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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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How Stem Cells Decide Their Fate

Source: Memorial Sloan Kettering - On Cancer
Date: 08/13/2019
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Stem cells are defined by their ability to differentiate into other, more specialized cell types. When one stem cell divides into two (which are then called daughter cells), three things can happen to the new cells: Both cells can continue being stem cells, both cells can differentiate into a new cell type, or the cells can go their separate ways, with one maintaining the properties of a stem cell and the other becoming something new.

“It may be surprising, but as much as stem cells have been studied, we don’t know much about how they make this commitment when they divide,” says Michael Kharas, who is in the Sloan Kettering Institute’s Molecular Pharmacology Program. Dr. Kharas led a team from SKI, in collaboration with investigators at Weill Cornell Medical College, that discovered new details about how dividing stem cells choose what to become. Their findings were published August 13 in Cell Reports.

Dr. Kharas’s lab uses human and mouse blood (hematopoietic) stem cells to study how certain types of leukemia develop.

Knocking Out an Important Protein

When both daughter cells are the same cell type, this is called symmetric division. That’s true whether they continue being stem cells or become something new. When one cell stays a stem cell and the other differentiates, it’s called asymmetric division. This happens about 30 percent of the time.

“The beauty of asymmetric division is that you’re maintaining your stem cell numbers,” Dr. Kharas explains. “If every time a stem cell divides, it loses its identity as a stem cell, you will eventually deplete all the stem cells. But if all the cells remain stem cells, you’ll never get the variety of cell types you need to form an entire blood system.”

Previous work in the Kharas lab has focused on a protein called MUSASHI-2. The researchers found that when MUSASHI-2 is knocked out in blood stem cells, the cells lose their “stemness.” They are more likely to differentiate and become nonstem cells. Additionally, they have less of the asymmetric type of division.Targeting RNA-binding proteins has been identified as a new approach in the development of drugs for leukemia.

In the new study, the investigators — led by first authors Yuanming Cheng and Hanzhi Luo, of Dr. Kharas’s lab, and Franco Izzo from Weill Cornell — focused on a different protein: METTL3. Both MUSASHI-2 and METTL3 are RNA-binding proteins, but the METTL3 protein is the key enzyme that can add chemicals called methyl groups to specific RNA nucleotides. This process is called methylation, and it decorates RNA with marks called m6A. 

Ultimately, this helps regulate the stability of the RNAs and the efficiency of protein production. Targeting RNA-binding proteins has been identified as a new approach in the development of drugs for leukemia.

Taking a Closer Look at Stem Cells

To study the role of m6A, the researchers compared the blood-forming systems of mice that had METTL3 knocked out and those that did not, to see how blood development was affected. They found that the mice without the protein seemed to have an accumulation of blood stem cells, suggesting that the cells were unable to become more specialized cells. 

To get a better look at what was going on, the lab of Dan Landau at Weill Cornell studied the cells with a type of analysis called single-cell RNA sequencing (RNA seq). RNA seq enables researchers to determine which genes are being expressed, or turned on, in cells. This revealed that there were actually fewer stem cells than originally thought. But some of the cells seemed to be stuck in an intermediate state between stem cell and differentiated cell that the scientists had never seen before.

“These stem cells had reduced ability to symmetrically differentiate. Based on these findings, we believe that METTL3 — and therefore, RNA methylation — controls this specific type of division in hematopoietic stem cells,” Dr. Kharas notes. “This research suggests a general mechanism for RNA methylation in controlling how stem cells regulate their fate when they divide.”

Implications for Cancer Treatment and Beyond

Dr. Kharas explains that there are two main implications for this new finding.

Many researchers and pharmaceutical companies are focused on developing new leukemia drugs that target the RNA methylation process. “It’s important to know how these drugs might work and what unintended consequences they may have,” he says.

But perhaps more interesting to the researchers who worked on the project are the implications for understanding the division and differentiation of hematopoietic stem cells.

“Now that we have identified this new population of cells in our lab, we may be able to use them as a model to understand the intricate steps that happen when a stem cell decides to differentiate,” Dr. Kharas concludes. “It may eventually provide a new approach for growing large numbers of stem cells for the development of cell therapies.”

Dr. Kharas is a scholar of the Leukemia and Lymphoma Society. The MSK team was funded by a National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Career Development Award, an NIH/NIDDK grant (R01-DK101989-01A1), an NIH/National Cancer Institute grant (1R01CA193842-01), a Kimmel Scholar Award from the Sidney Kimmel Foundation, a V Scholar grant from the V Foundation for Cancer Research, a Geoffrey Beene Award from the Geoffrey Beene Cancer Research Center at MSK, an Alex’s Lemonade Stand ‘A’ Award Grant, and funding from the Starr Cancer Consortium. Dr. Luo is supported by a New York State Stem Cell Science training award. The Weill Cornell team received funding from a Burroughs Wellcome Fund Career Award for Medical Scientists, an American Society of Hematology Scholar Award, and the Leukemia and Lymphoma Society Translational Research Program.

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

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

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

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

Homing in on the Vitamin B6 Pathway

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

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

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

Effects on Fast-Growing Cells

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

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

Looking for Combination Approaches

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

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

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

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Unique Genetic Change Found in Rare Ovarian Tumor Could Spare Patients from Unnecessary Treatment

Source: Memorial Sloan Kettering - On Cancer
Date: 01/27/2020
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As research has revealed more about the genomics of cancer, it’s changed the way that doctors think about the disease. There is not a single type of breast tumor or colon tumor, for example, but many variations of each kind of cancer. The differences are in tumors’ appearance under a microscope, their molecular signatures, and distinct changes that drive their growth.

This variety is also found with ovarian tumors. There are many types, and not all behave or respond to treatment in the same way. For a rare ovarian tumor called sclerosing stromal tumor (SST), the situation is even more complicated. SST is not a cancer but a benign tumor that can be misdiagnosed as cancer.

“If a woman with SST is misdiagnosed as having ovarian cancer, she would likely be given more-aggressive treatments that she wouldn’t need,” says Britta Weigelt, a Memorial Sloan Kettering research scientist and senior author of a study published January 2 in Nature Communications. “Although these tumors can cause a lot of pain and other symptoms, they can be successfully treated with surgery alone because they do not spread.”

The Rarest of Rare Tumors

In the study, the investigators reported that they had identified a unique molecular change in SSTs. This allows for the accurate diagnosis of this tumor. They also say that some of the biological insights learned may be applicable to other kinds of tumors.

SSTs make up about 5% of an already rare type of ovarian tumor called sex cord-stromal tumor. Most of these tumors, which can also grow in the testes, are cancerous. Despite how uncommon SSTs are, the researchers from MSK and their colleagues at Massachusetts General Hospital in Boston, as well as collaborators from outside the United States, were able to obtain 26 samples that were confirmed to be this type of tumor. “This was, by a wide margin, the largest collection of these tumors ever studied with genetic approaches,” says Sarah Kim, the first author of the study and a fellow in Dr. Weigelt’s lab. “I completed four years of residency, and I never saw a single patient with it. There’s a lack of familiarity with SST in the medical community.”

Of Ovarian Tumors and Hedgehogs

The type of change that drives SST is called a fusion gene. Fusion genes occur when part of a chromosome breaks off and attaches to another part of a chromosome, linking two genes that are not normally linked. Fusion genes are found most commonly in pediatric tumors, especially sarcomas and blood cancers. Similarly, SST also affects younger women — usually in their 20s or 30s.

In SST, one of the genes involved in the fusion is called FHL2. The other gene is called GLI2. FHL2 is a gene that’s naturally expressed at high levels in ovarian tissue. When it fuses to GLI2, it drives the production of a tumor-causing protein.

In the Nature Communications study, 21 of the 26 samples tested had GLI2 fusion genes. The investigators reviewed data for more than 9,000 tumors in a large database and didn’t find any other instances of a FHL2-GLI2 fusion gene, confirming that this fusion is unique to SST.

Further research uncovered that the protein created from the fusion is involved in the Sonic hedgehog pathway. This signaling pathway is important for embryonic development. It has also been implicated in cancer, especially certain brain tumors and basal cell skin cancers. When the researchers tested drugs that target the Sonic hedgehog pathway in SST cell models in a dish, the cells responded, confirming that this pathway was driving cell growth.

“We started this project because SST is a clinical conundrum,” Dr. Kim says. “These findings will make things easier for both doctors and patients, by making it simpler to identify this rare tumor.”

“This study also provides new biological clues about Sonic hedgehog and its role in cancer,” Dr. Weigelt says. “We hope that it may help in the understanding of other tumors that pose diagnostic and clinical challenges.”

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A Decade of Progress in Cancer Care, and What’s Next

Source: Memorial Sloan Kettering - On Cancer
Date: 02/04/2020
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In January, the American Cancer Society reported that the rate of cancer deaths in the United States had fallen 2.2% from 2016 to 2017. This was the largest single-year decline in cancer mortality ever reported.

Many factors have contributed to the continuing decline in cancer deaths. The reduction in the number of people who smoke is chief among them. But advances in diagnosis and treatment, especially those made during the past ten years, have also played a significant role. Experts anticipate that, with further advances in research, cancer survival will continue to improve over the next decade and beyond.

In an interview, Larry Norton, a medical oncologist and Senior Vice President at Memorial Sloan Kettering, talked about some of the biggest achievements in cancer care made between 2010 and 2019, and what he hopes to see next.

Immunotherapy

By any estimate, immunotherapy has been the past decade’s most noteworthy advance in cancer medicine. It was one of the earliest attempts regarding the nonsurgical treatment of cancer. Making it effective, though, has taken more than 100 years, coming into its own only in the 2010s.

The field dramatically accelerated in 2011 with the US Food and Drug Administration’s approval of ipilimumab (Yervoy®) for melanoma. This drug, in a class called immune checkpoint inhibitors, was based on research conducted by immunologist James Allison and developed in clinical trials with the help of MSK physician-scientists. Dr. Allison, who led the Sloan Kettering Institute’s Immunology Program from 2002 to 2012, won a Nobel Prize in 2018 for this pioneering work. Several other checkpoint inhibitor drugs followed. What these therapies have in common is that they take the brakes off the immune system, enabling it to destroy cancer.

“In addition to melanoma, these are some of the first new drugs to really have an impact on lung cancer,” Dr. Norton says. “They also have become very important for treating bladder cancer and other cancers.”

Chimeric antigen receptor (CAR) T cell therapy was another big leap forward in immunotherapy. In this approach, pioneered by MSK’s Michel Sadelain, scientists genetically engineer a patient’s own immune cells to make a new protein that can latch on to cancer. This turns those altered cells into powerful cancer fighters.

What’s Next?

Researchers are looking for ways to make immunotherapy drugs effective in more people and for more types of cancer. One approach that’s promising is using cancer vaccines and viruses to activate tumor cells and make them more visible to the immune system. These treatments are likely to be combined with checkpoint drugs and CAR T.

Targeted Therapies

Targeted therapies came into their own in the late 1990s and early 2000s, with the approval of drugs like trastuzumab (Herceptin®) and imatinib (Gleevec®). But in the 2010s, they became part of standard treatment for many more cancers. Dozens of new drugs were approved for both solid tumors and blood cancers. These therapies are designed to exploit weaknesses found primarily in cancer cells while sparing healthy tissue.

Thanks to studies called basket trials, researchers have learned that the same drug may work against many types of cancer if the tumors have the same genetic changes. One of the most striking examples of this pan-cancer approach is larotrectinib (Vitrakvi®), which the FDA approved in 2018.

Advances in targeted therapy for blood cancers, especially chronic lymphocytic leukemia, acute myeloid leukemia, and acute lymphocytic leukemia, have led to a number of drug approvals. These drugs have fewer side effects than traditional chemotherapy. Because of that, they can be given to people who are unable to tolerate more intense treatment because of their age or other health problems.

What’s Next?

Researchers are learning more about how tumors develop resistance to targeted drugs. In addition, they’re studying the role of tumor heterogeneity, which allows some tumor cells to escape the effect of these drugs.

According to Dr. Norton, another exciting area of research is tackling the noncancerous cells that surround tumors, called the tumor microenvironment. “Some of these cells stimulate cancer growth, and we can also go after them with drugs,” he says. “To paraphrase a Zen koan: Targeting only the tumor is like trying to clap with one hand. You may have to hit both sides of the equation to really make a difference.”

Molecular Diagnostics

With the development of tests like MSK-IMPACT™, launched in 2014, and MSK-ACCESS, launched in 2019, doctors now have the ability to look for hundreds of cancer-causing mutations across of range of tumor types with a single test. As of the end of January 2020, more than 50,000 tumors from more than 43,000 patients have been analyzed with MSK-IMPACT. More recently, MSK-ACCESS has enabled doctors to study tumors using a blood test called a liquid biopsy rather than having to do a more complicated tissue biopsy.

What’s Next?

Molecular diagnostics looks for a number of changes in cells. These might include chromosomal gains and losses, changes in gene copy numbers, structural rearrangements, and broader mutational signatures. Analysis of messenger RNA (the genetic material that carries information from DNA to a cell’s protein-making machinery) is becoming an important diagnostic tool, too.

Unlike other genetic tests, MSK-IMPACT and MSK-ACCESS look for mutations in a person’s normal tissue for comparison. This bonus analysis is revealing new clues about which cancers are inherited.

Diagnostic tests that include normal tissue are also uncovering more details about clonal hematopoiesis (CH). This age-related condition leads to an increased number of white blood cells that carry cancer-causing mutations. CH is not cancer, but people who have it have an increased risk of cancer. “We’re learning more and more about the role that CH cells play in relation to many kinds of cancer, not just blood cancers,” Dr. Norton says.

Screening and Early Detection

In the 2010s, large studies confirmed the benefits of many screening tests, such as colonoscopies for colon and rectal cancer and low-dose CT scans for people at an increased risk of lung cancer because of their smoking history. There have been a number of advances in mammograms and other types of breast screening as well. For example, MRIs can be used to classify a woman’s risk of developing breast cancer.

What’s Next?

Dr. Norton says that the personalization of cancer screening will play a big role over the next decade. “Not everyone needs to have the same level of monitoring,” he notes.

MSK’s Precision Interception and Prevention program combines the principles of precision medicine with research on prevention and early detection. The goal of this approach is to prevent cancer from occurring or stop it at the earliest stages, when it’s easier to treat.

Surgery

Over the past ten years, minimally invasive and robotic surgeries have become standard for more and more cancers. For many cancer types, studies have confirmed that these surgeries are just as effective as open surgeries at controlling disease but with less pain and quicker recovery. 

“Many of these surgical techniques have been advanced at MSK’s Josie Robertson Surgery Center,” Dr. Norton says. The center, which opened in 2016, enables surgeons to perform outpatient procedures in a state-of-the-art setting. More than half of the 20,000 surgeries done at MSK every year are now done on an outpatient basis.

What’s Next?

Although surgery will continue to be an important part of cancer care, Dr. Norton says that continuing advances in other treatments will enable some people to avoid surgery entirely. “For some people with breast cancer, drug therapies and radiation are becoming so effective that we might want to do research looking at whether they might not need surgery or will need only minimally invasive surgery,” he says.

Radiation Therapy

In radiation therapy, one of the important tenets over the past decade has been “less is more.” Advances like intensity-modulated radiation therapy and image-guided radiation therapy use computer programs and advanced imaging to deliver stronger doses of radiation while sparing healthy tissue. Oftentimes, fewer radiation treatments are needed to achieve the same benefits. There have also been advances in identifying which tumors can be effectively controlled with less radiation overall, which reduces side effects.

What’s Next?

In 2019, the New York Proton Center opened in East Harlem. The center aims to provide treatment and to conduct clinical trials comparing proton therapy to other types of radiation. Proton therapy is already in use, especially for head and neck cancers and pediatric tumors. Experts expect it to become more widely used in the 2020s.

Pediatric Cancer

Survivorship rates for pediatric cancers continued to improve in the 2010s. About 80% of children with cancer can now be cured with available treatments. For the remaining 20%, there has been an increased focus on personalized medicine.

All children treated at MSK Kids receive testing with MSK-IMPACT. And clinical trials developed by MSK’s Early Drug Development Service can now include children as young as 12. For children with very rare mutations, protocols for single-patient use (SPU) can provide lifesaving treatment.

What’s Next?

Initiatives like MSK’s Pediatric Translational Medicine Program and the Expanded Genomics Program aim to make personalized medicine an option for more children with cancer. And when investigators conduct SPUs, they collect data to learn how and why certain drugs work or don’t. These findings can lead to future trials.

Supportive Care and the Patient Experience

Research reported in 2017 confirmed that systematic monitoring of patient-reported symptoms during chemotherapy improves survival outcomes. Patient input and the patient experience are now incorporated into the design of clinical trials. These measures empower patients to actively report their symptoms. Doctors and nurses are then able to intervene early, ultimately improving patients’ quality of life as well as survival rates.

What’s Next?

Investigators at MSK are continuing to focus on the influence of nutrition, integrative medicine, and exercise in improving patients’ well-being during and after treatment — as well as their cancer outcomes. Digital health and telemedicine are another exciting frontier in cancer management and research, Dr. Norton says. Clinical trials already underway aim to look for measurable benefits from these interventions.

Many of the advances in cancer treatment and diagnosis seen over the past ten years are possible thanks to funding from donors, Dr. Norton explains. “You can make progress with philanthropic support that you can’t accomplish any other way,” he says. “It gives researchers freedom to be creative in a way that no other type of funding makes possible.”