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What Can Be Learned from a Negative Clinical Trial? Findings from a Sarcoma Study at ASCO 2019

Source: Memorial Sloan Kettering - On Cancer
Date: 06/02/2019
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At this year’s American Society of Clinical Oncology (ASCO) annual meeting, researchers from around the world have gathered to learn about the latest advances in cancer treatment. Much of the research being discussed highlights meaningful improvements in cancer care. At least one study, however, is attracting a lot of attention despite disappointing results.

That study, for advanced soft-tissue sarcoma, was called the ANNOUNCE trial. ANNOUNCE was a randomized study that compared a combination treatment of the chemotherapy drug doxorubicin and the targeted drug olaratumab (Lartruvo®) to doxorubicin on its own. The trial found that adding olaratumab to chemotherapy did not increase survival.

Based on an earlier report from this phase III study, Eli Lilly, the company that makes olaratumab, announced in April 2019 that it is withdrawing the drug from the market.

Memorial Sloan Kettering sarcoma expert William Tap led the ANNOUNCE trial as well as earlier studies on olaratumab. In an interview, he talked about why the findings from the study were disappointing and what’s next for sarcoma treatment.

What was MSK’s role in the research that led to olaratumab’s approval?

We led the phase II trial, which was published in June 2016. That study included 133 people with many subtypes of sarcoma. The participants were randomized to receive either olaratumab and doxorubicin or doxorubicin alone. All of the participants had advanced disease that had spread beyond the original tumor.

The average survival of people who got the combination was 26.5 months, compared with 14.7 months for those who got standard treatment, which was doxorubicin alone. Sarcoma is very hard to treat, and there are few good options once it has spread and can no longer be eliminated with surgery. The findings that olaratumab extended life for nearly a year were remarkable. We felt very hopeful based on those results.

The drug was given accelerated approval from the US Food and Drug Administration in October 2016 based on that study’s impressive results and the unmet need for sarcoma treatments. It also received conditional approval in Europe.

What are you presenting at ASCO this year?

These are the results from the follow-up phase III trial. The FDA required this study to confirm the benefit seen in the earlier trial. Unlike the earlier study, this one unfortunately was negative. Overall survival, which is how long someone lives after starting treatment, was not statistically higher in the group that got olaratumab.

Nearly three-quarters of new cancer drugs fail in phase III trials. But it’s much more unusual for a drug to fail a phase III trial after receiving accelerated or conditional approval.

Those of us in the sarcoma research community are still trying to understand why we saw such different results between the two trials. There are a lot of possibilities. It may be differences in the way the two studies were designed. It could also be the types of patients who were enrolled in the studies and the specific subtypes of disease that they had.

One thing that’s important to mention is that olaratumab didn’t add any serious side effects, compared with chemotherapy alone.

What did you learn from this study?

Sarcoma is a rare disease, and anytime you’re able to collect this much data on a rare disease, it’s going to be useful. There are not many large, multicenter studies on sarcoma. What we’ve learned will be helpful in our overall understanding of this disease. It will also help us design other clinical trials in the future.

One remarkable outcome was that the survival in the control group, those who got only doxorubicin, was higher than what we’ve ever seen in any other phase III clinical trial. Many of these patients did quite well, even without receiving any benefit from olaratumab. This is the third time in the past five years where a negative phase III study has shown such measurable improvements in the control arm compared with historical outcomes.

There are likely several reasons that these patients did so much better than expected. We think it’s because of overall advances in the way this disease is treated — including progress in surgery, radiation, and supportive care. There have also been improvements in treating particular subtypes as we increase our understanding of what drives them.

I can’t overstate the exceptional effort from everyone who worked on the phase II and phase III trials. For this trial, we were able to enroll and care for 509 participants at 110 hospitals in 25 countries.

Eli Lilly announced in April that it was removing olaratumab from the market. What will happen to people who are already taking the drug?

At MSK, we are not recommending that anyone start taking the drug. For those who are already taking it, we are phasing out that treatment.

There are some patients who perceive that the drug is helping them. It’s possible it is, since sarcoma is a heterogeneous disease and not all tumors behave the same way. But we don’t yet have enough insight to know which subtypes or disease characteristics may respond to olaratumab.

The drug company is working with people who have been taking the drug and, in some circumstances, will continue to provide it. The details are still being determined.

What else should people know about this research?

This shows the complexity of researching a disease like sarcoma, which is actually not one cancer but about 50 or 60 diseases. Each sarcoma has its own biology. It’s important for us to continue studying all these different types so that we can develop more-effective, personalized therapies.

I’m worried that what happened with olaratumab will negatively impact the development of other sarcoma drugs. Because sarcoma is less common than many other cancers, it’s already hard to get funding for it. Treatment is getting better, as our results for patients in the control group showed, but there is still a great need to find better drugs.

This is just the nature of science sometimes. There is no reason to give up hope.

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Ro Versus Musashi: How One Molecule Can Turn Cancer Cells Back to Normal

Source: Memorial Sloan Kettering - On Cancer
Date: 06/19/2019
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Since 2012, Memorial Sloan Kettering cancer biologist Michael Kharas has focused on studying a family of proteins called Musashi. These proteins play a role in acute myeloid leukemia (AML) as well as in many solid tumors, including colorectal, breast, lung, and pancreatic cancers. Musashi proteins function by binding to messenger RNAs. These molecules serve as a template for making proteins.

On June 19, 2019, in Nature Communications, Dr. Kharas’s team reported that they have identified a molecule that appears to block the function of Musashi-2. This protein plays a role in making cancer grow and spread. The compound appears to eliminate tumor cells in human cancer cell lines and in mice.

“This research provides a strategy for how to develop inhibitors for RNA-binding proteins,” says Dr. Kharas, who is in the Sloan Kettering Institute’s Molecular Pharmacology Program. “Historically, it’s been difficult to develop inhibitors to proteins that bind to RNA because of their challenging structural properties.

“We don’t think this particular compound will ultimately make it into clinical trials,” he adds, “but we now have a road map to guide us in future drug development.”

Turning Cancer Cells Back to Normal

This latest work builds on earlier research from Dr. Kharas’s lab, in which the investigators started with more than 150,000 molecules that could potentially block Musashi-2. They then developed a number of tests that could rapidly look for effective molecules in an automated way. Eventually, they settled on a molecule called Ro 08-2750, or just Ro for short.

In the current study, the team used structural biology to look at where Ro binds to Musashi-2. “Based on this research, we have an idea of where to start in designing additional molecules that could be used as drugs,” Dr. Kharas says. “We know the binding region and how the drug fits.”

Researchers know that Musashi-2 plays a role in how aggressive cancer is. The protein is present in more than 70% of people with AML. Solid tumors that contain a high level of the protein are more likely to grow, spread, and resist treatment. It appears that Musashi-2 allows cancer cells to continue growing and resist signals to die.

“Musashi-2 is required for cancer stem cells to survive,” Dr. Kharas explains. Cancer stem cells are cancer cells that have the ability to give rise to all types of cells within a tumor. “When Ro was added to AML cells in a dish, the cells became normal. They stopped growing and died.” The same effects were observed in mice that had AML

A Cooperative Effort among Several Labs

This research was possible due to collaboration among many different experts at MSK. The project was overseen by Gerard Minuesa, a postdoctoral researcher in Dr. Kharas’s lab.

SKI computational chemist John Chodera, SKI structural biologist Dinshaw Patel, and Yehuda Goldgur, Head of MSK’s X-Ray Crystallography Core Facility, helped determine the structure of the Musashi-2 protein and how Ro binds to it. SKI computational biologist Christina Leslie helped with the gene expression data generated from this research.

“Thanks to this study, we’ve shown that it’s possible to develop drugs for these difficult targets,” Dr. Kharas concludes. “It provides a path forward for future work, so we can eventually develop drugs that can be tested in clinical trials in people with cancer.”

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Research Clarifies How IDH Mutations Cause Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 07/01/2019
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A family of genes called IDH are associated with cancer. These genes make enzymes called isocitrate dehydrogenases. The enzymes help break down nutrients and generate energy for cells. Mutations in IDH genes prevent cells from differentiating, or specializing, into the kind of cells they are ultimately supposed to become.

When cells can’t differentiate properly, they may begin to grow out of control. Scientists are still learning about what controls this process.

Now a team of researchers working in the lab of Memorial Sloan Kettering President and CEO Craig Thompson have made discoveries about how this malfunction occurs, at least in test tubes. Although the work is still in an early stage, they hope their findings will eventually contribute to new approaches for developing cancer drugs.

“Although IDH mutations are not very common overall, there are some diseases where these genetic changes contribute to a significant portion of cases,” says Juan-Manuel Schvartzman, a postdoctoral fellow in the Thompson lab, an instructor in the Gastrointestinal Oncology Service, and the first author of a paper recently published in the Proceedings of the National Academy of Sciences (PNAS). “For these subtypes of cancer, better targeted therapies are needed.”

IDH mutations are found in about one-quarter of people with acute myeloid leukemia (AML), the most common type of leukemia in adults. They may also be found in a type of bile duct cancer called cholangiocarcinoma, a bone cancer called chondrosarcoma, low-grade glioma, and some kinds of lymphoma. The mutations occur much less frequently in more common cancers, such as colon cancer, breast cancer, and lung cancer.

Deciphering Underlying Changes

To learn more about how IDH mutations block differentiation, the investigators studied them in the context of a well-characterized model: cells called fibroblasts that can be coaxed to become muscle cells. By figuring out how the mutations prevent muscle cells from forming properly, the team aimed to get at the underlying defects in cells that these mutations cause.

Earlier research showed that IDH mutations influence cells through epigenetic changes. Epigenetics involves changes in gene expression that do not cause changes in the DNA sequence. Many of these have to do with the way DNA is packaged in the nucleus of a cell. The strands are wrapped around spool-like proteins called histones. Small chemical groups attached to DNA and histones — including fragments called methyl groups — can affect how DNA is spooled. Ultimately, this can influence how and when genes get made into proteins.

Specifically, IDH mutations lead to the formation of a molecule called 2-hydroxyglutarate (2HG). This molecule, in turn, can block the removal of methyl groups.

In the PNAS paper, the investigators dove deeper into the specific epigenetic changes caused by IDH mutations. “What we found was that they didn’t have much to do with DNA methylation, which is what we previously thought,” Dr. Schvartzman says. “Instead, they were related to methylation on histones.”

This change affects how the DNA strands are wrapped around histones. When they are tightly wrapped, it can prevent certain regions of DNA from being accessible. This can affect which genes get made into proteins.

Expanding the Development of Drugs

There already are drugs that are approved to work in AML caused by IDH mutations. Ivosidenib (Tibsovo®) targets IDH1, and enasidenib (Idhifa®) targets IDH2. Both of these drugs prod cancer cells into differentiating normally. But investigators say that there are many more avenues to be explored for new drugs that work against IDH-mutant cancers.

“I’m very interested in looking not just at tumors that are IDH mutant but more broadly at how these cellular changes affect the ability of those cells to differentiate,” Dr. Schvartzman says. “In addition to the buildup of 2HG, there are other changes in the cell that may prevent methyl groups from being removed from histones. We want to study those as well.

“It’s a little early to talk about how this could be applied to new drugs,” he concludes. “But one thing that’s exciting is the ability to understand more about how cells are wired and how different cellular changes affect levels of methylation. There are many enzymes we can start to explore that could be interesting for new cancer drugs.”

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FDA Approves Pexidartinib, a Targeted Therapy for a Tumor of the Joints

Source: Memorial Sloan Kettering - On Cancer
Date: 08/05/2019
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On August 2, the US Food and Drug Administration announced that it had approved pexidartinib (TuralioTM) for certain people with tenosynovial giant cell tumor (TGCT). It is the first drug approved specifically to treat this rare tumor of the joints.

Memorial Sloan Kettering medical oncologist and sarcoma expert William Tap led the clinical trials for this drug. The results of a phase III study were published in June 2019 in The Lancet.

“For the right patient, this is a drug that can really help,” Dr. Tap says. “However, because of the potentially serious side effects, it’s important to consult with doctors who understand this disease and this drug.”

A Valuable Drug for a Debilitating Condition

TGCT, also called pigmented villonodular synovitis (PVNS), is not considered a cancer because it doesn’t spread to other parts of the body. But it is a condition that can be painful and debilitating. It most often affects the knees. The disease is most often treated with surgery. If it continues to come back, people with the condition may run out of treatment options.Tenosynovial giant cell tumor (TGCT) is also called pigmented villonodular synovitis (PVNS).

In the phase III study, which enrolled patients in the United States, Europe, and Australia, 120 people were randomized to receive either the drug or a placebo. After nearly six months, 39% of people who got the drug had a measurable response, meaning that their tumors got smaller. Many of those who responded to the drug had noticeable improvements in range of motion and a reduction in pain in the affected joint. No one who received a placebo had any measurable response.

The drug is a targeted therapy that works by blocking a protein called colony-stimulating factor 1 kinase. This protein drives the development and growth of these tumors.

Pexidartinib is approved for people who can no longer have surgery for their tumor, or who are trying to avoid amputation. Because the drug can cause liver damage, the FDA did not approve pexidartinib for people who can be treated surgically or if the tumor is not seriously affecting a person’s quality of life.For the right patient, this is a drug that can really help.William D. TapMedical oncologist

“Unfortunately, this drug can cause a specific type of liver toxicity called cholestatic hepatotoxicity,” Dr. Tap explains. “It’s exceedingly rare, but when it occurs, it can be very dangerous. It’s important that people who get the drug are treated somewhere where they can be closely monitored for liver problems.” He explains that for this reason, only certain pharmacies will be able to dispense the drug, and doctors will have to go through a certification process before they can prescribe it.Back to top 

Meaningful Improvements for a Neglected Condition

Despite the warnings, Dr. Tap says the approval of pexidartinib is an important breakthrough that can lead to meaningful improvements in many people’s lives.

“TGCT has been neglected by much of the medical community and the pharmaceutical industry for a long period of time,” he notes. “Even though it’s rare, it has a relatively high prevalence. This is because it tends to first affect people when they are in their 20s and 30s. If it can’t be successfully treated with surgery, they have to live with it for the rest of their lives. So there are a lot of people out there who are coping with this disease.”

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8 Questions with Valerie Rusch: Lung Cancer Surgeon Reflects on Advances and Providing Excellent Care

Valerie Rusch is Vice Chair for Clinical Research in the Department of Surgery at MSK. She is a thoracic surgeon who treats lung cancer and esophageal cancer, malignant pleural mesothelioma, and other tumors of the chest. She was the first woman named as a service chief and promoted to full Member in her department at MSK.

1. In October, you will become president of the American College of Surgeons. What does that entail?

The group is the world’s largest surgical organization. It represents 80,000 surgeons across all specialties, both nationally and internationally. Its mission is to improve care by setting high standards for surgical practice and education. I will be the college’s 100th president but only the fourth woman to hold the position. My role is to represent the organization at educational conferences around the world.

2. Did you always know you wanted to be a doctor?

My father was in the Navy Medical Corps during World War II and later became an otolaryngologist. This gave me some exposure to the medical world. In college, I worked as an operating room technician for two summers. My father’s family was Swiss, and a bilingual education was important, so I attended the Lycée Français in New York City. I considered multiple career paths, including being an interpreter, but ultimately was most attracted to medicine. I ended up going to medical school at the College of Physicians and Surgeons at Columbia University.

3. How do you cope with being a woman in a male-dominated field?

There have been challenges. But my father always said, “No one can argue with excellence.” Although I’ve certainly encountered instances of prejudice, I’ve focused on delivering excellent clinical care, helping my patients, and taking advantage of research opportunities to develop new treatments. It has been rewarding to see substantially more women in surgery and to see them increasingly accepted within the surgical community.

4. How did you get interested in thoracic surgery?

During my residency in general surgery at the University of Washington, I was exposed to many surgical subspecialties. I found that thoracic surgery provided a blend of technically challenging procedures and cognitive decision-making. I particularly appreciated the meaningful long-term relationships that develop during the care of people with cancer.

5. When did you come to MSK?

In 1989, I was recruited to travel to New York City and interview for a position at MSK. It came at the perfect time because I had recently decided to focus my career on cancer care. Thoracic surgeons do a lot of different things, including lung transplants, reconstruction after trauma, and treatment of benign diseases. Cancer was where I felt I could make the biggest difference.

6. How has treatment for lung cancer changed over time?

Minimally invasive surgical techniques have made recovery easier, and we can operate more safely on older patients due to advances in pre- and postoperative care. New radiotherapy techniques can help patients who cannot have surgery. Lung cancer screening with CT imaging has led to many more people being diagnosed with very early-stage tumors, when they may be cured by surgery or radiation therapy alone. And targeted therapies and immunotherapies have led to higher survival rates in people with more advanced lung cancers.

7. What is a challenge that remains?

One emotional challenge is the guilt that patients feel because the majority of these cancers are linked to smoking. They tend to hold themselves responsible for their disease. Also, smoking rates have declined in North America but remain high in many parts of the world.

8. How does MSK support people with lung cancer?

We have many medical and psychosocial resources for patients throughout their treatment and afterward. Now that many of our patients are living longer, survivorship care has become important. Subsequent primary lung cancer after successful treatment of an initial lung cancer is a significant risk. We developed the first lung cancer survivorship program nationally to provide lifelong follow-up, supportive care, and screening. It has become a significant part of our care.

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What Causes Leukemia after Breast Cancer? Research Shows That a Mutation May Be Present All Along

Source: Memorial Sloan Kettering - On Cancer
Date: 09/09/2019
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Doctors have known for a long time that cancer survivors may be at risk of a rare aftershock: developing a secondary leukemia years or even decades later. Because some chemotherapy drugs can damage the DNA in the bone marrow, where leukemia forms, experts have assumed that the drugs trigger the formation of cancerous blood cells that lead to leukemia.

A new study of people with breast cancer treated at Memorial Sloan Kettering is turning that idea on its head. The findings suggest that in some people, leukemia-causing gene mutations may be present in blood cells from the time that breast cancer is originally diagnosed, before chemotherapy is ever given. Although this discovery is important, the study looked at only a small group of patients, so larger studies are needed to confirm the findings.

“In the past, we’ve never been able to predict which breast cancer patients may be at risk for developing leukemia in the future,” says medical oncologist Elizabeth Comen, first author of the study published August 27 in the Journal of the National Cancer Institute (JNCI). “Our findings provide new clues about how and when these leukemias may originate. They also suggest that we may be able to identify who is at risk of developing leukemia, paving the way to prevent secondary leukemias.”

About 70% of secondary leukemias occur in people who have been treated for breast cancer. (The rest are in people treated for other types of cancer, mostly other solid tumors.) Around 0.5% of people treated for breast cancer eventually develop a secondary leukemia.

Searching for a Change in the Blood

The investigators focused on seven women treated for breast cancer at MSK who later developed a specific type of leukemia called acute myeloid leukemia. They studied the original tumor tissue that was removed at the time of surgery to look for signs of cancer in the blood. They focused on white blood cells, a component of the immune system, which are often present in the environment surrounding tumor cells.

“In four of the seven women who went on to develop leukemia, we could detect cancer-causing mutations in the immune cells that were removed with their original tumors,” says physician-scientist Ross Levine, senior author of the study. “Previous studies have reported cases in which leukemia mutations were observed years before people with solid tumors developed therapy-related leukemia. We were able to show that in many cases, secondary leukemia arises because preexisting altered blood cells are already there at the time of the first cancer.”

The changes observed in the immune cells are due to a phenomenon called clonal hematopoiesis (CH), which Dr. Levine studies. People with CH have an increased number of white blood cells that carry mutations that are also found in blood cancers. Some people with CH will go on to develop leukemia, although most do not.

“CH mutations are part of aging,” Dr. Comen says. “You can think of them like gray hairs or wrinkles but in the immune system.” Studies have suggested that between 10 and 20% of people over age 70 have signs of CH in their blood.

A Unique Collaboration

The JNCI study came about because of a unique collaboration among members of MSK’s Breast Medicine Service, Leukemia Service, and Department of Pathology. Physician-scientist Jorge Reis-Filho, Chief of the Experimental Pathology Service and an expert in uncovering detailed molecular information from archival tumor samples, was another co-author on the study.

Dr. Reis-Filho used a lab technique called laser capture microdissection (LCM) to separate immune cells from tumor cells within the tumor tissue. “This technology has been around for more than a decade,” he explains, “but this was the first time that we used this method to ask such an important clinical question and to define the clinical impact of mutations affecting immune cells.”

Although the mutations are present much earlier than previously known, the investigators don’t completely dismiss the role of chemotherapy in the development of leukemia. They believe that these drugs may make the environment for leukemia more hospitable and may help it grow and spread more effectively.

Next Steps for a Surprising Finding

Much more research needs to be done to validate these findings in a larger number of people. The investigators also plan to expand this work to look for the presence of immune cells with CH mutations in other types of solid tumors. Drs. Comen and Reis-Filho are currently developing new ways to look for these mutations that are less labor-intensive than LCM.

According to Dr. Levine, there are several long-term goals of this research. “Once we know who is at risk of developing leukemia, we can monitor them so we can catch the disease early. It’s also possible that these findings could influence the treatment that patients get for their initial cancer,” he says. “Ultimately, we hope this research will lead to ways to prevent or reverse the progression from CH to leukemia.”

These efforts are all part of a larger push in CH research across MSK under the Precision Interception and Prevention Program, which is led by Luis Diaz, Head of the Division of Solid Tumor Oncology.

“This study — of breakthrough potential — is a great example of the kind of science that can only be accomplished by a dedicated multidisciplinary team melding laboratory expertise and clinical insight,” says co-author Larry Norton, Senior Vice President in the Office of the President of MSK and Medical Director of the Evelyn H. Lauder Breast Center. 

“While this study provides key insight into how we may better predict who is at risk for a future leukemia, it is not cause for alarm. The risk of leukemia still remains exceptionally small for people with breast cancer,” Dr. Comen says. “Those who have specific concerns should speak to their doctors.”

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How an Altered Gatekeeping Protein Can Cause Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 09/16/2020
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Cancer is caused by gene mutations, but sometimes it’s hard to figure out which mutations actually drive tumor growth and which are just along for the ride. One way to determine this is to look for so-called mutational hot spots. These areas of the genome are mutated in tumors more frequently than would be expected by chance. The frequency suggests that they may play an active role in cancer.

MSK-IMPACTTM, Memorial Sloan Kettering’s diagnostic test that looks for genetic changes in more than 400 genes in patients’ tumors, has proven quite useful in the discovery of new hots pots. Researchers in the Human Oncology and Pathogenesis Program (HOPP) have used the identification of one particular hot spot to explain why a gene called XPO1 causes cancer. The findings were published online July 8 in Cancer Discovery.

“Researchers already knew that XPO1 regulates which proteins are located in a cell’s nucleus and which get moved to the cytoplasm. This is a basic function for any cell,” says senior author Omar Abdel-Wahab, a physician-scientist in HOPP. “But until now, nobody has ever shown how the alteration of the XPO1 protein could cause cancer. This study shows how this happens.”

Decoding the Function of an Important Protein

XPO1 is often mutated in blood cancers — especially many types of lymphoma. XPO1 mutations are also found in some solid tumors. A drug that targets these mutations, called selinexor (Xpovio®), was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma. It is being tested in clinical trials for other cancers at several institutions, including MSK. But researchers weren’t sure which patients were most likely to respond to the drug.

An analysis of MSK-IMPACT data led by study co-author Barry Taylor, a computational oncologist and Associate Director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, suggested that a specific mutation in XPO1, called E571, was common in cancer. To study the function of that particular mutation, Dr. Abdel-Wahab’s team put a version of the gene with the E571 mutation into mice. The mice developed cancer at a high rate. The researchers then did additional studies in the mice and in human cancer cells to find out how the mutation causes cancer.

“We found that the mutant form of XPO1 promoted excessive cell growth,” says first author Justin Taylor, an MSK medical oncologist and member of Dr. Abdel-Wahab’s lab. “Further analysis showed that this occurs because of XPO1’s role as a gatekeeper that regulates which proteins can exit the nucleus.” The researchers found that mutations affect the function of this gate, changing which proteins stay in the nucleus and which leave and go to the cytoplasm.

Dr. Taylor adds that the research also revealed why the drug is effective. “The mutation changes the electrical charge of the XPO1 protein, which makes selinexor bind to it more strongly. This makes the cancer cells more prone to die.”

Developing a More Personalized Approach

Clinical trials for selinexor are ongoing. Currently, MSK is participating in a trial for people with liposarcoma. The results of a trial for people with myelodysplastic syndrome were presented at a recent meeting of the American Society of Hematology.

Dr. Abdel-Wahab says that the E571K mutation may prove to be an effective way to determine who is likely to benefit from selinexor. This could influence future clinical trials of the drug and lead to a more personalized approach to who gets the drug.

The researchers also plan to study the role of other XPO1 defects in cancer, including cases where the gene is overexpressed but not necessarily mutated.

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Meet Julia Glade Bender, Who’s Focused on Developing Better Treatments for Kids with Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 09/20/2019
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Julia Glade Bender is a pediatric oncologist and Vice Chair for Pediatric Clinical Research at MSK Kids. She specializes in treating children with solid tumors of the bone and soft tissue, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and germ cell tumors.

She is a leader in developing clinical trials and other treatments for children with cancer that does not respond to standard treatment.

We spoke with Dr. Glade Bender about the challenges of treating rare childhood cancers and how personalized medicine is leading to better therapies for tumors that are especially hard to treat.

What makes cancer in children different from cancer in adults?

Most cancer in adults is spurred by a lifetime of exposure to outside factors — like tobacco smoke and UV light — combined with the natural DNA damage that comes with aging. Harmful genetic mutations begin to accumulate and eventually can tip the balance and cause cancer. Childhood cancers, in contrast, are often triggered by a unique event, such as a rearrangement in the chromosomes that creates an entirely new gene. These alterations can happen early in a child’s life or even before they are born.

Additionally, solid tumors in children usually arise in a different type of cell. Most adult cancers are carcinomas, which develop out of the tissues that line the inner and outer surfaces of the body, like the skin and the lining of the intestines and other organs. Childhood cancers are usually sarcomas, which form in cells in the muscles, bones, and other connective tissues.

What are some of the biggest challenges of treating cancer in children?

We can cure 80% of kids with existing treatments, especially chemotherapy, radiation, and surgery. But for the remaining 20%, new options are urgently needed.

Because these cancers are so rare, even if we have an idea of which drugs we should use to treat them, it’s difficult to develop clinical trials. A certain number of patients are required for clinical trials. For rare subtypes of uncommon cancers, which may occur in only a few dozen children in the whole country, this isn’t always possible.

Although we already have successful treatments and can cure the majority of children with cancer, we know that these treatments can have long-term effects on their health, well into adulthood. We hope to eventually develop treatments that don’t have these side effects.

How is targeted therapy changing treatment?

At MSK Kids, all children receive testing with MSK-IMPACTTM. This test helps us find particular mutations that may be driving the growth of tumors and suggest ways to treat them.

Clinical trials developed by MSK’s Early Drug Development Service can now include children as young as 12. Previously the age was 18. Although we always make the case that kids are not just little adults, we know that when it comes to things like side effects, kids over the age of 12 are more closely aligned with adults than they are with younger kids.

For a few mutations, we have drugs that have already been approved for use in kids by the US Food and Drug Administration. The biggest success is probably larotrectinib (Vitrakvi®), which is approved for solid tumors that have a mutation in a gene called NTRK.

For other, rarer mutations, we may develop a protocol for single-patient use (SPU). These compassionate-use plans require tremendous resources, including finding a drug — and a company willing to supply it — then getting permission from the Institutional Review Board and the FDA to administer the drug. It can be a lengthy and labor-intensive process.

We always collect a lot of data when we do SPUs, so that we can learn as much as possible about how and why these drugs work or don’t.

How does research done at MSK Kids help children who aren’t able to come here for treatment?

Because we collect so much information with our SPU protocols, they can eventually lead to clinical trials that may be expanded to other hospitals. That has already happened with five drugs that started as SPUs.

Members of MSK Kids also participate in a number of collaborative groups. I’m involved with the Pediatric MATCH Trial, which is a national effort to get drugs to as many patients as possible. It’s co-sponsored by the National Cancer Institute and the Children’s Oncology Group. We are already looking at eight different parts for different drug targets, and we’re adding new ones all the time.

Through these efforts we not only develop trials but also help set the standard of care for the treatment of children with cancer throughout the country and the rest of the world.

You came to MSK Kids about a year ago, after spending most of your career at another hospital. Can you talk about the move?

One thing that’s really special at MSK Kids is the collaboration with specialists beyond pediatrics, whether that’s scientists working in labs or medical oncologists who work with adults. We have a lot we can learn from one another.

Another thing that’s interesting about being at MSK is that this is where some of the earliest successful treatments for childhood cancer were developed 30 or 40 years ago. And some of those pioneering doctors are still here.

Now we’re at the forefront of this new era in personalized medicine. You’ve got this interplay between the mothers and fathers of chemotherapy and the new leaders in targeted therapy. To cure the greatest number of children, you really need both. 

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For MSK’s Gynecologic Oncologists, Uncommon Cancers Aren’t Always Rare

Source: Memorial Sloan Kettering - On Cancer
Date: 09/27/2019
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In its annual listing of the country’s best hospitals, U.S. News & World Report ranked Memorial Sloan Kettering number one in gynecology for 2019. MSK’s oncologists, surgeons, nurses, and pathologists are the leaders in diagnosing and treating well-known gynecologic cancers, such as cervical cancer, endometrial cancer, and ovarian cancer.

They also have vast experience in treating uncommon gynecologic cancers. This includes types that some healthcare providers may see only once or twice in their whole careers.

Here are some of the less common gynecologic cancers that MSK’s experts are successfully treating.

Vulvar and Vaginal Cancers

Vulvar cancer affects about 6,000 women per year, and vaginal and related cancers affect another 5,000. About 60% of these cancers are associated with human papillomavirus infections; these cases tend to develop in younger women. The other 40% are often caused by a skin condition called lichen sclerosus, which usually occurs after menopause.

MSK gynecologic surgeon Mario Leitao specializes in treating vulvar and vaginal cancers. These are usually squamous cell cancers similar to those that grow on other parts of the skin. Most women with these cancers have surgery as part of their treatment.

Dr. Leitao and his colleagues have conducted clinical trials on the use of sentinel node biopsies in these surgeries, including the use of new types of imaging agents to guide the procedure. Sentinel node biopsies involve removing only one or two lymph nodes in the groin area to test if the cancer has spread. This allows women to avoid side effects, like lymphedema of the legs, a debilitating and painful swelling that can occur when all the lymph nodes in that area are removed.

For those whose cancer comes back after treatment, MSK has additional options. “Our goal is to cure women when they first present with cancer,” Dr. Leitao says. “But when things don’t go the way we want, we’re a leading center for the larger, more complex surgeries that may be required.”

A rare subset of vaginal and vulvar cancers — about 1% — is melanoma. Dr. Leitao, medical oncologist Alexander Shoushtari, and radiation oncologist Marisa Kollmeier run a clinic for women with vulvar and vaginal melanoma. Patients are often able to see all three specialists on the same day.

As with other types of melanoma, immunotherapy with checkpoint inhibitor drugs is often used to treat gynecologic melanoma. The drugs may be given in combination with radiation therapy to improve their effectiveness.

“Each of these patients is unique, and we come up with a specialized treatment plan for each of them,” Dr. Leitao explains. “They all get their tumors tested with MSK-IMPACTTM, which can teach us a lot about the mutations driving these cancers. We are learning much more about the genetic and molecular makeup of gynecologic melanomas, with the goal of developing even better treatments in the future.”

Uterine Sarcoma

Most cancer of the uterus is endometrial cancer. This starts in the tissue that lines the uterus. Uterine sarcoma, which develops in the muscle or connective tissue, is much less common. There are several types of uterine sarcoma, including leiomyosarcoma, high-grade undifferentiated sarcoma, and endometrial stromal sarcoma. Uterine sarcoma is rare, making up less than 4% of all cancers of the uterus. Only 1,200 women are diagnosed with this disease in the United States each year.

Most uterine sarcoma is treated with surgery. Gynecologic oncologist Oliver Zivanovic specializes in these procedures. “The experience of the surgeon is very important,” he notes. “When these tumors are removed, achieving negative margins is very important. Some uterine sarcomas are quite large or infiltrate into the surrounding tissue, so it’s not always an easy surgery.”

For women who need chemotherapy after surgery, Dr. Zivanovic often collaborates with MSK medical oncologist Martee Hensley, an internationally recognized leader in treating these cancers.

One of the challenges of treating uterine sarcoma is that it often doesn’t have symptoms, or its symptoms are similar to much more common noncancerous conditions, like fibroids. Additionally, because it’s so rare, uterine sarcoma has no established screening methods. But experts at MSK have reported there is one group of women who are at a higher risk of leiomyosarcoma: those who have previously been treated for retinoblastoma, a type of eye cancer in children that is often hereditary.

For these women, Dr. Zivanovic and MSK ophthalmic oncologist Jasmine Francis have established a surveillance program, which offers annual exams with imaging including MRI and ultrasound. In addition to helping women at the highest risk of developing a second cancer, the investigators say that what they learn from these women will enable them to develop better detection strategies for all cases of uterine sarcoma.

Uncommon Ovarian Cancers

All ovarian cancers are considered rare, but some types are even less common. One of these, called small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), has had only about 500 documented cases to date. Despite its low incidence, MSK researchers have conducted extensive research on SCCOHT.

In 2014, MSK gynecologic surgeon Jennifer Mueller was part of a team that found a particular mutation in a gene called SMARCA4 present in this aggressive cancer. Although the discovery has not yet yielded any targeted therapies, further studies revealed that nearly half of these mutations are inherited. This discovery has important implications for family members of women diagnosed with these tumors.

Dr. Mueller recently performed risk-reducing surgery on a young woman who learned she had the SMARCA4 mutation after her sister was diagnosed with SCCOHT. The woman had her eggs retrieved and banked before the removal of her ovaries. “If it hadn’t been for the research done at MSK, as well as the genetic counseling offered to the family, this young woman would have never known she carried this risk,” Dr. Mueller says.

Dr. Mueller treats other less-common forms of ovarian cancer, including clear cell, endometrioid, and germ cell tumors. “For any woman who has one of these rare types, I would encourage her to get a second opinion with a pathologist who has experience in diagnosing them,” she says. “Getting a proper diagnosis can have a major impact on treatment decisions, which can, in turn, affect outcomes as well as a woman’s quality of life.”

Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) is a tumor that develops from fetal tissue after a pregnancy, including a full-term delivery, a miscarriage, or an ectopic pregnancy. If the tumor is cancerous, it is called a gestational trophoblastic neoplasm (GTN).

These tumors are treated with surgery. More advanced cases may require chemotherapy. MSK medical oncologist Carol Aghajanian is a nationally recognized leader in treating GTN when chemotherapy is needed.

“The good news is that GTNs are almost 100% curable,” Dr. Mueller says. “But because they are uncommon, it’s important to make sure that you have the correct diagnosis. If a woman is diagnosed with a cancerous form and it turns out not to be cancer, she may be given additional treatments that she doesn’t need.”

Supportive Services

For women with gynecologic cancers of all types, MSK’s Female Sexual Medicine and Women’s Health Program, run by psychologist Jeanne Carter, offers comprehensive, personalized care.

MSK also has physical therapists who specialize in pelvic physical therapy. This process can be helpful in dealing with pelvic pain and pressure, which is especially common after radiation treatments.

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MSK’s Expanded Genomics Program Takes a Deep Dive into the Causes of Childhood Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 09/30/2019
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MSK-IMPACT™ detects changes in more than 400 cancer-associated genes. The test has made a meaningful difference for many adults treated at Memorial Sloan Kettering. By identifying the mutations driving a tumor’s growth, test results may indicate which targeted therapy or immunotherapy is likely to work against a tumor. Results can also be used to find an appropriate clinical trial.

But the picture is quite different for children with cancer. About half of their tumors do not have a significant mutation that can be identified with MSK-IMPACT or any other standard clinical test. For these kids, developing new forms of molecular diagnosis is essential.

“As a whole, pediatric cancers are a collection of very diverse and very rare tumor types,” says MSK molecular geneticist and data scientist Elli Papaemmanuil. “Their genomes are very different from the genomes of most cancers seen in adults. We still have so much to learn about them.”

This is the motivation behind the establishment of MSK’s Expanded Genomics Program. The program, led by Dr. Papaemmanuil, was launched in September 2018 to develop a way to comprehensively map the unique changes driving each individual tumor. The ultimate goal is to understand and eventually identify personalized treatment approaches for every child treated for cancer at MSK Kids.

Going Beyond the Standard Approach

In the lab, the Expanded Genomics team has already performed an in-depth examination of tumors from more than 120 children treated at MSK. This analysis includes looking at the gene mutations detected by MSK-IMPACT, sequencing the rest of the tumor genome, and measuring levels of RNA. Changes in RNA can help indicate which genes are affected.

“We hope to be in a position where we can identify the novel genetic events that define each tumor and explain what’s driving the cancer,” Dr. Papaemmanuil says. “By learning more about these disease-defining changes, we aim not only to pinpoint which drugs are likely to be effective but also to develop diagnostic and prognostic markers.” These markers would help doctors determine which cancers may be more aggressive and require more treatment, and which tumors can successfully be cured with less-aggressive therapies, enabling patients to avoid side effects.

Finding New Clues about Cancer’s Origins

Another important aspect of genomic research in pediatric cancer is that it can identify which tumors may be caused by inherited mutations. Current literature, as well as work by MSK geneticist and pediatric oncologist Michael Walsh, suggests that about 10 to 15% of children with cancer have germline (hereditary) mutations.

Knowing when a cancer is caused by a hereditary mutation can benefit whole families because relatives can get tested for the same mutation. If they have it, they may be able to enroll in screening programs to catch cancer at an earlier stage or have preventive care.

A large proportion of cancer susceptibility genes affect repairing DNA damage under normal conditions. Expanded genomic analysis can readily pinpoint the evidence of damaged DNA in people with impaired DNA repair genes. This provides another way to identify people with inherited gene mutations.

Additionally, the presence of these mutations can suggest who may benefit from treatment with immunotherapy drugs, such as checkpoint inhibitors. These drugs work better against tumors that have a lot of mutations. Traditionally, they have not been used to treat pediatric cancers because tumors in younger people tend to have fewer mutations.

Taking Lab Findings into the Clinic

As promising as this research is, more work needs to be done before these types of analyses can be used to make decisions about patient care. “One of our big aims right now is to evaluate whether these comprehensive sequencing approaches are informative enough to be clinically helpful,” Dr. Papaemmanuil says. “We are still in the early stages of this research. Yet in our early findings, we showcase that with comprehensive sequencing techniques, we can identify diagnostic-, prognostic-, and therapy-informing markers that would have not been picked up by standard clinical sequencing tests.”

Her team is working with pediatric oncologists to validate their laboratory findings. They want to determine the best way to match each genetic signature to existing or investigational drugs. As an integral part of the MSK Kids Pediatric Translational Medicine Program, the Expanded Genomics team collaborates with doctors who can use the results from this wide-ranging genomic testing to find targeted therapies for childhood cancers.