially myelodysplastic syndrome and acute myeloid leukemia, as well as cardiovascular disease, heart attacks, and strokes.

The most common cause of CH is aging. Studies have suggested that between 10 and 20% of people over age 70 have signs of it in their blood. Smoking also increases the risk. “CH is very common. Millions of people have it,” Dr. Levine says. “But most people don’t know they have it, and doctors don’t know what to do with it. We thought it was important to do more research on this phenomenon so that we can start figuring out who may need intensive follow-up and treatment right away and who can be observed.”

“Right now we don’t have good ways to predict who is most likely to develop a blood cancer, so any new findings that come out of this clinic have the potential to make a big difference,” says Marcel van den Brink, Head of MSK’s Division of Hematologic Oncology.

In addition, certain types of chemotherapy and radiation therapy can increase the incidence of CH. This explains why cancer survivors carry a risk for secondary leukemia. The still-rare condition is happening more often because more people with cancer are surviving longer or are cured of their disease.

A study last year from Dr. Levine, MSK researcher Michael Berger, and their colleagues found that 25% of people with any type of cancer had CH, a higher number than had previously been observed. Of that group, 4.5% had specific mutations that are known to drive the formation of leukemia.

Treating Blood Cancer Earlier

Most people with CH will never develop blood cancer, but doctors are starting to understand which individuals with CH are at the highest risk. “This is one of the reasons this clinic is so important,” says MSK hematology fellow Kelly Bolton, who will be helping to run the new program. “We hope about 100 patients with high-risk forms of CH will participate in our first year.”

The MSK investigators who designed MSK-IMPACT, including molecular pathologist Marc Ladanyi and Dr. Berger, believed it was important to look for cancer-related genes in people’s normal tissue as well as in their tumors. This would help them determine whether a person’s cancer occurred completely by chance or whether inherited factors played a role. The easiest normal tissue to obtain is blood, and the gene mutations linked to CH started to show up as part of MSK-IMPACT testing.

As MSK launches its CH clinic, people who have undergone MSK-IMPACT testing for other cancers and have been found to have high-risk forms of CH in their blood will be contacted by their surgical or medical oncologist and invited to enroll in the program. MSK patients who are treated for low blood counts and found to have CH as part of their blood work will also be seen.

“In the past, CH has been just an incidental finding. When we were worried someone had an undiagnosed blood cancer, we would refer him or her to the Leukemia Service,” Dr. Bolton explains. “Now when we discover patients with high-risk forms of CH, we will have a clinic with experts in CH to manage and coordinate their care.”

For now, those who enroll in the clinic will have the opportunity to have their blood tested on a regular basis. People who are found to have a blood cancer will be able to start treatment immediately, when the disease is much easier to control.

Looking toward Future Treatments

In the future, MSK investigators hope to launch clinical trials of treatments that could block the progression from CH to active cancer. In addition, treatment for solid tumors may be tailored to protect people who already have an increased risk of developing a second cancer. But doctors don’t yet know enough about what drives the formation of CH to make any changes to treatment now.

Recent studies suggest that people with CH are at risk for cardiovascular diseases. However, testing for CH is not currently part of screening for them. “It’s important for people with CH to follow up with their primary-care doctors and make sure they have had the appropriate screenings for cardiovascular diseases,” Dr. Bolton says. “We will encourage everyone participating in our CH clinic to do this.”