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Experimental Cancer Drug Developed at MSK Leads to New Approach for Treating Alzheimer’s Disease

Source: Memorial Sloan Kettering - On Cancer
Date: 03/01/2018
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Like cancer, Alzheimer’s disease involves changes in proteins. When functioning normally, proteins are important for cells to work properly. Also like cancer, Alzheimer’s occurs more commonly in older people, reflecting the idea that it usually takes a long time for these kinds of cellular changes to build up to a point that they cause real damage.

So although it may be a bit surprising, it’s not an impossible stretch to think that a drug developed to treat cancer may also work against Alzheimer’s disease. A family of these drugs has its origins at Memorial Sloan Kettering.

MSK chemical biologist Gabriela Chiosis has developed compounds for both cancer and Alzheimer’s. This week she spoke about her work at the National Institutes of Health’s Alzheimer’s Disease Research Summit. Dr. Chiosis was among top researchers from around the world who were invited to present their research on the biology of Alzheimer’s.

“Of Dr. Chiosis’s many intriguing discoveries, one that stands out is that Alzheimer’s disease shares a common cellular abnormality with many cancers,” says Larry Norton, Deputy Physician-in-Chief for Breast Cancer Programs at MSK, who has collaborated with Dr. Chiosis on the development of drugs. “The fact that there is a common mechanism raises the possibility of a common therapy. So her research could have profound implications for many human diseases, particularly those associated with aging.”

Targeting the Disease Process

Dr. Chiosis’s current work is focused on a type of regulatory network found inside cells called epichaperomes. “Epichaperomes form under conditions of chronic stress, something that is found in both cancer and Alzheimer’s disease,” she says. “One of the roles of these networks is to enhance the processes that become disrupted in diseased cells. These processes include defective signaling, increased production of certain proteins, and inflammation.”

In 2005, Dr. Chiosis and her colleagues developed a drug called PU-H71 for the treatment of cancer. PU-H71 is now in a phase I/II trial for people with metastatic breast cancer. Based on their discoveries about PU-H71, she and her team later developed a related drug, which they called PU-AD, for Alzheimer’s disease.

Both drugs bind to a protein called Hsp90 but only when it’s incorporated into the epichaperome network. Hsp90 is a protein found in essentially every cell in the human body. Its normal role is to help with proper protein folding. But when it becomes part of the epichaperome, Hsp90 contributes to stabilizing the proteins inside cells that let the disease develop.

“The formation of the epichaperome keeps damaged cells alive while they remain dysfunctional,” Dr. Norton explains. “Dr. Chiosis’s discoveries about epichaperomes are important because they are so overarching and could apply to many diseases.”

Taking a Look Inside Cells

Dr. Chiosis’s research has also led to imaging methods for detecting epichaperomes in cancer and Alzheimer’s, called PU-PET and PU-AD PET, respectively. She has collaborated with other investigators at MSK, including radiochemists Jason Lewis and Naga Vara Kishore Pillarsetty and radiologists Mark Dunphy and Steven Larson, on their development.

The approach involves attaching a weak radioactive label to PU-H71 or PU-AD, which then can be imaged with PET scanning. For cancer, PU-PET allows doctors to identify who is most likely to benefit from PU-H71 treatment. It can also help doctors monitor how well the drug is working.

In her presentation at the NIH summit, Dr. Chiosis discussed how an understanding of the epichaperome network can be used to identify some of the changes that occur in a number of different pathways in brain cells. These pathways can lead to Alzheimer’s disease, and learning more about them could suggest possibilities for the development of new targeted drugs.

She also talked about how PU-AD PET can be used to visualize Alzheimer’s disease in the brain. “The negative effects on memory, behavior, and the ability to think clearly that are commonly witnessed in people with Alzheimer’s are due to accumulation of toxic proteins called amyloid and tau in the brain,” Dr. Chiosis says. “But toxic changes in the neuron may begin 20 years before these deposits or the clinical symptoms of the disease develop. As such, we believe that using PU-AD PET to detect Alzheimer’s during this long preclinical phase may provide a promising window of opportunity for treatment.”

Both the PU-PET and PU-AD PET scans are now being tested in clinical trials at MSK. Dr. Norton and Dr. Chiosis have established a company called Samus Therapeutics that is focused on developing these scans as well as new therapies that target the epichaperome.

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Kratom: What Research Tells Us about This Controversial Supplement for Pain Relief

Source: Memorial Sloan Kettering - On Cancer
Date: 08/08/2018
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In the past few years, a number of companies in the United States have begun selling an herbal product called kratom, mostly online. The product, sold as dried leaves or a powder in capsules, comes from a tropical tree that grows in Southeast Asia.

Proponents of kratom say that it acts as a painkiller and a sedative, among other effects. Some people believe it can treat opioid or alcohol addiction. But none of these benefits have been demonstrated in rigorous clinical trials.

Negative events associated with consuming products that contain kratom have been reported. Many of these cases were caused by long-term abuse. In addition, kratom products have been connected to recent outbreaks of salmonella that sickened about 200 people in several states.

Memorial Sloan Kettering neurologist and pharmacologist Gavril Pasternak is studying the active components of kratom to figure out what the herb does in the body. He’s collaborating on this work with medicinal chemist Susruta Majumdar, who was an assistant attending chemist at MSK and is now an associate professor at the Center for Clinical Pharmacology at the St. Louis College of Pharmacy and the Washington University School of Medicine.

Scientists believe that some of the ingredients naturally found in kratom may hold promise for developing new and better painkillers. These drugs could potentially have fewer side effects than those currently on the market.

How can a natural product become a medicine?

It’s not a crazy notion to think that a new drug could come from a tree. In fact, about half of all drugs sold today originated in living things, including plants, fungi, and bacteria found in the soil. These natural products include the heart drug digoxin, which is isolated from a flower called foxglove; the antibiotic penicillin, which comes from mold; and painkillers like morphine, which is made from poppies. Many cancer drugs are made from natural products too.

Natural products that are developed and sold as drugs may come directly from their source. They may also be created in the lab using chemical synthesis. Chemicals taken from living things may become the starting materials for making similar compounds. Chemists may alter naturally occurring molecules to come up with drugs that are more effective or have fewer side effects.

Can kratom block pain with less risk?

Like most herbal products that come from plants, kratom contains a mixture of many different chemical compounds. In 2016, Dr. Majumdar published a study in collaboration with Columbia University researcher Dalibor Sames showing that among the natural products found in kratom, two compounds activate opioid receptors in human cells — the same receptors activated by drugs like morphine and oxycodone, which are clinically used in the treatment of pain.

Later in the year, in collaboration with Jay McLaughlin of the University of Florida and MSK researchers Ying Xian Pan and Dr. Pasternak, Dr. Majumdar published another study, which reported that two compounds in kratom were more effective than morphine at blocking pain in mice. Their effectiveness was tested using what is called a tail-flick assay. In this assessment, a mouse’s tail is put next to something hot. The efficacy of the pain medication is determined by how many seconds it takes for the mouse to feel pain and flick away its tail.

Further investigations done in cells and mice determined how these molecules provided pain-blocking effects. “We found that these compounds are structurally different from drugs like morphine or fentanyl,” Dr. Majumdar says. “They bind to pain receptors in a different way.” Specifically, they act on the pathways that allow pain to be suppressed without acting on the pathways that suppress breathing. The addictive potential of the natural products found in kratom is presently being investigated and will soon be reported.

“This is a crucial safety issue since respiratory depression is responsible for overdose deaths from opioids,” adds Dr. Pasternak. He and Dr. Majumdar are continuing to work together to design novel drugs based on components in kratom that will be even more effective and safe.

The US Food and Drug Administration and US Drug Enforcement Administration are considering banning kratom. Scientists who study kratom say that such an action would effectively end their research because it would become exceedingly difficult to obtain and work with the compounds. Potentially promising leads for new drugs could be lost.

Can people with cancer take kratom now?

The type of kratom-derived drugs being developed by Drs. Pasternak and Majumdar are at least several years from being evaluated in clinical trials. But the experts in MSK’s Integrative Medicine Service who manage the About Herbs database frequently receive questions from people with cancer — as well as their doctors — about whether kratom as it is now sold is a safe and effective way to manage cancer pain. The database provides information about herbs and other complementary therapies that is based on scientific literature.

“A lot of people are interested in taking kratom for their cancer pain because they’re concerned about the addiction potential of traditional opioid drugs,” says pharmacist K. Simon Yeung, who manages About Herbs. “But right now, we don’t have enough information to know whether it is safe and effective for this purpose.”

“One problem with kratom is that it is a mixture of many different compounds whose levels can vary from preparation to preparation, making it quite difficult to determine what dose should be used,” Dr. Pasternak says. “People with cancer receive more effective and reliable pain relief with established painkillers.”

Dr. Yeung notes that concern about salmonellacontamination makes it even more important to avoid kratom products. “One FDA analysis found that half of all kratom products evaluated were contaminated,” he says. “Because chemotherapy and other cancer treatments can weaken a person’s immune system, getting one of these infections could be very serious.”

MSK doctors stress that people with cancer should not take any herbal substances without first discussing it with their healthcare team.

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Bull’s-Eye: Imaging Technology Could Confirm When a Drug Is Going to the Right Place

Source: Memorial Sloan Kettering - On Cancer
Date: 10/25/2019
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Targeted therapy has become an important player in the collection of treatments for cancer. But sometimes it’s difficult for doctors to determine whether a person’s tumor has the right target or how much of a drug is actually reaching it.

A multidisciplinary team of doctors and scientists from Memorial Sloan Kettering has discovered an innovative technique for noninvasively visualizing where a targeted therapy is going in the body. This method can also measure how much of it reaches the tumor. What makes this development even more exciting is that the drug they are studying employs an entirely new approach for stopping cancer growth. The work was published on October 24 in Cancer Cell.

“This paper reports on the culmination of almost 15 years of research,” says first author Naga Vara Kishore Pillarsetty, a radiochemist in the Department of Radiology. “Everything about this drug — from the concept to the clinical trials — was developed completely in-house at MSK.”

“Our research represents a new role for the field of radiology in drug development,” adds senior author Mark Dunphy, a nuclear medicine doctor. “It’s also a new way to provide precision oncology.”

Targeting a Unique Protein Network

The drug being studied, called PU-H71, was developed by the study’s co-senior author Gabriela Chiosis. Dr. Chiosis is a member of the Chemical Biology Program in the Sloan Kettering Institute. PU-H71 is being evaluated in clinical trials for breast cancer and lymphoma, and the early results are promising.

“We always hear about how DNA and RNA control a cell’s fate,” Dr. Pillarsetty says. “But ultimately it is proteins that carry out the functions that lead to cancer. Our drug is targeting a unique network of proteins that allow cancer cells to thrive.”

Most targeted therapies affect individual proteins. In contrast, PU-H71 targets something called the epichaperome. Discovered and named by Dr. Chiosis, the epichaperome is a communal network of proteins called chaperones.

Chaperone proteins help direct and coordinate activities in cells that are crucial to life, such as protein folding and assembly. The epichaperome, on the other hand, does not fold. It reorganizes the function of protein networks in cancer, which enables cancer cells to survive under stress.

Previous research from Dr. Chiosis and Monica Guzman of Weill Cornell Medicine provided details on how PU-H71 works. The drug targets a protein called the heat shock protein 90 (HSP90). When PU-H71 binds to HSP90 in normal cells, it rapidly exits. But when HSP90 is incorporated into the epichaperome, the PU-H71 molecule becomes lodged and exits more slowly. This phenomenon is called kinetic selectivity. It helps explain why the drug affects the epichaperome. It also explains why PU-H71 appears to have fewer side effects than other drugs aimed at HSP90.

At the same time, this means that PU-H71 works only in tumors where an epichaperome has formed. This circumstance led to the need for a diagnostic method to determine which tumors carry the epichaperome and, ultimately, who might benefit from PU-H71.

A New Way to Match Drugs to Tumors

In the Cancer Cell paper, the investigators report the development of a precision medicine tactic that uses a PET tracer with radioactive iodine. It is called [124I]-PU-H71 or PU-PET. PU-PET is the same molecule as PU-H71 except that it carries radioactive iodine instead of nonradioactive iodine. The radioactive version binds selectively to HSP90 within the epichaperome in the same way that the regular drug does. On a PET scan, PU-PET displays the location of the tumor or tumors that carry the epichaperome and therefore are likely to respond to the drug. Additionally, when it’s given along with PU-H71, PU-PET can confirm that the drug is reaching the tumor.

“This research fits into an area that is sometimes called theranostics or pharmacometrics,” Dr. Dunphy says. “We have found a very different way of selecting patients for targeted therapy.”

He explains that with traditional targeted therapies, a portion of a tumor is removed with a biopsy and then analyzed. Biopsies can be difficult to perform if the tumor is located deep in the body. Additionally, people with advanced disease that has spread to other parts of the body may have many tumors, and not all of them may be driven by the same proteins. “By using this imaging tool, we can noninvasively identify all the tumors that are likely to respond to the drug, and we can do it in a way that is much easier for patients,” Dr. Dunphy says.

The researchers explain that this type of imaging also allows them to determine the best dose for each person. For other targeted therapies, doctors look at how long a drug stays in the blood. “But that doesn’t tell you how much is getting to the tumor,” Dr. Pillarsetty says. “By using this imaging agent, we can actually quantify how much of the drug will reach the tumor and how long it will stay there.”

Plans for further clinical trials of PU-H71 are in the works. In addition, the technology reported in this paper may be applicable for similar drugs that also target the epichaperome.

This work was supported in part by National Institutes of Health grants (R01 CA172546, R56 AG061869, R01 CA155226, P01 CA186866, P30 CA08748, and P50 CA192937); William and Alice Goodwin, the Commonwealth Foundation for Cancer Research, and the Center for Experimental Therapeutics at MSK; and Samus Therapeutics.

MSK holds the intellectual rights to PU-H71 and [124I]-PU-H71. Gabriela Chiosis, Mark Dunphy, Steven Larson, Jason Lewis, Naga Vara Kishore Pillarsetty, Anna Rodina, Tony Taldone, and Pengrong Yan of MSK are inventors on the intellectual property, which MSK has licensed to Samus Therapeutics. As a result of this licensing arrangement, MSK has financial interests in Samus Therapeutics. Dr. Chiosis and co-author Larry Norton, Senior Vice President of MSK and Medical Director of the Evelyn H. Lauder Breast Center, have partial ownership in Samus Therapeutics and are members of its scientific advisory board, and Dr. Taldone has consulted for the company.

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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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Key enzyme found in plants could guide development of medicines and other products

Source: Salk Institute
Date: 09/06/2019
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Salk research explains how plants are able to efficiently manufacture the compounds they use to adapt to stress

Plants can do many amazing things. Among their talents, they can manufacture compounds that help them repel pests, attract pollinators, cure infections and protect themselves from excess temperatures, drought and other hazards in the environment.

Researchers from the Salk Institute studying how plants evolved the abilities to make these natural chemicals have uncovered how an enzyme called chalcone isomerase evolved to enable plants to make products vital to their own survival. The researchers’ hope is that this knowledge will inform the manufacture of products that are beneficial to humans, including medications and improved crops. The study appeared in the print version of ACS Catalysis on September 6, 2019.

“Since land plants first appeared on earth approximately 450 million years ago, they have developed a sophisticated metabolic system to transform carbon dioxide from the atmosphere into a myriad of natural chemicals in their roots, shoots and seeds,” says Salk Professor Joseph Noel, the paper’s senior author. “This is the culmination of work we’ve been doing in my lab for the past 20 years, trying to understand plant chemical evolution. It gives us detailed knowledge about how plants have developed this unique ability to make some very unusual but important molecules.”

Previous research in the Noel lab looked at how these enzymes evolved from non-enzyme proteins, including studying more primitive versions of them that appear in organisms such as bacteria and fungi.

As an enzyme, chalcone isomerase acts as a catalyst to accelerate chemical reactions in plants. It also helps to ensure the chemicals that are made in the plant are the proper form, since molecules with the same chemical formula can take two different variations that are mirror images of each other (called isomers).

“In the pharmaceutical industry, it’s important that the drugs being made are the correct version, or isomer, because using the wrong one can lead to unintended side effects,” says Noel, who is director of Salk’s Jack H. Skirball Center for Chemical Biology and Proteomics and holds the Arthur and Julie Woodrow Chair. “By studying how chalcone isomerase works, we can learn more about how to accelerate the manufacture of the correct isomers of pharmaceuticals and other products that may be important to human health.”

In the current study, the investigators used several structural biology techniques to investigate the enzyme’s unique shape and how its shape changes as it interacts with other molecules. They pinpointed the part of chalcone isomerase’s structure that allowed it to catalyze reactions incredibly fast while also ensuring it makes the proper, biologically active isomer. These reactions lead to a host of activities in plants, including converting primary metabolites like phenylalanine and tyrosine into vital specialized molecules called flavonoids.

It turned out that one particular amino acid, arginine, that was one of many amino acids linked together in chalcone isomerase sat in a location, shaped by evolution, that allowed it to play the key role in how chalcone isomerase reactions were catalyzed.

“By doing structural studies and computer modeling, we could see the very precise positions of arginine within the enzyme’s active site as the reaction proceeded,” says first author Jason Burke, a former postdoctoral research in Noel’s lab who is now an assistant professor at California State University San Bernardino. “Without that arginine, it doesn’t work the same way.”

Burke adds that this type of catalyst has been long sought by organic chemists. “This is an example of nature already solving a problem that chemists have been looking at for a long time,” he adds.

“By understanding chalcone isomerase, we can create a new toolset that chemists will be able to use for the reactions they’re studying,” Noel says. “It’s absolutely vital to have this kind of foundational knowledge to be able to design molecular systems that can carry out a particular task even in the next generation of nutritionally dense crops capable of transforming the greenhouse gas carbon dioxide into molecules essential for life.”

Other researchers on the paper were James La Clair, Ryan Philippe, Joseph Jez, Marianne Bowman, Gordon Louie, and Katherine Woods of Salk; Anna Pabis, Marina Corbella, and Shina Kamerlin of Uppsala University in Sweden; George Cortina of the University of Virginia; Miriam Kaltenbach and Dan Tawfik of the Weizmann Institute of Science in Israel; and Andrew Nelson of the University of Texas at Austin.

This work was also supported by the Howard Hughes Medical Institute, United States National Science Foundation grant EEC-0813570, the Wenner-Gren Foundations, European Research Council ERC grant agreement 30647, and a Wallenberg Academy Fellowship from the Knut and Alice Wallenberg Foundation. The Swedish National Infrastructure for Computing provided the computer time for the simulations conducted in this study.

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Study Reveals a New Way That Stress and Aging Lead to Alzheimer’s

Source: Memorial Sloan Kettering - On Cancer
Date: 01/16/2020
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The body is presented with stressors throughout life. These stressors include genetic and environmental challenges that accumulate over time and damage cells, circuits, and organs. This can lead to a wide variety of maladies, including cancer and age-related brain disorders.

Sloan Kettering Institute scientist Gabriela Chiosis and her colleagues study the effects of stressors on proteins and the networks they make up in cells. In a new study published in Nature Communications, her team discovered how stress rewires key connections in the brain. These changes lead to malfunctions associated with Alzheimer’s disease. In addition, they demonstrated how a drug that’s currently being tested in clinical trials for Alzheimer’s, called PU-AD, may correct faulty wiring and preserve brain functions. In lab mice, the drug rewired circuitry within the hippocampus, the part of the brain associated with memory. The result was improved memory without any side effects.

“This study is the culmination of years of research in my lab,” Dr. Chiosis says. “It’s a paradigm-shifting way to think about Alzheimer’s.”

Identifying Common Factors in Cancer Biology and Alzheimer’s Disease for Therapeutics

In 2016, Dr. Chiosis led a study showing that in cancer cells, proteins called chaperones band together in response to stressors associated with cancer and form faulty networks. She named this faulty network of chaperones the epichaperome.

As their name implies, chaperone proteins take care of our cells. They help proteins get made and ensure that cellular activities are coordinated properly. The epichaperome, on the other hand, changes how proteins interact with one another. It causes them to improperly organize inside cells and accelerates the course of disease.

An experimental drug developed at MSK called PU-H71 targets these faulty epichaperomes when they form in cancer. Dr. Chiosis’s 2016 study found that the effectiveness of PU-H71 on tumors depends on how many chaperones have banded into epichaperomes: The more the chaperones have switched to become epichaperomes, the more effective PU-H71 was.

Looking for Epichaperomes in Alzheimer’s Disease

In the new study, Dr. Chiosis and her team analyzed brain tissue from people with Alzheimer’s disease. They compared these to tissues from people of the same age without Alzheimer’s. Higher numbers of chaperones banded into epichaperomes in brain tissue from people with Alzheimer’s compared with healthy brain tissue. These findings were validated in multiple mouse and cellular models of Alzheimer’s disease.

Alzheimer’s is a progressive neurodegenerative disease with complex causes. Many stressors can contribute to it, including diabetes, stroke, high blood pressure, and traumatic brain injury. Genetic risk factors and other age-related changes can also damage brain circuitry over decades. “We decided to look at whether this complex matrix of stressors that change the brain is related to epichaperome formation,” Dr. Chiosis says.

This turned out to be the case. Her team found that in the Alzheimer’s brain tissue, epichaperomes assisted the incorrect organization of many proteins required for normal brain function, including memory and higher-order executive function. Faulty disorganization of memory-related proteins seemed to cascade into defective communication between neurons. That disruption ultimately led to brain dysfunction.

“These changes were similar to network failures seen in electrical or mechanical components that eventually lead to system failure and shutdown,” explains Dr. Chiosis, a member of SKI’s Chemical Biology Program. “The epichaperome acts like a scaffold that allows the misconnectivity of proteins, and in turn, neuronal circuits collapse and underlie age-related cognitive dysfunction.”

Based on their discoveries, Dr. Chiosis and her colleagues, including neuroscientists at Weill Cornell Medicine, the New York University School of Medicine, and the Nathan Kline Institute for Psychiatric Research, developed a term to describe this phenomenon: protein connectivity–based dysfunction (PCBD). “Many people who study Alzheimer’s are thinking about circuits in the brain. But there’s no clear understanding of how stressors due to aging and the environment change the way proteins interact,” she says. “Our research demonstrates that epichaperome formation rewires brain circuitry in Alzheimer’s by enabling proteins to misconnect, leading to downstream PCBD and cognitive decline.”

Validating Findings in Animal Models of Disease

Armed with this knowledge about epichaperomes, Dr. Chiosis and her team treated a mouse model of Alzheimer’s with PU-AD. Like PU-H71 in cancer, PU-AD uncouples the faulty protein networks created by epichaperomes. They found that PU-AD corrected how proteins interacted in the mice. The drug was able to fix signaling problems between neurons. The treated brains resembled those of normal mice.

Further research showed that after Alzheimer’s mice were given PU-AD, they performed much better in tests that evaluate memory function. They also survived longer than mice given a placebo. This indicates that the drug treatment was safe and effective.

The first clinical trial of PU-AD launched in 2019 to confirm in healthy volunteers that the drug is safe. PU-H71 is already in clinical trials for lymphoma, breast cancer, and other cancers. That drug appears to be safe, and researchers are optimistic that the same will hold true for PU-AD. PET imaging versions of both drugs are also being studied in clinical trials as a way to track changes in cells and PCBD in living patients, with the hope that the drug treatment reverses damage in real time.

Summing up the findings in such diverse disorders as cancer and Alzheimer’s disease, Dr. Chiosis says, “Epichaperomes are disease hallmarks that we are just beginning to understand. The idea that we might be able to target this whole network with drugs and treat such complex diseases as cancer and Alzheimer’s is pretty remarkable.”

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Snake stem cells used to create venom-producing organoids

Source: Cell Press
Date: 01/23/2020
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Organoids have become an important tool for studying many disease processes and testing potential drugs. Now, they are being used in a surprising and unexpected way: for the production of snake venom. On January 23 in the journal Cell, researchers are reporting that they have created organoids of the venom glands of the Cape coral snake (Aspidelaps lubricus cowlesi) and that these glands are capable of producing venom.

“More than 100,000 people die from snake bites every year, mostly in developing countries. Yet the methods for manufacturing antivenom haven’t changed since the 19th century,” says senior author Hans Clevers of the Hubrecht Institute for Developmental Biology and Stem Cell Research at Utrecht University in the Netherlands. “It’s clear there is a huge unmet medical need for new treatments.”

He adds: “Every snake has dozens of different components in their venom. These are extremely potent molecules that are designed to stop prey from running away. They affect systems as varied as the brain, neuromuscular junctions, blood coagulation, and more. Many of them have potential bioprospecting applications for new drugs.”

Clevers’ lab traditionally focuses on organoids made from human and mouse cells. But some of his students decided to study stem cells and develop organoids from reptiles. “This is a field that does not exist, so they thought it was interesting to study the most iconic reptilian organ, the snake venom gland,” he says. “Once we grew the venom glands as organoids, we realized that they make a lot of venom.”

The investigators started with the Cape coral snake because they knew a breeder who was able to supply some fertilized eggs. The snakes were removed from the eggs before hatching, and small pieces of tissue were removed from various organs and placed into gels, along with growth factors. In addition to the venom glands, the researchers also made organoids of the snake liver, pancreas, and gut.

“It would have been difficult to isolate stem cells from these snakes because we don’t know what they look like,” Clevers explains. “But it turned out we didn’t need to. The cells soon began dividing and forming structures.” In fact, he says, the venom gland organoids grew so fast that in just one week, they were able to break them apart and re-plate them, generating hundreds of plates within two months. He notes that if it could be commercialized, this method would be much more efficient than the way venom is currently produced–by raising snakes on farms and milking their glands.

The researchers were able to identify at least four distinct types of cells within the venom gland organoids. They confirmed that the venom peptides produced were biologically active and resembled the components of venom from live snakes.

A challenge of the work was determining gene-expression levels in the venom gland organoids. “The genomes of most snakes have not been annotated,” Clevers says. The investigators were able to identify certain genes that were active under expansion conditions, suggesting that these pathways–including most importantly the Wnt pathway–may play a role in reptilian stem cell growth.

One of the collaborators on the study was Freek Vonk, a herpetologist and well-known Dutch television host who Clevers calls “the Steve Irwin of Holland.” Vonk is affiliated with Leiden University and the Naturalis Biodiversity Center.

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This study was funded by ALS foundation Netherlands, a Sir Henry Dale Fellowship, the Wellcome Trust, and the Royal Society. Clevers is inventor on several patents related to organoid technology; his full disclosure is given at https://www.uu.nl/staff/JCClevers/. Two of the study’s authors are employees of MIMETAS BV, the Netherlands, which is marketing the OrganoPlate. OrganoPlate is a registered trademark of MIMETAS.

Cell, Post et al.: “Snake Venom Gland Organoids” https://www.cell.com/cell/fulltext/S0092-8674(19)31323-6

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How plants sound the alarm about danger

Source: Salk Institute
Date: 03/13/2020
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Team led by Salk scientists provides a detailed picture of how plant hormones communicate through gene regulation

LA JOLLA—Just like humans and other animals, plants have hormones. One role of plant hormones is to perceive trouble—whether an insect attack, drought or intense heat or cold—and then signal to the rest of the plant to respond.

A multicenter team led by current and former investigators from the Salk Institute is reporting new details about how plants respond to a hormone called jasmonic acid, or jasmonate. The findings, which were published in Nature Plants on March 13, 2020, reveal a complex communication network. This knowledge could help researchers, such as members of Salk’s Harnessing Plants Initiative, develop crops that are hardier and more able to withstand assault, especially in an era of rapid climate change.

“This research gives us a really detailed picture of how this hormone, jasmonic acid, acts at many different levels,” says Professor Joseph Ecker, co-corresponding author and Howard Hughes Medical Institute investigator. “It enables us to understand how environmental information and developmental information is processed, and how it ensures proper growth and development.”

The plant used in the study was Arabidopsis thaliana, a small flowering plant in the mustard family. Because its genome has been well characterized, this plant is a popular model system. Scientists can take what they learn in A. thaliana and apply it to other plants, including those grown for food. Jasmonic acid is found not only in A. thaliana but throughout the plant kingdom.

“Jasmonic acid is particularly important for a plant’s defense response against fungi and insects,” says co-first author Mark Zander, a staff researcher in Ecker’s lab. “We wanted to precisely understand what happens after jasmonic acid is perceived by the plant. Which genes are activated and deactivated, which proteins are produced and which factors are in control of these well-orchestrated cellular processes?”

The researchers started with plant seeds grown in petri dishes. They kept the seeds in the dark for three days to mimic the first few days of a seed’s life, when it is still underground. “We know this growth stage is super important,” says co-first author and co-corresponding author Mathew Lewsey, an associate professor at La Trobe University in Melbourne, Australia, who previously worked in Ecker’s lab. The first few days in the soil are a challenging time for seedlings, as they face attacks from insects and fungi. “If your seeds don’t germinate and successfully emerge from the soil, then you will have no crop,” Lewsey adds.

After three days, the plants were exposed to jasmonic acid. The researchers then extracted the DNA and proteins from the plant cells and employed specific antibodies against their proteins of interest to capture the exact genomic location of these regulators. By using various computational approaches, the team was then able to identify genes that are important for the plant’s response to jasmonic acid and, moreover, for the cellular cross-communication with other plant hormone pathways.

Two genes that rose to the top in their degree of importance across the system were MYC2 and MYC3. These genes code for proteins that are transcription factors, which means that they regulate the activity of many other genes—or thousands of other genes in this case.

“In the past, the MYC genes and other transcription factors have been studied in a very linear fashion,” Lewsey explains. “Scientists look at how one gene is connected to the next gene, and the next one, and so on. This method is inherently slow because there are a lot of genes and lots of connections. What we’ve done here is to create a framework by which we can analyze many genes at once.”

“By deciphering all of these gene networks and subnetworks, it helps us to understand the architecture of the whole system,” Zander says. “We now have this very comprehensive picture of which genes are turned on and off during a plant’s defense response. With the availability of CRISPR gene editing, these kinds of details can be useful for breeding crops that are able to better withstand attacks from pests.”

Another noteworthy aspect of this work is that all of the data from the research has been made available on Salk’s website. Researchers can use the site to search for more information about genes they study and find ways to target them.

Other authors of the study included Anna Bartlett, J. Paola Saldierna Guzmán, Elizabeth Hann, Amber E. Langford, Bruce Jow, Joseph R. Nery and Huaming Chen of Salk; Lingling Yin of La Trobe University; Natalie M. Clark and Justin W. Walley of Iowa State University; Aaron Wise and Ziv Bar-Joseph of Carnegie Mellon University; and Roberto Solano of Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas in Madrid, Spain.

The work was funded by a Deutsche Forschungsgemeinschaft research fellowship and an EU Marie Curie FP7 International Outgoing Fellowship, and by grants from the National Science Foundation; the National Institutes of Health (R01GM120316); the Division of Chemical Sciences, Geosciences and Biosciences, Office of Basic Energy Sciences of the U.S. Department of Energy (DE-FG02-04ER15517); the Gordon and Betty Moore Foundation (GBMF3034); the Ministry of Economy (BIO2016-77216-R), Industry and Competitiveness of Spain; the ISU Plant Sciences Institute; and the Howard Hughes Medical Institute.

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Tardigrades use unique protein to protect themselves from desiccation

Source: Cell Press
Date: 03/16/17
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Tardigrades, the microscopic animals also known as water bears and moss piglets, have captured the imagination of scientists for almost 250 years, thanks to their Muppet-like appearance and their ability to survive extreme environments that would destroy most other living things. One of these skills is the ability to endure being dried out for up to a decade or longer. In Molecular Cell on March 16, a team of scientists report that this knack for survival is due to a unique set of proteins they dubbed tardigrade-specific intrinsically disordered proteins (TDPs).

“The big takeaway from our study is that tardigrades have evolved unique genes that allow them to survive drying out,” says Thomas Boothby, the Life Sciences Research Foundation Postdoctoral Fellow at the University of North Carolina, Chapel Hill, and the study’s first author. “In addition, the proteins that these genes encode can be used to protect other biological material–like bacteria, yeast, and certain enzymes–from desiccation.”

For a long time, it was assumed that a sugar called trehelose gave tardigrades the ability to tolerate desiccation. Trehelose is found in a number of other organisms that can survive being dried out, including yeast, brine shrimp, and some nematodes. But biochemical studies of tardigrades have found trehelose at low levels or not at all, and sequencing has not revealed the gene for the enzyme required to make this sugar.

“The question has been, ‘If tardigrades aren’t relying on trehelose to survive desiccation, what do they use instead?'” Boothby says. He and his team set out to discover how they do it.

The first step of the research was to look at which genes were active under various conditions: unstressed, drying out, and frozen. The researchers identified genes that were upregulated and expressed at high levels when the animals began to dry out. The proteins that these genes encode, the TDPs, are in a class of proteins called intrinsically disordered proteins (IDPs). Unlike most proteins, IDPs have no fixed three-dimensional structure.

After they found the TDP genes expressed at high levels during the drying-out period in one species of tardigrade, the team looked at two other species and found the same genes. One species, which had the genes turned on all the time, is able to survive drying out much more quickly that the others. “We think it can do this because it has so many of these proteins around already and doesn’t need time to make them,” Boothby says.

To verify that these TDPs were what gave tardigrades their unique abilities, the researchers put the genes encoding them into yeast and bacteria, and confirmed that the TDPs protected these other organisms.

Trehelose helps other organisms to survive drying out by forming glass-like solids when they dry, rather than crystals. Boothby and his colleagues found that TDFs form similar glass-like solids, and showed that when the glassiness of TDPs was disrupted, it correlated with a loss of their protective abilities.

Boothby says TDPs have a number of potential uses, including protecting crops from drought and safeguarding medications that normally require cold storage. “Being able to stabilize sensitive pharmaceuticals in a dry state is very important to me personally,” he says. “I grew up in Africa, where lack of refrigeration in remote areas is a huge problem. These real-world applications are one of the things that led me to study tardigrades.”