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Double Jeopardy: Gene-Sequencing Test Uncovers New Clues about a Defect Seen in Many Tumors

Source: Memorial Sloan Kettering - On Cancer
Date: 07/18/2018
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Healthy cells contain two copies of each gene: one from your mother and one from your father. But cancer cells don’t play by the rules, and they can disrupt that arrangement.

A collaborative team of researchers from Memorial Sloan Kettering has found that a genetic state called whole-genome doubling is more common in cancer than expected. In addition, they were able to show a connection between this phenomenon and worse outcomes in people with cancer. The findings were published online July 16, 2018, in Nature Genetics. This research helps set the stage for a new way to categorize cancer and could ultimately help guide treatment decisions.

“This was a big surprise,” says senior author Barry Taylor, Associate Director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO). “It turns out that almost 30% of all cancers have this change, across all different types of cancer. That makes whole-genome doubling the second most common feature of cancer after mutations in the p53 gene.”

Unexpected Discoveries from Genetic Testing

Whole-genome doubling is just what it sounds like. It means that a cell has gone from having two copies of every gene in its genome to four. It’s one of the many different types of genetic errors that can enable cancer cells to grow out of control. Until now, it was unknown how often it occurs.

The new discovery was uncovered thanks to MSK-IMPACT™. This diagnostic test of tumor tissue looks for mutations in 468 genes that are known to drive cancer. The test is available to people being treated at MSK for advanced cancer. It helps doctors determine which therapies are most likely to offer a benefit, including experimental new drugs in clinical trials.

To ensure that the mutations detected by MSK-IMPACT are part of the cancer, pathologists also test some of the person’s normal tissue. This is usually a blood sample. Directly comparing the tumor genome to the inherited genomes in normal blood allowed the researchers in this study to tell the whole-genome doubling apart from other changes specific to the cancer.

Sequencing with MSK-IMPACT began in 2014. Since then, discoveries about genetic changes in normal blood have led to other important results. These include findings about how common inherited cancer genes are and the presence of a blood condition known as clonal hematopoiesis.

MSK-IMPACT also anonymously links the genomic data for each person to their clinical records. Investigators are then able to find connections that they wouldn’t be able to make with the genomic information alone.

“We looked to see whether people whose tumors had whole-genome doubling had different outcomes than those whose tumors did not,” Dr. Taylor explains. “It turns out they did. This genetic change was associated with lower survival rates in the people who had it, regardless of cancer type and other clinical and molecular features.”

Validating the Findings in Future Research

Because MSK-IMPACT testing is performed on advanced cancers, the researchers used another set of data to confirm their findings. They looked at The Cancer Genome Atlas (TCGA), a database of tumor information from more than 10,000 people with cancer. TCGA includes information on cancers that are newly diagnosed and at all stages, from I to IV. The researchers found that the rate of whole-genome doubling in these tumors was about the same as what was seen in the MSK-IMPACT data.

“This suggests that whole-genome doubling happens sooner in the development of cancer rather than later,” Dr. Taylor says. “We don’t think it’s an event that initiates cancer, but it occurs early in a tumor’s evolution.”

He adds that the findings help explain why people with advanced cancer that has spread often fare differently from one another. Some survive for years after their cancer has spread, while others do not. The variation in outcomes may be due to whole-genome doubling in the tumors. However, the causes behind these differences are not yet known.

More research is needed to validate the study’s findings before they can be used to influence patient care. But in the future, genome doubling could help guide personalized medicine, directing doctors to the people who need the most-aggressive treatment.

The co-authors on this study included MSK Physician-in-Chief José Baselga as well as CMO Director David Solit and Associate Director Michael Berger. The first author was Craig Bielski, a computational biologist in Dr. Taylor’s lab.

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A Family Discovers an Unexpected Cancer Risk in Their Genes

Source: Memorial Sloan Kettering - On Cancer
Date: 07/19/2018
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When his younger brother, Mitchell, was found to have urothelial cancer in 2011, Elliot Katz never expected that diagnosis might save his own life.

Mitchell, now 64, initially had surgery with then-MSK urologic surgeon Raul Parra to remove a tumor in his kidney. A short time later, the cancer came back, and he had genetic testing with MSK-IMPACT™. In addition to looking for 468 mutations that are known to drive tumor growth, the test can reveal cancer-related mutations in the normal tissue that someone with cancer may have inherited.

Mitchell’s test results showed that he had a hereditary condition called Lynch syndrome. Lynch syndrome is associated with a genetic predisposition to a number of different cancer types. It’s most commonly linked to colon and rectal cancers but is also known to increase the risk of developing uterine, urothelial, ovarian, and other gastrointestinal cancers.

A Cancer Risk That Runs in Families

Families that carry one of the genes for Lynch syndrome usually have many members, spanning several generations, who have had cancer, especially colorectal cancer. Elliot and Mitchell’s father died of lymphoma when he was in his early 40s, but their family didn’t have a cancer history otherwise. Their mother lived to her 90s.

After Mitchell learned he had Lynch syndrome in 2015, he met with MSK genetic counselor Meg Sheehan, who explained the risks to him and recommended that other family members get tested. “I was very surprised to find out I had this condition,” he says. “Once I knew, it was important to me that my family have testing too, just in case they had the same thing.”

Elliot, now 66, met with Janice Berliner, a genetic counselor who works at MSK Basking Ridge, to get tested. Elliot was found to share his brother’s mutation for Lynch syndrome.

Focusing on More-Frequent Cancer Screenings

Because he was over age 50, Elliot had already begun undergoing screening colonoscopies, but only one polyp — a sign of possible precancer — had ever been found. Once he learned he had Lynch, he began undergoing colonoscopies every two years. The standard recommendation for the general population is every ten years. In October 2017, a few small polyps were found in Elliot’s colon. “Because I knew about Lynch, I decided not to wait,” he says. “I went back in six months.”

At that next exam, Elliot was found to have an early-stage colorectal cancer. “I’m lucky,” he says. “If I hadn’t known about Lynch, I would have waited much longer to have my next colonoscopy. I probably would have missed the boat.”

In April 2018, MSK surgeon José Guillem performed laparoscopic surgery to remove the tumor and a portion of Elliot’s colon. Dr. Guillem also removed a number of lymph nodes to determine whether the cancer had spread. They were all clear, which indicated that Elliot would not need any follow-up chemotherapy or radiation.

In addition to being a surgeon, Dr. Guillem is Director of MSK’s Hereditary Colorectal Cancer Family Registry. This registry allows researchers to learn more about the genetic causes of colorectal cancer and to develop new ways to prevent, diagnose, and treat cancers of the colon and rectum. It also makes it easier for people who have inherited this risk to undergo more regular monitoring.

Lynch mutations are autosomal dominant, which means a person with Lynch has a 50% chance of passing it down to a child. Elliot and his wife don’t have any children, but Mitchell’s two daughters, ages 29 and 34, were also found to carry a mutation for Lynch syndrome. Despite their young age, they began undergoing annual colonoscopy screenings to check for polyps or other signs of colorectal cancer. This is an action they never would have known to take otherwise.

“Very few centers provide patients with information about inherited risk at the same time their tumors are genetically screened,” comments geneticist Kenneth Offit, who directs MSK’s Niehaus Center for Inherited Cancer Genomics. “The experience of the Katz family shows the potential benefit of genomic sequencing, not only to offer targeted therapy but also to empower prevention and early detection.”

Mitchell is receiving an immunotherapy drug called atezolizumab (Tecentriq®) for his urothelial cancer. This drug has been found to work well for many people with Lynch syndrome. He continues to see MSK medical oncologist Gopa Iyer for his treatment and has had no evidence of disease in the four years since he started receiving the drug.

Elliot is recovering from his surgery and doing very well. He’s walking for exercise almost every day and has resumed most of his other daily activities. He says he has lost weight, and his blood pressure is better than it’s been in years. He now plans to follow up with colonoscopies every year.

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Research Advances the Genetic Understanding of Pineoblastoma, a Rare Brain Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 07/20/2018
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In recent years, there have been many advances in treating children with cancer, but brain tumors remain a major challenge. For many pediatric brain tumors, the current treatments often are not very effective or are very toxic. Experts at Memorial Sloan Kettering are focused on learning more about the genetic and molecular underpinnings of these cancers.

Pediatric Neuro-Oncology Service Chief Matthias Karajannis is leading many of these efforts. Dr. Karajannis, along with a team from MSK and several other hospitals in the United States and Germany, published a paper in Nature Communications that focuses on a rare brain tumor called pineoblastoma. This type of tumor accounts for less than 1% of all primary brain tumors. The study reports that pineoblastomas in adults and children are distinct from each other — something that was not previously known. The findings also point the way toward developing better therapies for the disease.

“Over the past decade, we’ve made major progress in understanding the distinct biological differences in various pediatric brain tumors,” Dr. Karajannis says. “Now this research in the lab is starting to bear fruit and help us better diagnose and treat patients, especially those with rare tumors like pineoblastoma.”

Decoding the Alterations in a Rare Cancer

Pineoblastoma is a member of the class of tumors called primitive neuroectodermal tumors (PNETs). It usually occurs in children and young adults, but the tumors can sometimes appear in older adults. One of the findings from the new study is that the adult form of the disease more closely resembles other, less-aggressive PNETs, while the pediatric form is driven by a different set of molecular changes. These distinct changes make pineoblastoma in children more aggressive.

Pineoblastoma arises in the pineal gland. This pea-size organ in the brain produces and controls certain hormones, including melatonin, which affects sleep. The symptoms of pineoblastoma are similar to those of other brain tumors, including headaches, nausea and vomiting, and problems with eye movement and vision. It can also cause a buildup of fluid in the brain.

Sometimes pineoblastoma runs in families that have a certain inherited mutation. These inherited mutations lead to errors in one of the proteins that control small molecules called microRNAs. MicroRNAs monitor which genes get turned on and off. When errors aren’t property controlled, they can drive the formation of tumors. The new study found that in nonfamilial pineoblastoma, dysregulation of microRNAs occurs because of a different mutated gene, called DROSHA.

A Breakthrough in Understanding Brain Tumors

In the paper, the investigators report the latest discoveries based on the genetic and molecular analysis of 16 pineoblastoma tumors removed from patients, including 13 children. They looked at more than the changes in DNA that were connected with the disease, however. They also considered what is called the methylation profile. Methylation is one way that DNA gets modified without changing the DNA sequence. Earlier this year, another study from Dr. Karajannis and his collaborators reported a new system for distinguishing 100-plus types of brain tumors based on their methylation profiles.

“We were surprised to find these different molecular fingerprints between the adult and pediatric forms of the disease,” Dr. Karajannis says. “Another surprising finding was that, similar to what is seen in familial pineoblastoma, dysregulation of microRNAs appears to play a major role in the development of pineoblastoma that comes up sporadically. We also found that one of the genes involved in the formation of pineoblastoma is connected to brain development in embryos as well. This provides an intriguing link between the formation of this tumor and normal brain development.”

The investigators also identified repeated mutations in a gene called ARRB2. This gene has previously been linked to kidney and liver cancers. Very little is currently known about how ARRB2 functions, however.

“Further studies will be needed to assess the role of ARRB2 and the other genes we found to be recurrently mutated in pineoblastoma,” Dr. Karajannis concludes. “But our findings open up new avenues of research toward novel therapies that exploit the abnormal processing of microRNA that we’ve observed.”

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In Good Hands: Meet Hand Sarcoma Surgeon Edward Athanasian

Source: Memorial Sloan Kettering - On Cancer
Date: 07/24/2018
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Sarcoma is not one distinct cancer but more than 50 different types. These tumors can arise in a variety of body tissues, including muscle, nerve, cartilage, and bone. Most commonly, they begin in the torso or leg, but they can occur anywhere, including in a hand or finger.

Memorial Sloan Kettering’s Edward Athanasian is the only surgeon in the United States who is trained in both surgical oncology and hand surgery. We recently spoke with Dr. Athanasian, who is also Chief of the Hand and Upper Extremity Service at the Hospital for Special Surgery in New York City. Here, he describes the unique challenges of operating on sarcomas and other tumors in the hand. He explains how people who have been diagnosed with one of these rare cancers can benefit from MSK’s approach and expertise.

How common are sarcomas in the hands and fingers?

They are relatively uncommon. I would estimate that at MSK we’ve done about 100 hand surgeries for sarcoma in the past 20 years. That’s not a big number, but it’s more than anywhere else. If you include tumors in the wrist, elbow, and arm, that number would be significantly higher.

Bone tumors in the hand are very rare, so the majority of hand tumors are in the soft tissues, such as the muscles and fatty tissues. Some of the types of sarcoma that I’ve treated recently include synovial sarcoma, liposarcoma, and epithelioid sarcoma. Most of the people I see are adults, but I do operations on children as well.

Why is it so unusual for someone to be trained in both surgical oncology and hand surgery?

In many ways, these two surgical specialties are very different from one another. In surgical oncology, the emphasis is on doing a wide excision, which means removing the tumor as completely and thoroughly as possible. Whereas in hand surgery, the training is focused on repairing damage and restoring and maximizing function. It can be very hard for a hand surgeon to shift gears and say, “OK, I’m going to cut out all of this tissue regardless of how it affects function.”

This is how my training is different. I have a complete understanding of the need to achieve appropriate margins around the cancer at the time of the surgery. That is always my primary goal because it’s the only way to maximize the likelihood that the tumor is removed entirely. But at the same time, I’m still thinking about how to accomplish the most successful reconstruction, which optimizes appearance and function after the cancer is gone.

What are some of the biggest challenges of hand surgery?

Microsurgical reconstruction, including complex nerve reconstruction, is an important part of what we do. These surgeries involve working with delicate instruments under a microscope. The procedures can be very long and complex. They are really a team effort.

Often I am in charge of the excision portion of the operation. I work with our plastic surgeons during the reconstruction. Sometimes I don’t know how much tissue I’ll have to remove until my part of the procedure has been completed. The plastic surgeons need to be prepared with plans for three or four different reconstructive procedures for the soft tissue depending on the results after the tumor is removed.

We’re very careful and as precise as possible when explaining surgical options to patients. Sometimes, amputation of the whole hand offers the best chance for fully removing the cancer and maximizing the chances of a cure. At other times, we are able to remove the cancer completely from the hand and restore near normal function. It’s imperative that they understand how their hand’s function might be different after the tumor is removed. They also need to have an understanding of the limitations of reconstructive procedures. We want people to have realistic expectations for both short-term and long-term function and outcomes.

What difficulties do people with these cancers face?

From the standpoint of work and daily life, it can be devastating to lose a hand, or even part of a hand. Losing your thumb is an especially significant problem. It’s so important for picking up and holding things and interacting with the surrounding environment. We’ve developed surgical techniques for saving people’s thumbs. Sometimes we take the big toe and make it into a thumb, but if we don’t have to, we’re better off trying to save enough of someone’s thumb that they’re still able to use it, even if it’s shorter.

There can be serious emotional aspects for many people. These issues often go beyond the cancer diagnosis itself. Your hands are a major part of how you interact socially and how you present yourself to other people. Some people adapt easily, but for others it can be traumatic to lose even the tip of one of their fingers.

What advantages does MSK offer to people with these cancers?

We have a strong collaborative team. In addition to working closely with our plastic surgeons, I also frequently collaborate with medical oncologists and radiation oncologists. Kaled Alektiar has conducted research on the best way to use radiation to shrink tumors before surgery. This can often make it easier for me to remove the cancer and improve our options for sparing fingers.

We have a great relationship with the hand therapists at MSK and the Hospital for Special Surgery as well as surrounding regional hand therapy centers. Physical and occupational therapy after these surgeries is absolutely essential. Therapists help people recover from surgery and get back to normal as much as possible. For people who are not able to have their therapy in New York City, we can coordinate with other facilities.

Hand tumors can be incredibly complex and difficult problems, and people who have them need our help. People come to us from all over the country and other countries as well. I have dedicated my career to this, and I consider it a privilege to be doing this work at Memorial Sloan Kettering.

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FDA Approves Ivosidenib (Tibsovo®), a Targeted Drug, for Acute Myeloid Leukemia

Source: Memorial Sloan Kettering - On Cancer
Date: 07/26/2018
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The US Food and Drug Administration has approved the drug ivosidenib (Tibsovo®) for the treatment of certain people with acute myeloid leukemia (AML) that has stopped responding to other therapies. Memorial Sloan Kettering hematologist-oncologist Eytan Stein was a co-leader of the study that led to the drug’s approval. The results of the trial were published last month in the New England Journal of Medicine (NEJM), and the drug was approved on July 20, 2018.

Ivosidenib is the first drug in a class called IDH1 inhibitors to receive FDA approval. It works in a similar way as enasidenib (Idhifa®), a drug approved in 2017 to treat AML that’s driven by a mutation in a related gene, IDH2. Both drugs represent a “new approach to treating cancer,” says Dr. Stein.

“Instead of killing cancer cells, like other leukemia drugs, it reprograms them and transforms them into normal, healthy, functioning cells,” he says.

About 10% of people with AML have mutations in the IDH1 gene, and another 15% have IDH2 mutations. These mutations are also found in other types of leukemia as well as myelodysplastic syndromes, glioblastoma, and bile duct cancer. Targeting these mutations is a growing area of cancer drug development.

MSK President and CEO Craig Thompson led the basic science research that explains how IDH1 mutations drive AML, in collaboration with MSK physician-scientists Ross Levine and Omar Abdel-Wahab. The Peter and Susan Solomon Family Foundation supported that research, which was first reported in 2010. The investigators found that the mutations produce a cancer-causing enzyme called hydroxyglutarate (2HG). This enzyme stops the development of the blood cells called myeloid cells when they are in an immature form, which leads to leukemia.

Ivosidenib brings down the level of 2HG, so the blood cells can begin to develop normally again.

The NEJM study was a multicenter phase I trial that reported data on 125 people whose cancer had stopped responding to other treatments. The researchers found that of those treated with ivosidenib, almost 42% responded. Nearly 22% had a complete remission, meaning that their cancer was no longer detectable. The overall survival was longer than what would be expected for people with this stage of AML, and severe side effects were rare.

MSK Leukemia Service Chief Martin Tallman also participated in the study.

Ivosidenib and enasidenib are both made by Agios Pharmaceuticals.

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Getting a Correct Diagnosis Is Vital for Treating Sarcoma, a Rare Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 07/31/2018
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Receiving a diagnosis of sarcoma can be overwhelming. But it can be especially confusing because many people have never heard of sarcoma and many doctors have never treated it. It’s so rare that it makes up only about 1% of all cancers.

Unlike tumors that occur in a particular organ, sarcomas can appear almost anywhere in the body. There are more than 50 different kinds. The differences arise from their location, their tissue of origin, and the genetic changes that drive them. These factors mean making an accurate diagnosis can be a challenge.

Memorial Sloan Kettering pathologist Cristina Antonescu’s work has focused exclusively on sarcoma for more than 20 years. “In this new era of personalized medicine, it’s important to know what’s driving a tumor to identify the best treatment approach,” she says.

Soft tissue sarcoma arises in connective tissues, which include fat, muscle, tendons, blood vessels, and cartilage. It’s diagnosed in about 13,000 people in the United States every year. Additionally, about 3,500 bone sarcomas are diagnosed annually in the United States.

Members of MSK’s sarcoma team have expertise not only in diagnosing but also in treating all different types and subtypes of sarcoma, some of which are potentially deadly. Some sarcomas can be treated with surgery alone. Others may require a more wide-ranging approach to offer the best chance of fully eliminating the tumor and preventing it from coming back. Treatments may include chemotherapy, radiation therapy, immunotherapy, and targeted drugs.

In recognition of MSK’s expertise in treating sarcoma, the team recently received a SPORE (Specialized Programs of Research Excellence) grant from the National Institutes of Health. MSK is the only single institution in the country to receive SPORE funding for sarcoma research. The project is led by surgeon-scientist Samuel Singer.

Specialized Diagnostic Approaches in Sarcoma

One of the first steps in any cancer diagnosis is preparing tissue taken from a biopsy to look at under a microscope. But unlike with many other cancers, determining a sarcoma tumor’s type based on its appearance alone can be difficult, especially for pathologists who don’t see them regularly. “Sometimes different kinds of sarcoma resemble each other,” says MSK Surgical Pathology Service Chief Meera Hameed, who specializes in sarcoma. “Other times, there may be cells that look very different from each other found within the same sarcoma tumor.”

For this reason, Dr. Hameed explains, looking at tumors under the microscope often doesn’t provide enough information alone to make a diagnosis. This makes molecular pathology a vitally important piece of the sarcoma puzzle. Some of these tests are done using immunohistochemistry, a type of analysis that enables a pathologist to identify the presence of certain proteins in a tumor sample. But genomic sequencing and other types of molecular analysis are often the best way to pinpoint a sarcoma’s unique characteristics.

MSK geneticist and pathologist Marc Ladanyi, Chief of the Molecular Diagnostics Service, is an internationally recognized leader in this field. Dr. Ladanyi has developed molecular diagnostic tests not just for sarcoma but for many other types of cancer as well. In addition, in his research lab, he has identified many of the genetic abnormalities that are known to drive sarcoma growth.

Diverse Class of Tumors with Varied Underlying Causes

More than one-third of all sarcomas are caused by a type of genetic abnormality called a fusion gene. These genes are created when a piece of a chromosome breaks off and is transferred to an unrelated gene, which causes the formation of a protein that drives uncontrolled cell growth.

MSK doctors use a special technology to detect gene fusions. Dr. Ladanyi and colleagues helped develop and refine that test, and the work is now setting the stage for diagnosis of cancers driven by fusion genes worldwide.

The other two-thirds of sarcomas are triggered by individual gene mutations, which can be detected with MSK-IMPACT™. This test, developed by the Molecular Diagnostics Service, looks for mutations in more than 400 genes that are known to play a role in cancer.

Applying Research to Sarcoma Patient Care

One of the essential contributors to MSK’s expertise in sarcoma is a database of more than 10,000 people treated for sarcoma. It was started more than 20 years ago by pioneering sarcoma surgeon Murray Brennan, who led MSK’s Department of Surgery for many years.

The database includes clinical records and medical history, images of pathology samples, and — more recently — details about the genetic and other molecular changes driving tumor growth. “Gaining a better understanding of what drives these tumors can help us come up with new ways to target them,” Dr. Ladanyi says. “Our ultimate goal is to be able to eventually find the Achilles’ heel for every type of sarcoma.”

“This is an exciting time to be doing sarcoma research,” Dr. Antonescu concludes. “It’s moving so quickly. We are able to take discoveries that we make about gene fusions and other mutations and immediately translate them into new diagnostic tests that can guide treatments. That’s the beauty of working at MSK.”

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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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Does Vitamin D Reduce the Risk of Getting Cancer?

Source: Memorial Sloan Kettering - On Cancer
Date: 08/09/2018
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In June 2018, two papers were published that suggested that high levels of vitamin D circulating in the blood may be associated with a lower risk of cancer. One looked at breast cancer and the other at colon and rectal cancer.

These are only the latest in a large number of studies on vitamin D and cancer published over the past few decades. Some have looked at prevention and others at whether vitamin D improves outcomes after someone has been diagnosed. The findings overall have been mixed.

We spoke with Memorial Sloan Kettering medical oncologists Leonard Saltz, a colorectal cancer expert, and Monica Fornier, a breast cancer expert, about these studies. Here’s what you should know about the “sunshine vitamin” and its connection to cancer.

What did these latest studies show?

The colon cancer study, published in the Journal of the National Cancer Institute, combined data from 17 other studies that followed a total of more than 12,000 people. It found that levels of vitamin D in the blood that are considered deficient (below 20 nanograms per milliliter, or ng/mL) were associated with a 31% higher cancer incidence compared with those in the high range (between 50 and 62.5 ng/mL).

The breast cancer study, published in PLoS One, looked at more than 5,000 women ages 55 and older. It found that women with high vitamin D levels in their blood (60 ng/mL or more) had an 80 percent lower incidence for breast cancer compared with those who had low levels (20 ng/mL or less). The researchers also found that among women with vitamin D blood levels in the upper range, the highest levels were associated with the lowest incidence.

What are the limitations of this kind of research?

“These findings are compelling, but we have to be careful about studies that link lifestyle to cancer,” Dr. Fornier says. “It’s hard to make direct connections because there are so many possible factors.”

“One big caveat is that having high vitamin D levels could just mean that someone has a better lifestyle and a healthier diet,” Dr. Saltz adds. “It’s also important to note that a link has not been found in a controlled study looking at whether taking vitamin D after colon cancer surgery can prevent recurrence.”

He also refers to another study, published in July 2018 in JAMA Oncology, which concluded that taking high doses of vitamin D was not associated with cancer prevention and should not be done for this purpose.

What does vitamin D do in the body?

One of the most important jobs of vitamin D is maintaining bone health. It helps to promote the absorption of calcium from food into the intestines. It also maintains the levels of calcium and phosphate in the blood that are needed for bone formation and regeneration.

Much less is known about the role that the vitamin might play in cancer, but it may have to do with its function in regulating pathways related to cell growth and regulation. “There are some studies in the lab that suggest vitamin D may have certain cancer prevention properties due to the way it functions,” Dr. Saltz says. “However, the connection to how that may translate to a benefit in people is pretty soft.”

To fully understand the relationship, experts would need to conduct randomized clinical trials. If they were able to confirm the link, these studies could also look at the appropriate dose of vitamin D and determine how long someone would need to take it to see a benefit.

Are vitamin D deficiencies becoming more common?

Studies have suggested that more than one billion people worldwide have vitamin D deficiencies, including more than 40% of the US population. “People don’t spend their lives outside as much as they used to,” Dr. Fornier explains. “Many people are scared to get any sun at all because of concerns about skin cancer. Of course, it’s important to be careful, but a little bit of sun, especially early or late in the day when it is less strong, is not bad.”

Diet also plays a role, and many people may not consume enough foods that are rich in vitamin D. These foods include certain types of fish and other seafood and eggs. Some foods, including milk, orange juice, and many cereals, are also fortified with vitamin D.

Dr. Fornier adds that because of the side effects of certain breast cancer treatments, maintaining healthy levels of vitamin D is especially important for the people she treats. Hormone therapies used to treat breast cancer, particularly the class of drugs called aromatase inhibitors, can reduce bone density and make fractures more common.

Based on what we know, should people take vitamin D supplements to reduce cancer risk?

“It would be great if you could go down to the pharmacy and grab a bottle of vitamin D, and then you would never have to worry about cancer again,” Dr. Saltz says. “But of course it’s not that simple.”

Right now, the Institute of Medicine doesn’t find enough evidence to recommend vitamin D as a way to prevent cancer, he notes. (The IOM provides evidence-based research and recommendations for public health and science policy.) “But it does say that vitamin D is important for bone health, and we very much support that for people whose levels are found to be low,” he adds.

In addition, taking vitamin D at very high levels can result in digestive and kidney problems.

What else can people do to reduce their cancer risk?

If people are concerned about their risk of colorectal cancer, there are many measures they can take, Dr. Saltz says. “We know that people who eat a healthy diet that’s low in refined carbohydrates and sugar and high in whole grains, vegetables, and seafood have a decreased risk of colon cancer. Data also suggest that high consumption of tree nuts — but not peanuts — is associated with a lower risk of recurrence after surgery for colon cancer. In addition, there’s also evidence that drinking coffee is correlated with decreased risk for colon cancer. I was happy to hear that.”

Dr. Fornier emphasizes the importance of regular exercise as well. “We are learning more and more about the importance of exercise, not just for general health but for bone health and mental health in particular,” she says. “A bottle of vitamins cannot substitute for a healthy lifestyle.”

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Cord Blood Transplants Provide an Opportunity for a Cure from Blood Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 08/30/2018
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Allogeneic stem cell or bone marrow transplants can be lifesavers for people with a blood cancer such as leukemia or lymphoma. After chemotherapy is used to destroy the cancer, blood-forming stem cells from a donor are infused to repair and restore the bone marrow.

Unfortunately, only about one-quarter of the people who need an allogeneic transplant have a sibling who is a genetic match and able to donate stem cells. The other three-quarters need to find another donor for their transplant.

People can receive bone marrow or stem cells donated by an adult who is not related to them. But many who need a transplant are not able to find a matched donor from any of the volunteer donor registries. These people can benefit from a different procedure called a cord blood transplant, which uses stem cells from the umbilical cord blood of a healthy newborn. Stem cell donations from adult volunteers and cord blood collections are found through Be the Match or another donor registry.

We recently spoke with Juliet Barker, Director of Memorial Sloan Kettering’s Cord Blood Transplant Program. Here, she describes MSK’s expertise with cord blood transplantation.

What is cord blood, and why is it a good option for some people who need a stem cell transplant?

Cord blood is collected from the umbilical cord and placenta of healthy newborns and is a rich source of blood-forming stem cells. Parents have the option of donating it at birth. The cells are stored frozen in public cord blood banks.

A major advantage of cord blood is that the immune system of a newborn baby is not yet fully developed. This means that the match that’s required between the cord blood stem cells and the person receiving them is less strict.

However, even though the cord blood immune system is very malleable, it can still develop into a healthy immune system. Also, cord blood cells are very good at fighting cancer. This ability is called the graft-versus-leukemia effect. It can help prevent a person’s cancer from returning after their transplant.

What does it mean for donor cells to be matched, and why is it often hard for people to find a match?

The test that’s used to identify appropriate donors is called HLA matching. HLA stands for human leukocyte antigen. HLAs are proteins that are present on most cells in your body. Your immune system uses HLAs to recognize which cells belong in your body. When using an adult donor, it’s important that the donor and the person undergoing the transplant have HLAs that match so the donor immune system doesn’t attack the patient’s normal tissues, a complication called graft-versus-host disease.

A person’s HLA type is inherited from their parents, which is why siblings offer the best chance of finding a match. People’s HLA type can be determined with a simple blood test or cheek swab.

People of southern European, Asian, African, Hispanic, and Middle Eastern backgrounds tend to have more diverse HLA types. These types are less commonly found in adult volunteer donor registries. It can also be difficult for someone with a mixed background — for example, part Asian and part Hispanic — to find a donor who is a match. For them, cord blood transplants offer a good opportunity for a cure.

What kind of expertise does MSK have in performing cord blood transplants?

MSK has one of the most active and successful cord blood transplant programs in the world. We have performed more than 350 cord blood transplants in adults and children — more than half of them being of non-European ancestry.

However, these transplants are complex. They offer great benefits, provided the hospital where the transplant is done has the expertise to manage the potential complications. MSK has experts who can tackle transplant complications as a matter of routine.

How did you become an expert in cord blood transplants?

I did my medical training in Australia, where I’m from. In 1996, I came to the United States to the University of Minnesota to train under famous transplant specialists, including John Wagner. Dr. Wagner is a pioneer in cord blood transplantation.

In Minnesota, I was trained in doing stem cell transplants in adults. I was chosen to develop the adult cord blood transplant program there. I was in the right place at the right time. In 2001, our team reported in the New England Journal of Medicine on the then-new technology of combining two different cord blood collections from two different babies, a procedure known as double-unit transplantation. This approach has been very successful and has since been adopted as the standard way of doing cord blood transplants in adults around the world.

Why did you decide to come to MSK?

In 2005, I had the opportunity to come to MSK and create the Cord Blood Transplant Program here. Thanks to the leadership of Richard O’Reilly beginning in the 1970s, MSK has many decades of experience in developing and improving stem cell transplants. MSK’s strong research focus also lends itself very well to the development and adoption of new innovations.

In addition, New York City is much more ethnically diverse than Minnesota. This has meant that there is a much greater number of people who will not find a matched donor. There are so many patients here who can benefit from cord blood transplants. This is one of the reasons why our program has been so successful. And now we are developing a number of new clinical trials to even further improve the results of these transplants.

What do we know about outcomes for people who undergo this type of transplant?

Recently, MSK analyzed the outcomes of double-unit cord blood transplants in adults with cancers of the blood and bone marrow. The investigation showed that our results are some of the best in the world. They are as good as transplants with cells from adult donors. This data will be presented at the annual conference of the American Society of Hematology later this year.

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Studying a Forerunner of Pancreatic Cancer Reveals New Clues about How the Disease Develops

Source: Memorial Sloan Kettering - On Cancer
Date: 09/03/2018
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One universal truth about cancer is that the later it’s detected, the harder it is to treat. Pancreatic cancer is one form of the disease that is almost always found when it’s advanced, making it an exceptional challenge. Because it’s rarely caught early in its development, this also means that researchers know less about what drives its formation and spread than they do with many other kinds of tumors.

Understanding how a cancer develops and grows, however, has important implications. It allows researchers to create better targeted therapies and develop better detection and screening methods. Now a study led by Memorial Sloan Kettering physician-scientist Christine Iacobuzio-Donahue is shedding new light on a phenomenon that sometimes leads to pancreatic cancer. The results were published September 3, 2018, in Nature.

A Possible Lead-Up to Cancer

When surgeons remove a cancerous pancreas, they often find groups of abnormal cells called pancreatic intraepithelial neoplasias (PanINs) in other parts of the organ. PanINs are also common in older people who do not have pancreatic cancer.

Although they are not cancer, some PanINs eventually become cancer. Experts aren’t sure how often that happens. “I think of them sort of like moles on the skin,” says first author Alvin Makohon-Moore. “It may not turn into anything serious, but it’s clear that some sort of change has taken place that could further transform into cancer.” Dr. Makohon-Moore is a postdoctoral fellow in Dr. Iacobuzio-Donahue’s lab.

In the new study, the investigators identified eight people who had undergone surgery for early-stage pancreatic cancer who also had PanINs in other parts of their pancreas. The patients were treated at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, where Dr. Iacobuzio-Donahue and her colleagues worked when this research began. Several investigators from Johns Hopkins also contributed to the Nature paper.

The Search for Genetic Similarities — and Differences

The pancreas tissue was dissected under a microscope, and the cells from each PanIN were separated from the tumor cells in a very precise way. The DNA from each PanIN was then extracted, and the researchers conducted whole exome sequencing. This involves sequencing all the sections of the genome that are known to encode proteins. The tumors were also sequenced. For both types of cells, the investigators sorted out which mutations were likely to be directing cancer growth (called driver mutations) and which were just along for the ride (called passenger mutations).

“The goal of this research was to find mutations that the tumors and PanINs had in common and other mutations that the PanINs and tumors had acquired independently,” Dr. Makohon-Moore explains. “Based on this, we could create evolutionary trees for each patient, to figure out how their tumors had evolved.”

Based on the driver mutations found in the PanINs and tumors, the team was able to determine which cancer-causing mutations led to invasive cancer and which were acquired later. Unexpectedly, they also found that the PanINs could move through the system of ducts in the pancreas.

Potential for Further Research

There are several important next steps in the research. One is to look at a greater number of PanINs and tumors to determine if there are any repeated genetic patterns. That’s difficult to do with samples from only eight people.

Another step is to look for attributes beyond the DNA that may be driving the formation of tumors. This will include studies of the cells around the PanINs. This area is called the microenvironment. Researchers will also look for changes in gene expression that are not reflected in the DNA sequence — called epigenetic changes.

“Eventually, we hope this research will give us a framework for interpreting the events that happen early in the development of pancreas tumors,” Dr. Makohon-Moore says.

He adds that this inquiry may provide an explanation for why pancreatic cancer comes back so often after surgery. Even for people with early-stage disease whose tumors are completely removed, the disease returns in 60 to 70% of them. “It could be that these tumors are not as localized as we think they are and that they have the ability to move around within the pancreas,” he says. “Our research may help provide a biological context for why this cancer is so aggressive.”