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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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Genetic Variations Help Explain Why Immunotherapy Works Differently in Different People

Source: Memorial Sloan Kettering - On Cancer
Date: 11/07/2019
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Since 2011, the immunotherapy drugs called checkpoint inhibitors have become an increasingly important treatment for certain cancers. This is especially true for people with melanoma and lung cancer.

Early on, investigators observed that these drugs are extremely effective for some people, even eliminating their cancer entirely. Unfortunately, they don’t work at all for many others. Considerable research has tried to understand why this is the case and exactly how these drugs work.

Memorial Sloan Kettering physician-scientist Timothy Chan has focused on these efforts. He is one of the corresponding authors of a study published November 7, in Nature Medicine that reports a new way to determine who is most likely to benefit from immunotherapy. The findings may help explain why immunotherapy works differently in people around the world.

“Our results help solve part of the mystery of why there is such a large variation in the effectiveness of immune checkpoint drugs,” says Dr. Chan, who leads the Immunogenomics and Precision Oncology Platform at MSK. “It’s important that future clinical trials of immune checkpoint drugs take our discovery into account. This is especially important for international phase III trials.”

Looking to Evolution and Population Diversity for Answers

For decades, the human leukocyte antigen (HLA) genes have been known to govern how the immune system responds to foreign substances in the body. Over thousands of generations, as early humans migrated out of Africa and around the planet, they evolved variations in their HLA genes. These changes protected them from infectious organisms that were found in different parts of the world.

“The classic battle between pathogens and the human immune system plays out in the HLA genes,” Dr. Chan says. A 2017 study from Dr. Chan was the first to show that HLA genes are important for the body’s ability to see cancer after immunotherapy as well. That study reported that people who had a greater number of different copies, or alleles, in their HLA-1 genes responded better to immunotherapy compared with those whose HLA-1 genes had fewer alleles. The new study builds on this previous work.

To quantify how efficient the immune system is at detecting cancer, the researchers looked at the HLA genes from more than 1,500 people who had received immune checkpoint drugs as part of clinical trials at MSK and other hospitals. Most of those included in the study had melanoma or non-small cell lung cancer, but other kinds of cancer were also represented.

People inherit one copy of HLA-1 from each parent. For each person analyzed, the team found that the more molecularly diverse, or different from each other, the two copies of each of their HLA-1 genes were, the more likely someone was to respond to treatment and survive their cancer. The investigators developed a novel way to measure this difference, which they call HLA evolutionary diversity (HED).

Dr. Chan’s co-corresponding author on the Nature Medicine paper, Tobias Lenz of the Max Planck Institute for Evolutionary Biology in Germany, is an expert in the evolution of the human immune system and the HLA genes. Research fellow Diego Chowell and graduate student Chirag Krishna from Dr. Chan’s lab and graduate student Federica Pierini from Dr. Lenz’s lab were the co-first authors.

Recognizing Tumors as Foreign

Dr. Chan has also looked at other factors that make immune checkpoint drugs more effective. In 2014, he led the first studies finding that patients who responded to these drugs tended to have a large number of gene mutations in their tumors. This is known as having a high tumor mutational burden (TMB). When tumors have a greater number of mutations, it is more likely that they will produce proteins that the immune system hasn’t seen before.

“For checkpoint inhibitor drugs to be effective, the immune system needs to be able to recognize cancer cells as foreign,” Dr. Chan says. “High TMB and diverse HLA genes are two sides of the same coin. Both make it more likely that the immune system will see the cancer.”

The researchers note in their study that high TMB and high HED are independent of each other, but the combined outcome of the two led to benefits from immunotherapy drugs that were greater than either of these effects on their own. “These are the yin and yang of T cell–based immune checkpoint treatment,” Dr. Chan says. “High TMB is less useful if a person is unable to present the mutations to the immune system. Having a high HED allows that to happen.”

Finding New Ways to Measure Genetic Diversity

Recent immunotherapy clinical trials have begun to include TMB in their evaluation of how effective checkpoint inhibitors are, Dr. Chan notes. “But among different trials, there is great variation in the role that TMB plays. No one has been able to figure out what’s going on,” he says. “It turns out, we should also be looking at HLA diversity. This finding may account for the unexplained variation that’s seen in the role of TMB in immunotherapy trials.”

He adds that it may also account for the different response rates that have been observed in different parts of the world. HED can vary dramatically depending on where someone lives.

The investigators are now working to develop a standardized way to report HED, so that it can be incorporated into future clinical studies. Dr. Chan’s team is in the process of evaluating HED with industry partners using global phase III trial data. They hope that this measure can eventually become a regular part of cancer diagnosis and be used to match people with cancer with the most personalized treatments.

This research was funded by National Institutes of Health grants (R35 CA232097, RO1 CA205426, and P30 CA008748), the PaineWebber Chair in Cancer Genetics at MSK, and a German Research Foundation grant.

Dr. Chan has filed for a patent related to HED. Additionally, he is an inventor on a patent application filed by MSK relating to the use of TMB in cancer immunotherapy. MSK and the inventors may receive a share of revenue from license agreements relating to these patent applications. Dr. Chan is also a co-founder of Gritstone Oncology and holds equity. He acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai, and he has served as an adviser for Bristol-Myers Squibb, Illumina, Eisai, and An2H.

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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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Machine Learning May Help Classify Cancers of Unknown Primary

Source: Memorial Sloan Kettering - On Cancer
Date: 11/14/2019
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Experts estimate that between 2 and 5% of all cancers are classified as cancer of unknown primary (CUP), also called occult primary cancer. This means that the place in the body where the cancer began cannot be determined. Despite many advances in diagnostic technologies, the original site of some cancers will never be found. However, characteristic patterns of genetic changes occur in cancers of each primary site, and these patterns can be used to infer the origin of individual cases of CUP.

In a study published November 14, a team from Memorial Sloan Kettering reports that they have harnessed data from MSK-IMPACT™ to develop a machine-learning algorithm to help determine where a tumor originates. MSK-IMPACT is a test to detect mutations and other critical changes in the genes of tumors. When combined with other pathology tests, the algorithm may be a valuable addition to the tool kit used to make more-accurate diagnoses. The findings were reported in JAMA Oncology.

“This tool will provide additional support for our pathologists to diagnose tumor types,” says geneticist Michael Berger, one of the senior authors of the new study. “We’ve learned through clinical experience that it’s still important to identify a tumor’s origin, even when conducting basket trials involving therapies targeting genes that are mutated across many cancers.”

Basket trials are designed to take advantage of targeted treatments by assigning drugs to people based on the mutations found in their tumors rather than where in the body the cancer originated. Yet doctors who prescribe these treatments have learned that, in many cases, the tissue or organ in which the tumor started is still an important factor in how well targeted therapies work. Vemurafenib (Zelboraf®) is one drug where this is the case. It is effective at treating melanoma with a certain mutation but doesn’t provide the same benefit in colon cancer, even when it’s driven by the same mutation.Cancer of Unknown Primary Origin

If it is unclear where in the body a cancer started, it is called cancer of unknown primary (CUP) or occult primary cancer.

Harnessing Valuable Data

Since MSK-IMPACT launched in 2014, more than 40,000 people have had their tumors tested. The test is now offered to all people treated for advanced cancer at MSK.

In addition to providing detailed information about thousands of patients’ tumors, the test has led to a wealth of genomic data about cancers. It has become a major research tool for learning more about cancer’s origins.

The primary way that pathologists diagnose tumors is to look through a microscope at tissue samples. They also examine the specific proteins expressed by cancers, which can help predict a cancer’s origin. But these tests do not always allow a definitive conclusion.

“However, there are occasionally cases where we think we know the diagnosis based on the conventional pathology analysis, but the molecular pattern we observe with MSK-IMPACT suggests that the tumor is something different,” Dr. Berger explains. “This new tool is a way to computationally formalize the process that our molecular pathologists have been performing based on their experience and knowledge of genomics. Going forward, it can help them confirm these diagnoses.”

“Because cancers that have spread usually retain the same pattern of genetic alterations as the primary tumor, we can leverage the specific genetic changes to suggest a cancer site that was not apparent by imaging or conventional pathologic testing,” says co-author David Klimstra, Chair of MSK’s Department of Pathology.

“Usually the first question from patients and doctors alike is: ‘Where did this cancer start?’ ” says study co-author Anna Varghese, a medical oncologist who treats many people with CUP. “Although even with MSK-IMPACT we can’t always determine where the cancer originated, the MSK-IMPACT results can point us in a certain direction with respect to further diagnostic tests to conduct or targeted therapies or immunotherapies to use.”

Collecting Data on Common Cancers

In the current study, the investigators used data from nearly 7,800 tumors representing 22 cancer types to train the algorithm. The researchers excluded rare cancers, for which not enough data were available at the time. But all the most common types are represented, including lung cancer, breast cancer, prostate cancer, and colorectal cancer.

The analysis incorporated not only individual gene mutations but more complex genomic changes. These included chromosomal gains and losses, changes in gene copy numbers, structural rearrangements, and broader mutational signatures.

“The type of machine learning we use in this study requires a lot of data to train it to perform accurately,” says computational oncologist Barry Taylor, the study’s other senior author. “It would not have been possible without the large data set that we have already generated and continue to generate with MSK-IMPACT.”

Both Drs. Berger and Taylor emphasize that this is still early research that will need to be validated with further studies. In addition, since the method was developed specifically using test results from MSK-IMPACT, it may not be as accurate for genomic tests made by companies or other institutions.

Improving Diagnosis for Cancer of Unknown Primary

MSK’s pathologists and other experts hope this tool will be particularly valuable in diagnosing tumors in people who have CUP. Up to 50,000 people in the United States are diagnosed with CUP every year. If validated for this purpose, MSK-IMPACT could make it easier to select the best therapies and to enroll people in clinical trials.

“This study emphasizes that the diagnosis and treatment of cancer is truly a multidisciplinary effort,” Dr. Taylor says. “We want to get all the data we can from each patient’s tumor so we can inform the diagnosis and select the best therapy for each person.”

This work was funded in part by Illumina, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Cycle for Survival, National Institutes of Health grants (P30-CA008748, R01 CA204749, and R01 CA227534), an American Cancer Society grant (RSG-15-067-01-TBG), the Sontag Foundation, the Prostate Cancer Foundation, and the Robertson Foundation.

Dr. Varghese has received institutional research support from Eli Lilly and Company, Bristol-Myers Squibb, Verastem Oncology, BioMed Valley Discoveries, and Silenseed. Dr. Klimstra reports equity in Paige.AI, consulting activities with Paige.AI and Merck, and publication royalties from UpToDate and the American Registry of Pathology. Dr. Berger reports research funding from Illumina and advisory board activities with Roche. All stated activities were outside of the work described in this study.

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Study in Mice Suggests Lactose in the Diet Feeds Dangerous Gut Bacteria When the Immune System Is Compromised

Source: Memorial Sloan Kettering - On Cancer
Date: 11/29/2019
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Infections with the Enterococcus bacterium are a major threat in healthcare settings. They can lead to inflammation of the colon and serious illnesses such as bacteremia and sepsis, as well as other complications.

Enterococcus infections are particularly risky for people having stem cell and bone marrow transplants (BMTs) to treat blood cancer. Studies have suggested that high levels of Enterococcus increase the incidence of graft-versus-host disease (GVHD), a potentially fatal condition in which immune cells from the donor’s stem cells attack the recipient’s organs.

Now, an international team led by scientists from Memorial Sloan Kettering has shown for the first time that foods containing lactose, a sugar that’s naturally found in milk and dairy products, help Enterococcus thrive in the gut, at least in mice. They also studied changes in the bodies of people having BMTs. The study was published November 29 in Science.

“These findings hint at a possible new way to reduce the risk of GVHD as well as dangerous infections,” says MSK physician-scientist and GVHD expert Jonathan Peled. “But they are still preliminary, and it’s too early to suggest cutting out lactose in the diets of people undergoing BMTs or other hospitalized patients who are at risk from Enterococcus.”

Focusing on the Microbiota

For several years, Dr. Peled and Marcel van den Brink, head of MSK’s Division of Hematologic Malignancies, have been studying the relationship between GVHD and microbiota — the community of microorganisms that inhabit the body. The two of them are co-senior authors of the new study.

Their previous research has shown that when harmless strains of microbes are wiped out, often due to treatment with antibiotics, Enterococcus and other harmful types of bacteria can take over due to lack of competition. As part of the new study, which included analysis of microbiota samples from more than 1,300 adults having BMTs, the team confirmed the link between Enterococcus and GVHD.

The investigators conducted further Enterococcus research in cell cultures and in mice. “Mouse models are very helpful for understanding the mechanisms in the gut that lead to GVHD,” says Dr. van den Brink, who is also Co-Director of the Parker Institute for Cancer Immunotherapy at MSK and leads a lab in the Sloan Kettering Institute’s Immunology Program. “We studied mice that had been given BMTs and found that the cells lining their intestines, called enterocytes, were no longer able to make lactase, the enzyme that breaks down lactose. The high levels of undigested lactose in turn led to a total domination of Enterococcus. It was shocking to see how one type of bacteria completely takes over.”

Dr. van den Brink adds that on top of the defective enterocytes, the loss of competing healthy strains of bacteria caused by antibiotic treatment makes problems in the gut even worse. “It’s a double whammy,” he says.

A Trip to the Pharmacy Leads to a Surprising Discovery

To study whether higher lactose levels were boosting the growth of Enterococcus, or whether the connection was only a coincidence, visiting researcher and first author Christoph Stein-Thoeringer went to the pharmacy to buy Lactaid®. These lactase-containing pills break down lactose, helping people who are lactose intolerant to eat dairy products without side effects.

The researchers discovered that when lactase was added to lab cultures of Enterococcus, the bacterial growth was blocked. So, they began to feed lactose-free chow to lab mice that had been given BMTs and found that mice on the special diet were protected against Enterococcus domination.

“We’re not suggesting this is a cure for GVHD,” Dr. van den Brink says. “But it appears to be an important modulator.”

The investigators have not yet tested the new findings in humans, but existing data suggests that the same connection between lactose and Enterococcus seen in the mice may be at play in people who have had BMTs. “We know which gene variants are associated with being lactose intolerant,” Dr. Peled notes. “We looked at our records and found that people who had these gene variants tended to have a harder time clearing Enterococcus from their guts than others did.”

He adds that many BMT recipients become temporarily lactose intolerant, likely due to the loss of enterocytes caused by chemotherapy. “We are considering doing a trial in which people eat a lactose-free diet or take Lactaid during their cancer treatment to see if the growth of Enterococcus is blocked,” Dr. Peled says.

A Global Effort

Another important aspect of the new study is that it didn’t just look at people treated at MSK. It also included patient samples from Duke University School of Medicine in Durham, North Carolina; Hokkaido University in Sapporo, Japan; and University Hospital Regensburg in Germany. Researchers from those three institutions also contributed to the Science paper.

“Researchers who study the microbiome know that the environment in which a person lives is a major factor,” Dr. van den Brink says. “We’ve made a major effort to collect samples from all over the world, so we know that when we find common features, they are likely to hold up worldwide.”

This work was supported by the German Research Foundation, a Young Investigator-Award from the American Society of Bone Marrow Transplantation, the Lymphoma Foundation, the Susan and Peter Solomon Divisional Genomics Program, the Parker Institute for Cancer Immunotherapy at MSK, the Sawiris Foundation, the Society of MSK, an MSK Cancer Systems Immunology Pilot Grant, the Empire Clinical Research Investigator Program, Seres Therapeutics, the Japan Society for the Promotion of Science, the Center of Innovation Program from Japan Science and Technology, a Conquer Cancer Foundation Young Investigator Award/Gilead Sciences, and more than a dozen National Institutes of Health grants (R01-CA228358, R01-CA228308, P30 CA008748, P01-CA023766, R01-HL125571, R01-HL123340, P01-AG052359, U01 AI124275, R01 AI032135, AI095706, U01 AI124275, KL2 TR001115-03, 2P30AG028716-11, R01CA203950-01, 1R01HL124112-01A, R01 CA203950-01).

Dr. Peled reports research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics and consulting fees from DaVolterra. Dr. van den Brink has received research support from Seres Therapeutics; has consulted, received honorarium from, or participated in advisory boards for Seres Therapeutics, Flagship Ventures, Novartis, Evelo, Jazz Pharmaceuticals, Therakos, Amgen, Magenta Therapeutics, WindMIL Therapeutics, Merck & Co. Inc., Acute Leukemia Forum (ALF), and DKMS Medical Council (Board). He also has IP licensing with Seres Therapeutics and Juno Therapeutics and stock options from Smart Immune.

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Largest Study of Its Kind Reveals New Targetable Genetic Causes of the Rare Blood Disorder Histiocytosis

Source: Memorial Sloan Kettering - On Cancer
Date: 12/04/2019
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Histiocytoses are a group of blood diseases that are diagnosed in only a few hundred people in the United States every year. Despite that rarity, researchers at Memorial Sloan Kettering have extensive experience with histiocytosis. MSK doctors care for more adults with histiocytosis than doctors at any other hospital in the country.

In recent years, MSK investigators have led a number of studies on the specific gene mutations that cause different types of histiocytoses (also called histiocytic neoplasms). On November 25, in Nature Medicine, an international team led by MSK reported findings from the largest study of its kind. They identified mutations for nearly all of the 270 people included in the study.

“We’ve known for some time that most cases of this disease are driven by a single mutation,” says MSK neurologist and histiocytosis expert Eli Diamond, one of the paper’s two senior authors. “In the past, we’ve been able to define those mutations for about 70% of patients.”

“Through the more extensive sequencing that we’ve done in this study, we can now define the mutations driving the disease in close to 100% of patients,” adds MSK physician-scientist Omar Abdel-Wahab, the paper’s other senior author. “For most of these mutations, we already have drugs to target them.”

Previous Success with Targeted Therapies

Histiocytosis occurs when the body makes an unusually large amount of abnormal white blood cells, referred to as histiocytes. These cells can build up and form tumors, which can grow in any part of the body. The bones and skin are most commonly affected.

The most common types of histiocytoses are Erdheim-Chester disease, which occurs mostly in adults; Langerhans cell histiocytosis and Rosai-Dorfman disease, which can affect both children and adults; and juvenile xanthogranuloma, which is found almost exclusively in children. All of these types were included in the study, as well as some other, rarer forms of the disease.

Thanks to earlier research done at MSK and elsewhere, experts already knew about the mutations driving many of these subtypes. That understanding has led to targeted therapies that are effective in treating them.

In 2017, vemurafenib (Zelboraf®) was the first drug approved for people with Erdheim-Chester disease. Vemurafenib targets mutations in a gene called BRAF. In October 2019, the US Food and Drug Administration announced that it had granted a Breakthrough Therapy Designation for the drug cobimetinib (Cotellic®) to treat histiocytosis with mutations in the genes MEK1 and MEK2. This designation indicates that the agency believes the drug is particularly promising. The clinical trials for both of these drugs were led by investigators at MSK.

“Another thing that’s important to note is that unlike treatment with most targeted therapies, where the tumors eventually become resistant to the drugs, when histiocytosis is treated with these therapies, patients’ responses tend to be long-lasting,” Dr. Diamond says. “Many people have remained on these drugs for years with durable benefits and few side effects.”

The new study opens up opportunities for even more people to be treated with targeted therapies. The researchers uncovered mutations in the RET, ALK, and NTRK genes. All of these mutations can be targeted with drugs that are already approved or are in clinical trials for other types of cancer with these mutations.

The study also reported for the first time that the gene CSF1R is implicated in certain cases of histiocytosis. CSF1R was already known to be important in the formation of a type of white blood cell called a macrophage.

“One of the strengths of this study is that it included all subtypes of histiocytosis. We have enough data to make these correlations between specific gene mutations and specific forms of histiocytosis,” says Dr. Abdel-Wahab, who leads a lab in MSK’s Human Oncology and Pathogenesis Program.

New Details about the Causes of Histiocytosis

The study revealed valuable information about the underlying origins of these diseases as well.

For example, doctors observed twins with histiocytosis. The investigators found that the common mutation driving the disease came not from the twins’ parents but from a mutation in the very early embryo that affected how their blood cells developed. These findings have implications for understanding how histiocytosis forms in many people.

Many of the patients whose data were included in the study were treated at MSK, but people treated at hospitals in Europe and other parts of the United States were included, too. Investigators from several other institutions were co-authors on the paper.

One way that the team was able to collect so many samples is through Make-an-IMPACT. This MSK initiative provides individuals with rare cancers the opportunity to receive genomic testing of their tumors at no cost. Histiocytosis is one of the cancer types included in this program.

“It’s very important that everyone who has histiocytosis gets their tumor sequenced,” Dr. Abdel-Wahab says. “It not only can help them but can also make important contributions to research.”

This work was supported by grants from the Histiocytosis Association, the Erdheim-Chester Disease Global Alliance, the American Society of Hematology, the Leukemia and Lymphoma Society, the Pershing Square Sohn Cancer Research Alliance, the Functional Genomics Initiative at MSK, The Society of Memorial Sloan Kettering, a Translational and Integrative Medicine Award from Memorial Sloan Kettering, the Geoffrey Beene Cancer Research Center at MSK, the Frame Family Fund, the Joy Family West Foundation, the Nonna’s Garden foundation, the Flanders Institute for Biotechnology in Belgium, and the National Institutes of Health (K08CA218901, UL1TR001857, P30CA008748, and 1R01CA201247).

This work was also supported by Cycle for Survival, MSK’s rare cancer fundraising program. Make-an-IMPACT is also funded by Cycle for Survival.

Dr. Abdel-Wahab has received grants from H3 Biomedicine and personal fees from H3 Biomedicine, Foundation Medicine, Merck, and Jansen unrelated to this manuscript.

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MSK Experts Report New Findings about Multiple Myeloma at the 2019 ASH Meeting

Source: Memorial Sloan Kettering - On Cancer
Date: 12/09/2019
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Multiple myeloma is a cancer that arises from the type of white blood cells called plasma cells. When normal plasma cells in the bone marrow develop certain genetic mutations, they may turn into myeloma cells.

At the annual meeting of the American Society of Hematology (ASH), held December 7 through 10 in Orlando, Florida, Memorial Sloan Kettering researchers reported on some of the latest advances in detecting and treating multiple myeloma.

A New Combination Therapy

One of those studies, led by MSK hematologic oncologist Ola Landgren, Chair of the Myeloma Service, is a phase II clinical trial looking at a new combination of drugs for those recently diagnosed with multiple myeloma.

In this trial, the participants had a targeted antibody drug called daratumumab (Darzalex®) added to a standard chemotherapy combination, called KRD, which is comprised of three drugs: carfilzomib (Kyprolis®), lenalidomide (Revlimid®), and dexamethasone (Ozurdex®).

“After someone completes treatment for multiple myeloma, the measure of how effective that treatment was is called minimal residual disease, or MRD,” Dr. Landgren explains. “MSK uses two very sensitive tests that can detect a single cancer cell in 100,000 or more plasma cells. If we can’t find any cancer, we feel quite confident the treatment has been successful.”

Among the 30 people who got the KRD-daratumumab combination, 77% of them were MRD negative after eight cycles of treatment. Based on cross-study comparison, the average level of MRD negativity seen with other therapies is 54% for those who get KRD alone, 58% for those who get KRD followed by an autologous stem cell transplant, and 59% for those who get a different chemotherapy combination called VRD-daratumumab followed by a transplant.

Daratumumab is currently approved by the US Food and Drug Administration for use in people who are unable to have transplants because of age or other health problems. Dr. Landgren says that based on these findings and other emerging studies, he thinks daratumumab could be used more widely.

Along with the biotech company Amgen, Dr. Landgren is working with the FDA to develop a large, randomized, multicenter clinical trial designed to evaluate KRD-daratumumab in comparison to the drug combinations that are currently considered the standard of care. He says that if the new combination is shown to be effective in a head-to-head comparison with current standard treatments, it could lead to wider approval of the drug.

“It’s too early to say that the addition of daratumumab to KRD, as a consequence of the high rate of MRD negativity, will result in an increasing proportion of newly diagnosed multiple myeloma patients opting for delaying their transplants, but it’s possible that may be the case,” he says. “Transplants are effective, but they are also associated with significant short-term as well as long-term toxicities, whereas side effects from daratumumab are quite minimal. The current phase II study is limited by small numbers and short follow-up, but the early results showing 77% of patients with no MRD are very exciting.”If we can

Learning How Multiple Myeloma Develops

Another important study looked at the early development of multiple myeloma. The disease is diagnosed in about 32,000 people in the United States every year, but experts estimate that by age 60 many more people — from 3% to 5% of the population — will have cells detectable in their blood that show signs of pre-myeloma.

These myeloma precursors can develop years or even decades before symptoms of the disease begin to develop. The symptoms include bone pain and frequent infections. Since the discovery of these early changes was made about ten years ago, the challenge has been determining who is most likely to develop the disease — and therefore should consider closer observation or possibly treatment — and those who don’t need to worry.

In the new research, an international group of investigators led by MSK hematologic oncologist Francesco Maura, a member of Dr. Landgren’s lab, developed a computational algorithm to understand when the first genetic driver of these pre-myeloma cells is acquired. Using genetic information from samples collected through two large, public databases, the researchers were able to reconstruct the life history of these blood cells long before the myeloma developed.

“We were quite surprised to find that many of the key changes associated with myeloma are acquired when people are in their 20s and 30s, even though the average age of disease onset is 63,” Dr. Maura says. “In this study, we developed a way to find the tumor cells’ mutation rate by looking at when the key drivers are accumulated and the degree to which they contribute to the formation of cancer.”

One of the main goals of this research is to understand who has a high risk of ultimately developing cancer so that it can be treated before symptoms start. “We also know that as it progresses, multiple myeloma develops additional mutations that make it more aggressive and harder to treat,” Dr. Maura says. “Ideally, we would want to eradicate the cancer when it is less complex.”

Dr. Landgren has received funding from the Leukemia and Lymphoma Society, the Rising Tide Foundation, the National Institutes of Health, the US Food and Drug Administration, the Multiple Myeloma Research Foundation, the International Myeloma Foundation, the Perelman Family Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, and Karyopharm. He has received honoraria from and/or served on the advisory boards of Adaptive, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer.

In addition to the funding he receives as a member of Dr. Landgren’s lab, Dr. Maura also has received funding support from The Society of Memorial Sloan Kettering.

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Targeted Drug Shows Promise Against HER2-Positive Breast Cancer That Stops Responding to Other Drugs

Source: Memorial Sloan Kettering - On Cancer
Date: 12/11/2019
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About 15 to 20% of breast cancer that has spread (metastatic cancer) is driven by a protein called HER2. Drugs that target HER2 are a critical tool for bringing this form of the disease under control. Unfortunately, most cancers eventually stop responding to HER2 drugs and begin growing again. Because of this, many breast cancer experts are focused on developing new ways to target HER2.

At this year’s San Antonio Breast Cancer Symposium, which is being held December 10 to 14, Memorial Sloan Kettering medical oncologist Shanu Modi was part of a multicenter group that presented findings from a phase II clinical trial of an experimental drug targeted at HER2-positive metastatic breast cancer. Dr. Modi is also the lead author of a paper detailing the results from the trial, which was published December 11 in the New England Journal of Medicine. The drug is called trastuzumab deruxtecan or DS-8201a.

“There are already two great options for treating HER2-positive metastatic breast cancer, and these existing drugs can provide people with months or years of controlled disease,” Dr. Modi explains. “But once they stop working, there is no standard approach. Therefore, there is a lot of excitement around new HER2-targeting drugs.”

Delivering a Potent Dose of Chemotherapy

DS-8201a is a type of medication called an antibody-drug conjugate. It consists of two parts: an antibody called trastuzumab attached to chemotherapy. The trastuzumab antibody is designed to seek out the HER2 protein. When it finds it, it delivers its payload of chemotherapy directly to the tumor, sparing healthy tissue.

DS-8201a is not the first antibody drug-conjugate developed for breast cancer. A drug called ado-trastuzumab emtansine (Kadcyla®) works in the same way but carries a different chemotherapy drug. That drug was approved by the US Food and Drug Administration for metastatic breast cancer in 2013. Antibody drug-conjugates are used to treat other types of cancer as well, especially blood cancers.

“DS-8201a appears to work in people who have stopped responding to ado-trastuzumab emtansine,” Dr. Modi says. “One reason why is that DS-8201a has twice as many molecules of chemotherapy linked to each antibody. Additionally, the chemotherapy that’s attached has some unique properties that make it very effective.”

Another Approach for a Challenging Disease

In the phase II study, called the DESTINY01 trial, 184 patients received DS-8201a by IV every three weeks. The participants had previously received trastuzumab and ado-trastuzumab emtansine but had stopped responding to them. More than 60% of the patients responded to DS-8201a. That means their tumors either shrank or stopped growing.

The average time from when patients received the drug until the tumors started growing again was about 16 months. Although there was no direct comparison to other therapies in this trial, these results are much better than the responses seen with other treatments given at this stage of treatment, usually chemotherapy, Dr. Modi explains.

The common side effects from the drug were nausea and lowered blood counts, and these were easily managed with medication. However, a small number of people in the trial had a severe response: They developed a condition called interstitial lung disease, which means their lungs developed scarring, leading to difficulty breathing. This risk was first noted in the phase I trial.There is a lot of excitement around new HER2-targeting drugs.Shanu Modimedical oncologist

In this phase II study, because the doctors knew that this could occur, patients were monitored very carefully. Anyone who developed lung problems or other severe side effects was taken off the drug. However, four people in the phase II trial died from interstitial lung disease.

Based on the findings from this trial, three large, multicenter phase III trials are already underway. Two of them are open at MSK, including one trial for people with lower levels of HER2. Dr. Modi expects MSK to be one of the main hospitals to recruit people for the trial.

“This disease is so challenging to treat, and the responses we’ve seen so far are amazing,” she concludes. “I felt good every time I was able to enroll one of my patients in this trial.”

This study was funded by Daiichi Sankyo, the company that developed DS-8201a. Daiichi Sankyo and AstraZeneca were collaborators on the study.

Dr. Modi has consulted for or served on the advisory boards of Genentech, Carrick Therapeutics, MacroGenics, Puma, GlaxoSmithKline, Novartis, AstraZeneca, Seattle Genetics, and Eli Lilly. She has served on the Genentech Speakers Bureau. She has also received compensation from Daiichi Sankyo for advisory services.

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Peering at Biological Molecules: A Conversation with Structural Biology Chair Christopher Lima

Source: Memorial Sloan Kettering - On Cancer
Date: 12/23/2019
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In June 2019, Christopher Lima was named Chair of the Sloan Kettering Institute’s Structural Biology Program. Dr. Lima replaced Nikola Pavletich, who had led the program since its creation in 2003 and who still has a lab in SKI. In addition to his new role, Dr. Lima is a Howard Hughes Medical Institute investigator and a faculty member in the Gerstner Sloan Kettering Graduate School of Biomedical Sciences.

We spoke with Dr. Lima about his research and his plans for the program. He also talked about the roles of technology and collaboration in advancing the field of structural biology.

What is structural biology?

Structural biology illuminates the function of important biological molecules through the study of their shape or architecture. What that means is being able to see at atomic or near-atomic resolution exactly how different molecules interact and activate or inhibit one another. It gives us a deep understanding of the mechanisms that are going on inside cells at the most basic level.

Inspiration on what to study can come from many areas. We may look at molecules that we know are essential for a fundamental process, like cell division. Or we may prioritize structural studies of gene products that we know are important because they are mutated in a disease or are targets of a drug.

What do you do in your lab?

We study pathways that are important for how RNA gets metabolized. There are many types of RNA, with some providing templates for translating genes into proteins. In addition, we study how proteins are modified after they get made, through a process called ubiquitination. We also use biochemistry to study these processes in test tubes.

We’ve been focused on these pathways for years because they are essential for life. Recently we’ve learned that several of the gene products that we work on may also be important for cancer. MSK-IMPACT™ is a test that looks for genetic changes in tumors. When that test was developed, DIS3, ZCCHC8-ROS1, and XPO1 were among the genes identified as being mutated or altered in cancers. Having already studied these genes puts us in a better position to understand what they do and whether they might be a good target for intervention.

There was a lot of excitement when SKI got a cryo-electron microscope (cryoEM) about three years ago. How has that instrument changed structural biology research here?

X-ray crystallography, which is an alternative technique, requires us to crystallize molecules into a single shape or structure before we can study them. What’s great about cryoEM is that it allows us to study mixed samples that exist in multiple shapes or states at the same time. That’s extremely powerful. CryoEM also helps us study very large molecules or complexes that are sometimes difficult to crystallize.

At the same time, X-ray crystallography is still a valuable tool. It typically gives us higher resolution than cryoEM, albeit on smaller systems. This allows us to focus on the parts we’re particularly interested in studying in much greater detail.

Can you give an example of how the two technologies work together?

Let’s say we have an enzyme that’s important for a certain cellular function and we want to learn where a drug binds to it. CryoEM may be able to show us which part of the enzyme to focus on, but if we want to redesign the drug and make it more potent, we need to know every single point of contact between the drug and the enzyme in the active site. Depending on the problem, X-ray crystallography can often get to that level of resolution.

What’s unique about doing structural biology research at SKI?

It’s part of our mission to do innovative basic science. I would put SKI on par with some of the very best research universities in the world. We often collaborate with investigators in other parts of MSK as well as at other institutions.

SKI is populated by people who have a fundamental interest in discovering the systems and pathways that matter most in biology. If those pathways turn out to be relevant for disease, which is sometimes the case, it then opens up a world of possibilities for the translational and clinical research that’s also going on here.

What are your plans for the Structural Biology Program?

When I was a grad student, structural biologists had to pick a particular technique to focus on, whether that was X-ray crystallography or something else. Today, we take a hybrid approach to determining how biological pathways work. As such, we hope to recruit multidisciplinary scientists who define themselves not by the method they use but by the biological problem they’re focused on.

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Understanding Biology’s Blueprint: 8 Questions with Kat Hadjantonakis

Source: Memorial Sloan Kettering - On Cancer
Date: 12/30/2019
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Earlier this year, Anna-Katerina “Kat” Hadjantonakis was named Chair of the Sloan Kettering Institute’s Developmental Biology Program. She succeeded Kathryn Anderson, who had led the program since it launched in 2003.

We spoke with Dr. Hadjantonakis about the field of developmental biology and how she got interested in this area of research.

What is developmental biology, and what does it have to do with cancer?

Developmental biologists study the genes, proteins, and other biological phenomena that control how cells multiply, change their identity, and reorganize themselves to give rise to different tissues and organs. This provides a blueprint to understand how our bodies form.

Cancer happens when normal developmental processes go awry. To learn how to fix them, you first need to know how they’re supposed to work.

What is the focus of your research?

My lab uses primarily mammalian models to learn how cells know what to become and how groups of these cells generate the blueprints of organs. We study tissue called the endoderm, which becomes organs, including the lungs, liver, and pancreas. We study how endodermal cells give rise to distinct organs with different functions.

Did you always know you wanted to be a scientist?

I went to school in the UK, and the education system requires that you narrow down your interests early. I excelled at biology and math, so I decided to go in that direction. I also excelled at fine art, especially photography, but sadly was unable to pursue that interest in parallel. I’m dyslexic and have always been better with processing images than words. I did my undergraduate and PhD degrees at Imperial College London. I’ve now come full circle because my lab uses a lot of microscopy, an adaptation of photography.

What led you to MSK?

When I was a postdoc at Columbia University, I met Kathryn at a meeting on mouse genetics. She told me MSK was creating the Developmental Biology Program and that I should consider applying. I was the first person hired after the program started.

Now that you’re Chair of the program, what are your plans for it?

Our first goal is to recruit three or four junior faculty members who will be leaders in their fields. We want people who work on the cutting edge of research, address important unsolved problems, and are collaborative and good institutional citizens. Kathryn is a true role model, and it’s fabulous that she’s staying on as faculty. I have some big shoes to fill.

Where in the UK did you grow up?

I grew up in London, but both of my parents were Greek. Even though I sound British, I have a long, unpronounceable Greek name. Growing up, I used to visit Greece every summer. I speak Greek, but with a British accent.

Do you still make art?

I don’t have time to practice art, but I live in the Chelsea neighborhood, the nexus of many art galleries. So I try to take advantage of those cultural opportunities.

What are your other hobbies?

Listening to music. I used to have a subscription to the Metropolitan Opera, but I relinquished it. Their performances started too early. My schedule is unpredictable, and I often failed to make it across town in time after work.

I cycle as much as I can. I see it as an efficient mode of transport and a decent form of exercise — a surrogate for not getting to the gym as often as perhaps I should! I ride a Citi Bike to work, weather permitting. When I first came to New York, I was petrified to ride here. I used to cycle in London and in Toronto, where I trained. The city has done a lot with building bike lanes and raising awareness of cyclists. I’m now brave enough to venture onto the streets.