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SOME OBESITY-LINKED DISEASES MAY BE RELATED TO CHOLESTEROL

Source: Brigham and Women's Hospital
Date: 1/25/2021
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Obesity is linked to an increased risk of many diseases, but much remains unknown about the molecular mechanisms underlying this connection. In a new study from Brigham and Women’s Hospital and Harvard Medical School, investigators have found an unexpected role for cholesterol and its effects on the immune system in driving some of these obesity-linked diseases — in particular, with conditions characterized by autoimmunity.

The association turns out to be mediated by interleukin-17 (IL-17), a cytokine that provides important protection against infections. When produced in excess, however, IL-17 is associated with autoimmune-related diseases including psoriasis, rheumatoid arthritis and multiple sclerosis.

“We know that IL-17 is linked with these diseases, and we know that IL-17 is increased in people who are obese,” said Brigham immunologist Lydia Lynch, PhD, senior author of the study published in Nature Immunology. “But the connection to cholesterol was surprising, because these diseases are not typically associated with high cholesterol.”

Discovering Unexpected Links

Dr. Lynch’s lab studies the effects of obesity and diet on the functions of immune cells. Her previous work found that obesity doesn’t affect every type of immune cell in the same way. “It’s not that obesity impairs all immune cells,” she said. “Instead, it skews them toward being IL-17 producers and therefore less cytotoxic, as it impairs natural killer cells and other cells that are associated with recognizing and fighting infections and cancer.”

In the current work, the researchers found the cells that produce high levels of IL-17 have lipid droplets inside of them, which is not typical of immune cells. Furthermore, mice that were fed a high-fat diet had higher IL-17 production. Alternatively, levels of IL-17 could be reduced by blocking lipid uptake in the mice.

When the team took a closer look at the type of lipids inside the cells, they discovered that in addition to triglycerides and fatty acids, which were expected, the cells contained cholesterol droplets. “It appeared that cholesterol was particularly associated with these IL-17-producing cells, suggesting a possible link between high cholesterol and IL-17-related diseases like psoriasis,” Dr. Lynch explained.

Combination of Obesity and Type 2 Diabetes Increases Risks

Dr. Lynch pointed out that one important aspect to note about the connections between obesity and disease is that the effects of obesity on the immune system are not the same in every individual. Other factors are involved as well.

For example, people who have obesity but do not have type 2 diabetes or other hallmarks of metabolic syndrome do not necessarily carry the same risks as those who have obesity and metabolic syndrome. Their immune system is less affected by obesity.

“It’s not just obesity on its own that affects disease risk, and it’s not just type 2 diabetes on its own either,” she said. “It’s the combination of obesity and type 2 diabetes that seems to have the worst effect on the immune system.”

Implications for Future Research

Although cholesterol appears to be associated with increased IL-17, the approach of treating high cholesterol to lower disease risk may not be so straightforward.

“We know that weight loss is associated with reduced IL-17, so lowering cholesterol through diet is probably beneficial,” Dr. Lynch said. “However, our early work has suggested that it may not be that simple. That’s because lowering cholesterol seems to cause these cells to start making their own lipids and cholesterol if they can’t take them up from the environment.”

She added, however, that much more work is needed before this connection can be fully understood.

Findings from this research have implications beyond autoimmune disorders. Previous work in Dr. Lynch’s lab focused on the role of the immune system in relation to obesity and cancer — specifically, how the cellular environment in people with obesity impairs immunosurveillance. This earlier research, which has suggested that metabolic reprogramming of natural killer cells may improve cancer outcomes in people with obesity, also has implications for immunosurveillance more broadly, including the connections between obesity and infectious diseases like COVID-19.

Research like Dr. Lynch’s is also helping to fuel treatment at the Brigham’s Center for Weight Management and Wellness, which offers medical, endoscopic and surgical weight management services and interventions. Caroline Apovian, MD, co-director of the center and a physician within the Brigham’s Division of Endocrinology, Diabetes and Hypertension says that research like this is instrumental in helping to understand what mechanisms cause patients with obesity to develop certain diseases.

“The more we understand about the triggers for certain obesity-linked disease’s, the better equipped we are to help our patients and adapt our treatment approaches.”

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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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Splicing May Be an Effective Target in the Fight against Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 07/18/2018
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Cancer is a disease of the genes. But genes don’t directly cause the uncontrolled cell growth that characterizes the disease — proteins produced by those genes do. Consequently, most precision cancer drugs target these malfunctioning proteins and block their activity.

Some investigators are looking to stop cancer by blocking steps on the path from gene to protein. One of these tactics focuses on a process called splicing. It has yielded a drug, called H3B-8800, which is now being evaluated in an early-stage clinical trial for myelodysplastic syndrome (MDS) and two types of leukemia.

“This drug works differently than other targeted drugs that block proteins,” says Memorial Sloan Kettering physician-scientist Omar Abdel-Wahab. “But we think it’s a very good approach because between 60 and 80% of people with MDS have the defect in splicing that this drug targets.”

A Promising New Focus for Cancer Drugs

Genes get translated into proteins through an intermediate molecule called messenger RNA (mRNA). If genes are the written instructions for how to make a protein, and the protein itself is the final product, then mRNA is the go-between that brings the plans to the construction crew. Splicing is one part of the manufacturing process. It determines which part of the genetic sequence gets used, and which part is cut out and thrown away. When splicing goes wrong, it can lead to defective proteins that drive cancer growth.

Dr. Abdel-Wahab studies the splicing process in his lab in the Human Oncology and Pathogenesis Program. Based on a recent discovery that genetic changes in the splicing process are very common in leukemias, he found that cells carrying these genetic changes are especially sensitive to drugs.

Research on splicing and mRNA is part of the broader field called epigenetics. Epigenetics is the study of changes in cell behavior that are not due to changes in the DNA sequence. It’s an increasingly important focus in cancer research. Dr. Abdel-Wahab is also a member of MSK’s Center for Epigenetics Research, which focuses on studies into how epigenetic changes can cause cancer.

Finding a Way to Correct Genetic Splicing Errors

H3B-8800, which is being developed by a company called H3 Biomedicine, is a version of a natural substance that was first found in soil bacteria. It was chemically modified to work better as a drug. Earlier this year, Dr. Abdel-Wahab, along with MSK MDS expert Virginia Klimek, was part of an international team that reported on the function and efficacy of H3B-8800 in a dish and in mouse models of leukemia. The study, published in Nature Medicine, found that H3B-8800 can induce cell death in cancer cells that are dependent on splicing.

“Mutations in splicing genes are very common in MDS, so we fully expect that these mutations are linked to the bone marrow dysfunction and low blood counts seen in MDS,” Dr. Klimek explains. “The development of this new targeted drug is exciting because it has the potential to help many people with MDS. We’re grateful for those who donated the blood and bone marrow samples that were used to make these discoveries, and which led to the development of H3B-8800.”

The drug is now being tested in a phase I clinical trial at MSK and several other hospitals to determine the highest dose that can be given safely and to look for side effects. At MSK, the trial is being led by Dr. Klimek. 

“This effort really highlights the importance of collaboration between doctors and scientists,” she adds. “Such collaborations enable us to take observations from patients into the research lab, where breakthrough discoveries can be made and turned into new treatments. Our collaborative approach and our tremendous research program are some of MSK’s greatest strengths.”

“Research in the lab has taught us a lot about how errors in splicing can impact the products of genes,” Dr. Abdel-Wahab notes. “We think these functions are particularly important for different kinds of blood cells, but it’s possible this approach may work for some solid tumors as well.”

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Meet Maria Jasin, an Award-Winning Biologist Who Studies DNA Repair

Source: Memorial Sloan Kettering - On Cancer
Date: 09/25/2019
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On September 25, Sloan Kettering Institute researcher Maria Jasin was presented with the Shaw Prize in Life Science and Medicine at a ceremony in Hong Kong. The annual Shaw Prizes honor life scientists, astronomers, and mathematicians from around the world who have made significant contributions in their fields of study. The prizes were first presented in 2002, and each comes with an award of $1.2 million.

Dr. Jasin, a member of SKI’s Developmental Biology Program, has received a number of other honors, including the 2018 Basser Global Prize from the Basser Center for BRCA at the University of Pennsylvania. She is also a member of the National Academies of Sciences and Medicine and the American Academy of Arts and Sciences.

We spoke with Dr. Jasin about her research and her collaborations at MSK.

What is the main focus of your work?

I study a process called homologous recombination. This is one of the main ways that cells repair DNA after it is damaged. A particularly dangerous type of DNA damage is a double-strand break, in which the two strands of the DNA double helix break in the same place. These breaks make it difficult for a cell to repair its genetic material.

In homologous recombination, a cell finds a DNA sequence in the genome that resembles the sequence at the break site. It mends the break by copying that undamaged sequence into the broken DNA.

How does your research relate to cancer?

In the late 1990s, I began a project with [Memorial Sloan Kettering medical oncologist and breast cancer specialist] Mary Ellen Moynahan, who was then a member of my lab. She was studying the connections between the genes BRCA1 and BRCA2, which are associated with the suppression of breast cancer, ovarian cancer, and other cancers. Their absence can also affect therapy response.

We found that when these genes are mutated, cells are prevented from being able to repair double-strand breaks by homologous recombination. When DNA can’t be repaired, damage in the genome can accumulate and eventually lead to cancer.

This research was a basis for other labs developing PARP inhibitors. These drugs are now often used to treat cancers containing BRCA mutations.

Can you explain the contributions your research has made to technologies like CRISPR?

When I started my own lab in the early 1990s, I wanted to study double-strand break repair as it applied to genetic engineering.

We took an enzyme that was used to induce double-strand breaks in yeast and modified it for mammalian cells. We then developed tools that would provide an indication that homologous recombination was taking place and repairing these breaks.

I still remember when my postdoc called me over and showed me the cell culture plate. There were all these colonies growing on it — revealing that we were able to induce a very precise genome modification. It worked! And better than I could have imagined! It was a stunning result. Up until that time, people had assumed that homologous recombination would not work in mammalian cells because, without a break, it was very inefficient. We also observed nonhomologous repair, which led to mutations at the site of the break.

It was clear to me from the beginning that this would be a powerful way to do gene modification. We still had a lot of things to figure out, including how to get DNA breaks at particular sites in the genome. But eventually it formed the basis of a number of gene-editing techniques, including the CRISPR system.

How did you find out that you won the Shaw Prize?

I was in Paris in May attending a conference. When I first got the announcement from the Shaw Foundation, I was so focused on the conference that I didn’t immediately understand they were telling me I had won. Once I figured it out, I was thrilled! I was with Erika Brunet, a former postdoctoral fellow who had organized the conference I was attending, and another former postdoctoral fellow, Fabio Vanoli, who is currently working in MSK’s Department of Pathology. We were able to celebrate a little bit in Paris. That was really nice.

A significant body of your research has focused on meiosis. What is that and why is it important?

Meiosis is the way that germ cells — eggs and sperm — form.

We usually think of double-strand breaks as something that puts the genome at risk for mutations. But meiosis is one case where we need homologous recombination to happen between maternal and paternal chromosomes. During the formation of germ cells, there are usually about 200 double-strand breaks. These breaks ensure that the germ cells get only one set of chromosomes and that offspring have genetic variation. You don’t get healthy sperm and eggs without it.

A lot of my research in this area has been done in collaboration with Scott Keeney [a member of SKI’s Molecular Biology Program]. We’ve worked together for more than 20 years. It’s been a highly productive partnership in terms of successful postdoctoral fellows and publications.

You started working at MSK right after finishing your training, and you’ve been here for your entire independent career. What’s special about working here?

MSK is a great place to collaborate, both with clinical researchers and with other basic science investigators. In addition, we get a lot of support from leadership to be creative when we want to explore a new project or a new avenue of study. A lot of other institutions don’t offer that.

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Research Points to a Potential New Approach for Treating Anemia

Source: Memorial Sloan Kettering - On Cancer
Date: 10/04/2019
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Anemia, a condition in which there are not enough red blood cells to transport oxygen throughout the body, affects millions in the United States every year. It can lead to fatigue, dizziness, and shortness of breath, among other symptoms. It’s a common side effect of certain cancer treatments, especially chemotherapy. Anemia occurs frequently in people with a type of blood cancer called myelodysplastic syndrome (MDS). And it’s widespread among people over age 65.

Therapies for anemia exist. They include the drug epoetin alfa (Procrit®, Epogen®), regular blood transfusions, and iron supplements. But researchers continue to be on the lookout for additional and better ways to boost the production of red blood cells. MSK physician-scientist Omar Abdel-Wahab, an expert in MDS, recently published a study in Science Translational Medicine that reported a new approach for treating anemia with medication.

“Anemia is a major medical problem,” says Dr. Abdel-Wahab, whose lab is part of MSK’s Human Oncology and Pathogenesis Program. “This study suggests a new type of drug that we could use to treat it. While the current standard therapies for anemia are very helpful, many people eventually fail to respond to these treatments. Additionally, routine use of blood transfusions has a major negative impact on quality of life and comes with potential side effects. Thus, developing entirely new ways to treat anemia is incredibly important.”

A Different Role for a Known Pathway

The new method was identified through a collaboration between Dr. Abdel-Wahab and Lingbo Zhang, a researcher at Cold Spring Harbor Laboratory and co-senior author of the paper.

The researchers performed a high-throughput screen, in which hundreds or thousands of compounds are tested at the same time. They were hoping to find drugs that could boost the production of red blood cells. They tested the compounds in cell cultures of red blood cell precursors (a type of blood stem cell that has the ability to develop into red blood cells).

They discovered that compounds that block a pathway called CHRM4 increased the production of red blood cells. This pathway is also known to have a regulatory effect on neurotransmitters, such as serotonin and dopamine. Its role in the production of red blood cells had not previously been identified.Anemia is a major medical problem.

After identifying the role of the CHRM4 pathway by studying blood cells in a test tube, the investigators analyzed the effects of giving the compounds to mice with MDS and in bone marrow samples from people with MDS. They also tried them in elderly mice that had reduced red blood cell production because of their age. (In mice, elderly means about 2 years old.) In each case, the drugs boosted the numbers of red blood cells that were made.

Identifying a Novel Therapeutic Approach

Drugs that block the CHRM4 pathway have already been approved by the US Food and Drug Administration to treat certain neurological disorders. The researchers are hoping to use these drugs as a starting point to make new medications that are more effective at treating anemia.

“These drugs don’t seem to have many side effects,” Dr. Abdel-Wahab says. “We think this is a good path to pursue.”

He adds that targeting CHRM4 could also be a good approach for treating hemolysis. This condition occurs when red blood cells break open and release hemoglobin into the blood. Hemolysis can happen in response to infections or drug reactions, among other situations, and can lead to anemia.

This research was funded by the Cold Spring Harbor Laboratory (CSHL) President’s Council; National Institutes of Health grants (CA045508, U01 HL127522, 1K08CA230319-01, and R01 HL128239); a CSHL–Northwell Cancer Translational Research Award; the Edward P. Evans Foundation; the Leukemia and Lymphoma Society; the Henry and Marilyn Taub Foundation; a Department of Defense Bone Marrow Failure Research Program grant (W81XWH-12-1-0041); and the Pershing Square Sohn Cancer Research Alliance.

Dr. Abdel-Wahab has served as a consultant for H3 Biomedicine, Foundation Medicine, Merck, and Janssen, and has received personal speaking fees from Daiichi Sankyo.

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Targeting Errors in How Proteins Are Made Is a Promising Approach for Cancer Treatment

Source: Memorial Sloan Kettering - On Cancer
Date: 10/09/2019
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Manufacturing proteins is a multistep process that’s hard-coded into how our cells operate. Genes, which are made of DNA, get translated into RNA, which in turn provides instructions on how proteins are made. One key step in this construction process is called RNA splicing. Like the editing of a film, when some pieces may be cut out and discarded, splicing involves removing portions of the RNA and stitching the remaining pieces back together.

New work from Memorial Sloan Kettering is illustrating that when splicing isn’t done properly, it can lead to cancer.

MSK physician-scientist Omar Abdel-Wahab focuses on studying this process in his lab. He recently published two studies looking at the role of specific RNA splicing factors in different cancers. One study focused on acute myeloid leukemia (AML); the other studied melanoma, particularly uveal (eye) melanoma.

“Our earlier research found that splicing factors are mutated at high frequency in a variety of cancer types,” says Dr. Abdel-Wahab, of the Human Oncology and Pathogenesis Program. “What we’re learning is that when these splicing factor proteins are mutated, they’re actually changing the function of the splicing machinery in cells. Importantly, they’re doing it in a way that promotes cancer.”

The research reported in both papers has already suggested possible approaches for targeting these defective splicing factors with drugs.

Combination Approach for Acute Myeloid Leukemia

The first paper, published October 2 in Nature, looked at a splicing factor called SRSF2. The SRSF2 gene is mutated in about one-quarter of AML cases. It turns out that these SRSF2 mutations are more likely to be present when cancer cells also have mutations in the IDH2 gene, which is commonly mutated in AML.

“We were surprised to find that mutations in SRSF2 are particularly frequent in AML that also has IDH mutations,” Dr. Abdel-Wahab says. “We decided to investigate this link.”

Two IDH genes — IDH1 and IDH2 — are commonly mutated in AML. Together, these mutations also are found in about one-quarter of AML cases. In the past few years, the US Food and Drug Administration has approved two drugs designed to target these mutations: enasidenib (Idhifa®) for IDH1 and ivosidenib (Tibsovo®) for IDH2.

“IDH mutations have been very clearly shown to drive leukemia development,” Dr. Abdel-Wahab explains. “What we showed in this paper is that the splicing errors caused by SRSF2 mutations are also part of this process. The interplay between these two types of mutations is very important.”

Dr. Abdel-Wahab’s lab is focused on developing drugs to target mutant splicing factors, including SRSF2. He is already conducting an early-stage clinical trial with one of these drugs, and more studies are planned.

“Now we’re really interested in trying to develop ways to target forms of AML that have both mutations,” he says. “The idea is that we could use these drugs together, so that we’re targeting the cancer from two sides.”We found that the mutation is disrupting a critical part of the splicing machinery in a way that drove the formation of cancer.

Targeting Melanoma with a New Kind of Therapy

In the second paper, published October 9 in Nature, Dr. Abdel-Wahab and his colleagues looked at another splicing factor, called SF3B1. Mutations in the SF3B1 gene are found in many types of cancer, including some types of leukemia and many solid tumors. They are most commonly found in uveal melanoma, a rare but aggressive eye cancer.

In this study, a collaboration with researchers at the Fred Hutchinson Cancer Research Center in Seattle, the investigators studied RNA sequencing data from people with several forms of cancer.

“We wanted to see if we could find a link to what the mutation is doing in these diseases,” Dr. Abdel-Wahab says. “We found that the mutation is disrupting a critical part of the splicing machinery in a way that drove the formation of cancer.”

As part of the study, the researchers were able to develop a way to block the altered RNA splicing caused by the mutated splicing factor. Instead of using a drug, they used a small piece of DNA called an antisense oligonucleotide. Oligonucleotide therapy is a relatively new form of treatment: A handful of oligonucleotide-based drugs have been FDA approved, mostly for genetic neurologic diseases.

Dr. Abdel-Wahab and his colleagues tested the antisense oligonucleotide in cultures of cells with SF3B1 mutations and found that it blocked the growth of cancer cells. They then tested the therapy in mice that were implanted with material from patient samples of uveal melanoma. The treatment reduced the size of the tumors in the mice.

“We would like to work to develop this antisense oligonucleotide as a treatment, so that we can eventually start a clinical trial,” Dr. Abdel-Wahab says. “It’s a challenging undertaking because of the way these oligonucleotides behave in the body. But we think it’s a promising approach.”

The October 2 Nature paper was funded by the Aplastic Anemia and MDS International Foundation, the Lauri Strauss Leukemia Foundation, the Leukemia and Lymphoma Society, a Japan Society for the Promotion of Science Overseas Research Fellowship, a Bloodwise Clinician Scientist Fellowship, the Oglesby Charitable Trust, National Institutes of Health grants (K99 CA218896 and R01 HL128239), an American Society of Hematology Scholar Award, Cancer Research UK, the Cancer Prevention and Research Institute of Texas, the Welch Foundation, a Department of Defense Bone Marrow Failure Research Program grant (W81XWH-16-1-0059), the Starr Foundation, the Henry and Marilyn Taub Foundation, the Edward P. Evans Foundation, the Josie Robertson Investigators Program, and the Pershing Square Sohn Cancer Research Alliance.

The October 9 Nature paper was funded by the Leukemia and Lymphoma Society, the Aplastic Anemia and MDS International Foundation, the Lauri Strauss Leukemia Foundation, the Conquer Cancer Foundation, an American Society of Clinical Oncology Young Investigator Award, an American Association for Cancer Research Lymphoma Research Fellowship, a Mahan Fellowship from the Fred Hutchinson Cancer Research Center, the Pershing Square Sohn Cancer Research Alliance, the Henry and Marilyn Taub Foundation, the Starr Cancer Consortium, National Institutes of Health grants (R01 DK103854 and R01 HL128239), the Evans MDS initiative, and the Department of Defense Bone Marrow Failure Research Program.

Dr. Abdel-Wahab has served as a consultant for H3 Biomedicine, Foundation Medicine, Merck, and Janssen, and has received personal speaking fees from Daiichi Sankyo.

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Three Scientists Are Named Winners of the Paul Marks Prize for Cancer Research

Source: Memorial Sloan Kettering - On Cancer
Date: 11/08/2019
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Memorial Sloan Kettering has named three investigators as the recipients of this year’s Paul Marks Prize for Cancer Research. The award recognizes promising scientists for their accomplishments in the area of cancer research. 

The winners for the 2019 Paul Marks Prize for Cancer Research are Nathanael Gray of the Dana-Farber Cancer Institute and Harvard Medical School, Joshua Mendell of the University of Texas Southwestern Medical Center, and Christopher Vakoc of Cold Spring Harbor Laboratory.

“The body of research represented by this year’s winners touches on three different but equally important areas of cancer research,” says Craig B. Thompson, President and CEO. “Each of the recipients is conducting investigations that will have a major impact on cancer care in the years to come.”

Since it was first presented in 2001, the biennial Paul Marks Prize for Cancer Research has recognized 31 scientists and awarded more than $1 million in prize money. The award was created to honor Dr. Marks, President Emeritus of MSK, for his contributions as a scientist, teacher, and leader during the 19 years he headed the institution.

The prize winners were selected by a committee made up of prominent members of the cancer research community. Each recipient will receive a medal and an award of $50,000 and will speak about their research at a scientific symposium at MSK on December 5.Paul Marks Prize for Cancer Research

The Paul Marks Prize for Cancer Research is intended to encourage young investigators who have a unique opportunity to help shape the future of cancer research. Named for the late Paul A. Marks, who served as President of Memorial Sloan Kettering for nearly two decades, the prize is awarded to up to three investigators every other year.

Nathanael Gray

Dr. Gray is the Nancy Lurie Marks Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School and the Dana-Farber Cancer Institute. He also leads the Dana-Farber chemical biology program.

Dr. Gray’s research centers on drug development and medicinal chemistry related to targeted therapies for cancer. Most traditional targeted therapies block the activity of cancer-causing proteins. Dr. Gray’s lab is taking a different approach: finding ways to degrade these proteins.

“The analogy used with conventional targeted therapies is that the drug is a key and the protein is a door that can be unlocked,” he says. “But what happens when you have a door with no keyhole and no combination? The only way you can get rid of the door is to blow it up. That’s the degradation approach.”

Most medicinal chemists work either at a drug company or in a chemistry department, but Dr. Gray sees great value in working at a cancer center. “This is the most valuable environment I could be in,” he says. “I’m collaborating with basic cancer scientists as well as physicians. All of us are focused on the problem of cancer. My job is to figure out which problems are tractable and then figure out an approach for solving them.”

Four drugs that Dr. Gray has had a hand in developing have already been approved by the US Food and Drug Administration or are currently in clinical trials. “We plan to continue working on targets that were once considered ‘undruggable’ by using this protein-degradation approach,” he says.

Joshua Mendell

Dr. Mendell is a professor and the Vice Chair of the Molecular Biology Department at UT Southwestern Medical Center. He is also a Howard Hughes Medical Institute Investigator.

His lab studies noncoding RNAs, which lack the instructions for making proteins. Much of his research focuses on a class of very small noncoding RNAs called microRNAs. “MicroRNAs regulate messenger RNA molecules, which do encode proteins,” Dr. Mendell says. “Over the years, my lab has investigated how these small noncoding RNAs contribute to tumor formation and how they become dramatically reprogrammed in cancer cells.”

One particularly important contribution from his lab was the discovery that MYC, a gene that’s overactive in many human cancers, promotes cancer in part by reprogramming microRNAs to favor tumor growth.

Not all microRNAs in cancer cells have the same function. Some act as oncogenes, meaning that they drive the formation of tumors. Others are tumor suppressors. This means that when levels of the microRNAs go down, tumors are able to form.

“We’re interested in finding therapies that change the activity of these microRNAs,” he explains. “For those that act as oncogenes, it could be beneficial to inhibit their activity. On the other hand, for those that act as tumor suppressors, we are working to restore their activity or increase their levels in cancer cells.”

Research in Dr. Mendell’s lab has expanded to include the study of other types of noncoding RNAs. “Other classes of noncoding RNAs are much more mysterious, and their mechanisms are more diverse compared to microRNAs,” he says. “We want to understand why our genome is producing so many RNAs that do not encode proteins and what role they may have in diseases, including cancer.”

Christopher Vakoc

Dr. Vakoc is a professor at Cold Spring Harbor Laboratory. His research is focused on gene regulation. Specifically, he is determining how certain genes drive cancer growth and looking for ways to disable those genes. “The objective of our research is to figure out how we can use drugs to turn off cancer-promoting genes as a way to eliminate tumors,” he says.

In his lab, Dr. Vakoc performs genetic screening with the gene-editing technique CRISPR to figure out which genes and proteins are most important for cancer. “We systematically subtract each one to learn which of them are vital for sustaining cell growth,” he says. “The idea is that if we find a protein that cancer cells are addicted to, we can look for a way to block them.”

Among his most important discoveries was identifying the protein ZFP64 as an essential factor in the growth of certain types of leukemia. His findings helped illustrate how this protein drives cancer growth and suggested new treatments.

Dr. Vakoc’s lab is currently studying cancer growth in several other kinds of cancer, including pancreatic cancer, lung cancer, and sarcoma. “A lot of our methods are universally applicable,” he says. “It’s been very illuminating for me to compare and contrast how solid tumors behave differently from blood cancers with respect to gene regulation. We’re using a variety of different approaches to develop methods for targeting these genes.”

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Research confirms nerve cells made from skin cells are a valid lab model for studying disease

Source: Salk Institute
Date: 01/15/2019
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Salk and Stanford team shows that induced neuronal cells derived from fibroblasts are similar to neurons in the brain, on the epigenomic level

The incidence of some neurological diseases—especially those related to aging, such as Alzheimer’s and Parkinson’s diseases—is increasing. To better understand these conditions and evaluate potential new treatments, researchers need accurate models that they can study in the lab.

Researchers from the Salk Institute, along with collaborators at Stanford University and Baylor College of Medicine, have shown that cells from mice that have been induced to grow into nerve cells using a previously published method have molecular signatures matching neurons that developed naturally in the brain.

The study, published in eLife on January 15, 2019, opens the door for better ways to model an individual patient’s disease. This technique would enable researchers to study how neurological conditions develop, as well as to test new therapies. The new technology also could help to advance research into gene therapies that are derived from a patient’s own cells.

“This research is charting the path for the most optimal way of creating neurons in the lab,” says Salk Professor Joseph Ecker, one of the study’s two senior authors. “By taking these cells and reprogramming them into neurons, you can potentially learn new things about how these diseases function on a cellular level, especially diseases driven by genetic changes.”

The cells used in the study, called fibroblasts, make up most of the connective tissue in animals and play an important role in wound healing. Researchers have been studying how to transform fibroblasts into neuron cells in laboratory dishes, but until now they didn’t know whether these newly created neurons accurately corresponded to neurons that had grown naturally in the brain.

The technique for inducing the fibroblasts to grow into neurons with the matching epigenome was developed by Stanford’s Marius Wernig, the paper’s co-senior author. With this method, making induced neuronal cells does not involve pluripotent intermediates. Instead, the cells are directly converted from fibroblasts to neurons.

“An important question in cellular engineering is how to know the quality of your product,” says co-first author Chongyuan Luo, a postdoctoral fellow in Ecker’s lab. “If we’re making neurons from fibroblasts, we want to know how they compare with neurons in the brain. We are particularly interested in looking at these cells at the level of the epigenome.”

The epigenome is made up of chemicals that attach to DNA and regulate when genes get turned on and translated into proteins. Differences between the epigenomes of induced and naturally grown neurons could result in different features of induced neurons that might make them less accurate models of neuronal behavior.

Using a technique developed in the Ecker lab called MethylC-seq, the researchers looked at every place in the genome where chemical groups called methyl groups are attached. They confirmed that these induced neurons have epigenomes that match neurons in the brain.

“This research was done in mouse cells, but we plan to use the same technology to study induced neurons made with human cells,” explains Ecker, who is director of Salk’s Genomic Analysis Laboratory and a Howard Hughes Medical Institute investigator. Ecker plans to also collaborate with colleagues to apply the technology to look at human cells to better understand age-related cognitive decline.

Other researchers on the paper were Rosa Castanon and Joseph R. Nery of Salk; Sean M. Cullen and Margaret A. Goodell of Baylor College of Medicine; and Qian Yi Lee, Orly L. Wapinski, Moritz Mall, Michael S. Kareta and Howard Y. Chang of Stanford.

The work was supported by the National Institutes of Health (grants P50-HG007735 and R01 DK092883), the California Institute for Regenerative Medicine (grant RB5-07466) and the Howard Hughes Medical Institute.

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Using more-specific ‘genetic scissors’ may avoid problems associated with gene editing

Source: Cell Press
Date: 03/21/2019
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Recent studies have suggested a potential barrier to making CRISPR gene-editing treatments a viable option for inherited blood-related disorders such as sickle cell anemia, thalassemia, and primary immunodeficiency syndromes. Stem cells may respond to having their genes edited by shutting down–and trying to get around this roadblock could increase the risk of cancer.

Now, a study from researchers in Italy has suggested that there could be a way to bypass these complications. The team found that using more-precise gene-editing technology that induces fewer breaks in DNA may keep stem cells’ natural damage-response pathways under control. The findings are published March 21 in the journal Cell Stem Cell.

“Genome editing is a very powerful strategy for precise genetic engineering of stem cells, but it requires a complex procedure,” says co-senior author Pietro Genovese, a scientist at the San Raffaele Telethon Institute for Gene Therapy in Milan. “Despite its tremendous therapeutic potential and the continuous advances in perfecting gene-editing platforms, the functional consequences of the editing process have yet to be fully elucidated.”

One of the barriers to successful genome editing turns out to be p53, a protein that’s often called “the guardian of the genome” due to its role in conserving the stability of DNA and preventing mutations. When CRISPR edits genes, it cuts both strands of DNA at particular locations. But these double-strand breaks can signal to p53 that something is wrong. The protein then kicks into action and prevents the cells from proliferating. This is the opposite of what’s desired when cells are being used as a potential therapy. Yet permanently shutting down p53 to prevent this defense mechanism can lead to the formation of tumors; defective p53 has been implicated in about half of all cancers.

The team in Milan found a way around this unwanted consequence. Gene editing uses nucleases as “genetic scissors” to induce DNA breaks, followed by an adeno-associated viral vector that delivers the corrective sequence. But when these scissors are not specific enough, they may cut DNA in many additional places. The investigators used a combination of highly specific nucleases and vectors to introduce only the desired break in the DNA of hematopoietic stem/progenitor cells (HSPCs).

“We showed that the impact of gene editing on HSPCs highly depends on the precision of the designer nuclease used,” says Luigi Naldini, another study co-senior author and director of the San Raffaele Telethon Institute for Gene Therapy. “If the nucleases are not highly specific, and thus cut the DNA not only at the intended target but also at a few additional off-target sites, we do see robust and prolonged p53 response leading to detrimental effects up to irreversible cell arrest.

“On the other hand,” he adds, “if the nuclease is highly specific–and we use highly purified reagents and optimized protocols–we only see a transient effect on cell proliferation. This appears to be fully reversible and compatible with maintenance of the important biological properties of the hematopoietic stem cells.”

“Earlier studies pointed to the theoretical risk of selecting for p53-inactivating mutations upon editing, thus highlighting a possible tumorigenic risk associated with gene-editing procedures in a way that could jeopardize its therapeutic potential,” says Raffaella Di Micco, the study’s third co-senior author, who heads a lab at the San Raffaele Telethon Institute for Gene Therapy. “Our work shows that HSPCs tolerate one or a few DNA breaks well, with only transient p53 activation and a limited impact on their functionality (mainly manifesting of delayed proliferation). This cellular response is slightly more prolonged when highly specific ‘genetic scissors’ are used in combination with adeno-associated viral vectors delivering the corrective DNA sequence. However, if we transiently inactivate the p53 response during gene editing we may counteract this effect and improve the yield of edited cells, without indication of increased mutations or genome instability.”

“The other major challenge of gene editing in HSPCs has been the relatively low efficiency of homologous recombination in HSPCs, which is required for introducing the corrective sequence delivered by the repair template,” Naldini concludes. “This hurdle has now been substantially alleviated by new techniques described in our and other recent papers.”

The researchers say this work provides molecular evidence for the feasibility and efficacy of genetic engineering in HSPCs. This gives them confidence that the technology will be successfully translated to human trials.

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This work was supported by grants from Telethon, the Italian Ministry of Health, and the Human Frontier Science Program (HFSP) Long- Term/Cross-Disciplinary Fellowship. It was also supported by an ATIP-Avenir program (Inserm/CNRS, France), the French Cancer Research Association (ARC foundation, France), a Pilot and Seed Grant from Ospedale San Raffaele, and a FIRC-AIRC fellowship for Italy.

Luigi Naldini has received funding from Editas Medicine for a collaborative gene editing project distinct from the work reported here. He is also member of the scientific advisory board of Sangamo Therapeutics. Luigi Naldini and Pietro Genovese are inventors on patents concerning application of gene editing in HSPC gene therapy owned and managed by the San Raffaele Scientific Institute and the Telethon Foundation, including a patent application on the use of p53 inhibitor in gene editing recently filed by several of the authors on this study.

Cell Stem Cell, Schiroli et al.: “Precise Gene Editing Preserves Hematopoietic Stem Cell Function Following Transient p53-Mediated DNA Damage Response” https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30071-2

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Researchers Find that Vitamin B6 Contributes to Survival of Acute Myeloid Leukemia Cells

Source: Memorial Sloan Kettering - On Cancer
Date: 01/13/2020
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Tumors require many building blocks to support the cell division needed to grow and spread. For that reason, an important approach in the development of new drugs is to look for ways to target the metabolism of cancer cells. A class of metabolism-influencing drugs called IDH inhibitors is already being used to treat some cases of acute myeloid leukemia (AML).

Researchers from the Sloan Kettering Institute and Cold Spring Harbor Laboratory (CSHL) recently discovered a surprising contributor to AML cell metabolism: an active form of vitamin B6, also known as pyridoxal 5’-phosphate. The findings were published January 13 in Cancer Cell.

“This research suggested for the first time that the vitamin B6 pathway might be important for sustaining cancer,” says co-corresponding author Scott Lowe, Chair of the Cancer Biology and Genetics Program at SKI. “We already knew that vitamin B6 served as a regulator for a whole series of enzymes that are needed to make the building blocks required for cell growth and proliferation.”

Homing in on the Vitamin B6 Pathway

The study involved a collaboration between Chi-Chao Chen, then a PhD student in the Lowe laboratory, and Lingbo Zhang, a CSHL Fellow, who searched for molecular vulnerabilities that could be targeted in AML cells while sparing normal cells. They used the gene-editing tool CRISPR to upset different genes in these cells and study the effects. One gene that rose to the top of the list of important players was PDXK.

The PDXK gene directs the production of proteins that produce PLP, the active form of vitamin B6. Previous research had established that PLP can be blocked with isoniazid, an antibiotic used to treat tuberculosis (TB) infections. In TB, isoniazid works by attacking enzymes produced by the Mycobacterium tuberculosis bacterium. In cell cultures and mouse models of AML, it curbed the function of PLP, which in turn inhibited the growth of cancer cells.

“When we further studied the vitamin B6 pathway, we uncovered the role of another protein having similar AML selectivity, called BCL2,” Dr. Chen said. “It turns out there is already a drug that blocks BCL2, called venetoclax (Venclexta®), which is approved to treat AML and other blood cancers. However, that drug works not by affecting metabolism, but by promoting cell death.”

Effects on Fast-Growing Cells

Dr. Lowe and his colleagues still aren’t sure why AML cells are so sensitive to drugs that block PLP. “It’s a bit of a puzzle, and something we still need to determine,” he says. “It could be that because these cells grow so fast, they’re just more vulnerable to the effects on this pathway than other types of cells.”

Though vitamin B6 is found in many foods including meat, fish, dairy products, and some fruits and vegetables, Dr. Lowe doesn’t think that people with leukemia need to be concerned about consuming these foods. He notes, “Although our study provides evidence that AML needs this vitamin to proliferate, there isn’t any indication that consuming it causes or facilitates cancer. Vitamin B6 is important for many functions in the body and eliminating it completely would cause serious harm.”

Looking for Combination Approaches

Research on vitamin B6 and leukemia is still in early stages, but it’s something Dr. Lowe and his team intend to pursue. “We don’t have any plans to start giving isoniazid to people with leukemia because we don’t think it’s sufficiently potent for this treatment. But isoniazid demonstrates that it’s possible to develop drugs that target this pathway,” Dr. Lowe says.

His group plans to work with the Tri-Institutional Therapeutics Discovery Institute of MSK, the Rockefeller University, and Weill Cornell Medicine to develop this approach. He expects that one likely tactic will involve combining a PLP inhibitor with venetoclax.

“Although vitamin B6 hasn’t previously been implicated in cancer, there have been studies linking other vitamins, including vitamin C and vitamin D,” Dr. Lowe concludes. “These latest findings further emphasize the importance of studying vitamin signaling pathways in cancer.”