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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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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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MSK Program Focuses on Speeding Up Development of New Leukemia Treatments

Source: Memorial Sloan Kettering - On Cancer
Date: 09/30/2019
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On September 3, Memorial Sloan Kettering launched the Center for Drug Development in Leukemia (CDD-L). This new program will focus on creating more phase I clinical trials for most types of leukemia in adults. Its goal is to rapidly bring novel therapies to people being treated at MSK.

We spoke to leukemia experts Eytan Stein, who will lead the new center, and Jae Park about how treatment for acute (fast-growing) leukemia has changed in the past few years. They shared their ideas on how this new center will further accelerate improvements in treating these blood cancers.

Dr. Stein specializes in treating acute myeloid leukemia (AML), one of the most common leukemias in adults. Dr. Park specializes in treating acute lymphocytic leukemia (ALL). This blood cancer is rare in adults but makes up three-quarters of leukemia in children.

How have treatments for leukemia changed over the past few years?

Dr. Park: For ALL in adults, one of the big improvements is the development of new immunotherapies, including blinatumomab (Blincyto®) and inotuzumab (Besponsa®). Blinatumomab is an antibody-based drug that works by linking T cells to leukemia cells. This enhances the T cells’ killing activity. Inotuzumab is an antibody with a drug attached, to allow the selective delivery of chemotherapy to leukemia cells. Both drugs have fewer side effects than chemotherapy. This is important because ALL is often diagnosed in older people, who may not be able to tolerate stronger drugs.

Dr. Stein: For AML, we have moved away from a one-size-fits-all approach, which was common for decades. As with ALL, people with AML tend to be older and therefore not strong enough for intensive chemotherapy. Now we have other options. One is a drug called venetoclax (Venclexta®), which targets a protein on leukemia cells called BCL2. The drug is given with another type of drug, called a hypomethylating agent, which affects cellular function. This combination treatment leads to remission in about 70% of people with AML, and those remissions tend to be long-lasting.

How has personalized medicine improved the treatment of leukemia?

Dr. Park: We’ve learned that about 40% of all cases of ALL have a genetic abnormality called the Philadelphia chromosome. This mutation is also commonly found in chronic myeloid leukemia. We’ve found that drugs that target the mutation also work for ALL, but they need to be combined with other drugs. We are now doing clinical trials to find the best combination for these drugs and are also using MSK-IMPACT™ to look for less-common mutations that can be targeted with different drugs.

Dr. Stein: For the 30% of people who don’t respond to the venetoclax combination or whose disease comes back after treatment, we have many options based on the mutations driving the cancer. For the approximately one-quarter of people who have mutationsin the genes IDH2 and IDH1, the US Food and Drug Administration recently approved the drugs enasidenib (Idhifa®) and ivosidenib (Tibsovo®), respectively. We are looking at adding targeted therapies for other mutations as well. For people with secondary AML, which develops after they have been treated for myelodysplastic syndrome or another cancer, a new drug that is a formulation of two older chemotherapies together seems to be effective.

What are the roles of blood and marrow stem cell transplantation and cell therapies, like chimeric antigen receptor (CAR) T therapy, in treating people with acute leukemia?

Dr. Park: For people with high-risk ALL or those whose disease comes back after chemotherapy, bone marrow transplantation has been the only chance of a cure. More recently, a new and improved form of cell therapy called CAR T has emerged as a promising treatment to achieve a deep and complete remission even in people who have failed all standard therapies, including bone marrow transplantation. This has generated a lot of excitement in the field. MSK is leading the effort to develop effective and safe CAR T cells for people with various blood cancers. What is most exciting about this form of cell therapy is that a single infusion of T cells can result in a long-lasting remission. With continued commitment and research in the field, we are optimistic that we will improve the outcome and quality of life of people with blood cancer.

What are you most enthusiastic about?

Dr. Stein: I’m excited about all of our clinical trials, specifically the phase I trials that the CDD-L is putting forward. We hope to eventually have a trial available for every patient who doesn’t respond to standard treatment. MSK is also a founding member of the Beat AML initiative overseen by the Leukemia and Lymphoma Society. Through these efforts, we want to have a clinical trial available for every individual who doesn’t respond to standard treatment.

Dr. Park: I’m excited about all the new treatment options for all people with ALL. In the next few years, we will focus our efforts on how to best use these therapies to minimize exposure to traditional chemotherapy and shorten the duration of therapies for people with ALL, which currently last several years. We hope to achieve these goals through a series of clinical trials. We’ll use sophisticated tools to detect an extremely low level of leukemia cells, called measurable residual disease, and identify who can benefit from these new therapies.

Beyond the hematologic oncologists, who are the other members of the MSK team that contribute to the care of people with leukemia?

Dr. Stein: Our molecular pathologists and hematopathologists make it possible for us to find the genetic mutations in each patient’s cancer so that we can match them with the right therapy. This kind of testing used to take many weeks, but now they are able to get us results within a few days. It enables us to get patients on trials right away so they can start treatment almost immediately.

Dr. Park: Our nursing staff on the Leukemia Service is phenomenal, and they’re a big reason to come to MSK. They have incredible experience in managing the side effects that may come from the newly approved and experimental therapies. They also understand the emotional and social needs that often come with a diagnosis of leukemia. Because of their expertise and support, we can ensure that most patients will complete their cancer treatments. Effective leukemia treatment requires strong teamwork, and we have an amazing team that I’m proud to work with every day.

Where is the CDD-L located?

Dr. Stein: People who participate in trials through the CDD-L will receive their care in the new David H. Koch Center for Cancer Care. Their treatment is provided within the Developmental Therapeutics Unit, a treatment area with a specialized cadre of nurses who have expertise in the care of people on phase I clinical trials.

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Research Points to a Potential New Approach for Treating Anemia

Source: Memorial Sloan Kettering - On Cancer
Date: 10/04/2019
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Anemia, a condition in which there are not enough red blood cells to transport oxygen throughout the body, affects millions in the United States every year. It can lead to fatigue, dizziness, and shortness of breath, among other symptoms. It’s a common side effect of certain cancer treatments, especially chemotherapy. Anemia occurs frequently in people with a type of blood cancer called myelodysplastic syndrome (MDS). And it’s widespread among people over age 65.

Therapies for anemia exist. They include the drug epoetin alfa (Procrit®, Epogen®), regular blood transfusions, and iron supplements. But researchers continue to be on the lookout for additional and better ways to boost the production of red blood cells. MSK physician-scientist Omar Abdel-Wahab, an expert in MDS, recently published a study in Science Translational Medicine that reported a new approach for treating anemia with medication.

“Anemia is a major medical problem,” says Dr. Abdel-Wahab, whose lab is part of MSK’s Human Oncology and Pathogenesis Program. “This study suggests a new type of drug that we could use to treat it. While the current standard therapies for anemia are very helpful, many people eventually fail to respond to these treatments. Additionally, routine use of blood transfusions has a major negative impact on quality of life and comes with potential side effects. Thus, developing entirely new ways to treat anemia is incredibly important.”

A Different Role for a Known Pathway

The new method was identified through a collaboration between Dr. Abdel-Wahab and Lingbo Zhang, a researcher at Cold Spring Harbor Laboratory and co-senior author of the paper.

The researchers performed a high-throughput screen, in which hundreds or thousands of compounds are tested at the same time. They were hoping to find drugs that could boost the production of red blood cells. They tested the compounds in cell cultures of red blood cell precursors (a type of blood stem cell that has the ability to develop into red blood cells).

They discovered that compounds that block a pathway called CHRM4 increased the production of red blood cells. This pathway is also known to have a regulatory effect on neurotransmitters, such as serotonin and dopamine. Its role in the production of red blood cells had not previously been identified.Anemia is a major medical problem.

After identifying the role of the CHRM4 pathway by studying blood cells in a test tube, the investigators analyzed the effects of giving the compounds to mice with MDS and in bone marrow samples from people with MDS. They also tried them in elderly mice that had reduced red blood cell production because of their age. (In mice, elderly means about 2 years old.) In each case, the drugs boosted the numbers of red blood cells that were made.

Identifying a Novel Therapeutic Approach

Drugs that block the CHRM4 pathway have already been approved by the US Food and Drug Administration to treat certain neurological disorders. The researchers are hoping to use these drugs as a starting point to make new medications that are more effective at treating anemia.

“These drugs don’t seem to have many side effects,” Dr. Abdel-Wahab says. “We think this is a good path to pursue.”

He adds that targeting CHRM4 could also be a good approach for treating hemolysis. This condition occurs when red blood cells break open and release hemoglobin into the blood. Hemolysis can happen in response to infections or drug reactions, among other situations, and can lead to anemia.

This research was funded by the Cold Spring Harbor Laboratory (CSHL) President’s Council; National Institutes of Health grants (CA045508, U01 HL127522, 1K08CA230319-01, and R01 HL128239); a CSHL–Northwell Cancer Translational Research Award; the Edward P. Evans Foundation; the Leukemia and Lymphoma Society; the Henry and Marilyn Taub Foundation; a Department of Defense Bone Marrow Failure Research Program grant (W81XWH-12-1-0041); and the Pershing Square Sohn Cancer Research Alliance.

Dr. Abdel-Wahab has served as a consultant for H3 Biomedicine, Foundation Medicine, Merck, and Janssen, and has received personal speaking fees from Daiichi Sankyo.

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Targeting Errors in How Proteins Are Made Is a Promising Approach for Cancer Treatment

Source: Memorial Sloan Kettering - On Cancer
Date: 10/09/2019
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Manufacturing proteins is a multistep process that’s hard-coded into how our cells operate. Genes, which are made of DNA, get translated into RNA, which in turn provides instructions on how proteins are made. One key step in this construction process is called RNA splicing. Like the editing of a film, when some pieces may be cut out and discarded, splicing involves removing portions of the RNA and stitching the remaining pieces back together.

New work from Memorial Sloan Kettering is illustrating that when splicing isn’t done properly, it can lead to cancer.

MSK physician-scientist Omar Abdel-Wahab focuses on studying this process in his lab. He recently published two studies looking at the role of specific RNA splicing factors in different cancers. One study focused on acute myeloid leukemia (AML); the other studied melanoma, particularly uveal (eye) melanoma.

“Our earlier research found that splicing factors are mutated at high frequency in a variety of cancer types,” says Dr. Abdel-Wahab, of the Human Oncology and Pathogenesis Program. “What we’re learning is that when these splicing factor proteins are mutated, they’re actually changing the function of the splicing machinery in cells. Importantly, they’re doing it in a way that promotes cancer.”

The research reported in both papers has already suggested possible approaches for targeting these defective splicing factors with drugs.

Combination Approach for Acute Myeloid Leukemia

The first paper, published October 2 in Nature, looked at a splicing factor called SRSF2. The SRSF2 gene is mutated in about one-quarter of AML cases. It turns out that these SRSF2 mutations are more likely to be present when cancer cells also have mutations in the IDH2 gene, which is commonly mutated in AML.

“We were surprised to find that mutations in SRSF2 are particularly frequent in AML that also has IDH mutations,” Dr. Abdel-Wahab says. “We decided to investigate this link.”

Two IDH genes — IDH1 and IDH2 — are commonly mutated in AML. Together, these mutations also are found in about one-quarter of AML cases. In the past few years, the US Food and Drug Administration has approved two drugs designed to target these mutations: enasidenib (Idhifa®) for IDH1 and ivosidenib (Tibsovo®) for IDH2.

“IDH mutations have been very clearly shown to drive leukemia development,” Dr. Abdel-Wahab explains. “What we showed in this paper is that the splicing errors caused by SRSF2 mutations are also part of this process. The interplay between these two types of mutations is very important.”

Dr. Abdel-Wahab’s lab is focused on developing drugs to target mutant splicing factors, including SRSF2. He is already conducting an early-stage clinical trial with one of these drugs, and more studies are planned.

“Now we’re really interested in trying to develop ways to target forms of AML that have both mutations,” he says. “The idea is that we could use these drugs together, so that we’re targeting the cancer from two sides.”We found that the mutation is disrupting a critical part of the splicing machinery in a way that drove the formation of cancer.

Targeting Melanoma with a New Kind of Therapy

In the second paper, published October 9 in Nature, Dr. Abdel-Wahab and his colleagues looked at another splicing factor, called SF3B1. Mutations in the SF3B1 gene are found in many types of cancer, including some types of leukemia and many solid tumors. They are most commonly found in uveal melanoma, a rare but aggressive eye cancer.

In this study, a collaboration with researchers at the Fred Hutchinson Cancer Research Center in Seattle, the investigators studied RNA sequencing data from people with several forms of cancer.

“We wanted to see if we could find a link to what the mutation is doing in these diseases,” Dr. Abdel-Wahab says. “We found that the mutation is disrupting a critical part of the splicing machinery in a way that drove the formation of cancer.”

As part of the study, the researchers were able to develop a way to block the altered RNA splicing caused by the mutated splicing factor. Instead of using a drug, they used a small piece of DNA called an antisense oligonucleotide. Oligonucleotide therapy is a relatively new form of treatment: A handful of oligonucleotide-based drugs have been FDA approved, mostly for genetic neurologic diseases.

Dr. Abdel-Wahab and his colleagues tested the antisense oligonucleotide in cultures of cells with SF3B1 mutations and found that it blocked the growth of cancer cells. They then tested the therapy in mice that were implanted with material from patient samples of uveal melanoma. The treatment reduced the size of the tumors in the mice.

“We would like to work to develop this antisense oligonucleotide as a treatment, so that we can eventually start a clinical trial,” Dr. Abdel-Wahab says. “It’s a challenging undertaking because of the way these oligonucleotides behave in the body. But we think it’s a promising approach.”

The October 2 Nature paper was funded by the Aplastic Anemia and MDS International Foundation, the Lauri Strauss Leukemia Foundation, the Leukemia and Lymphoma Society, a Japan Society for the Promotion of Science Overseas Research Fellowship, a Bloodwise Clinician Scientist Fellowship, the Oglesby Charitable Trust, National Institutes of Health grants (K99 CA218896 and R01 HL128239), an American Society of Hematology Scholar Award, Cancer Research UK, the Cancer Prevention and Research Institute of Texas, the Welch Foundation, a Department of Defense Bone Marrow Failure Research Program grant (W81XWH-16-1-0059), the Starr Foundation, the Henry and Marilyn Taub Foundation, the Edward P. Evans Foundation, the Josie Robertson Investigators Program, and the Pershing Square Sohn Cancer Research Alliance.

The October 9 Nature paper was funded by the Leukemia and Lymphoma Society, the Aplastic Anemia and MDS International Foundation, the Lauri Strauss Leukemia Foundation, the Conquer Cancer Foundation, an American Society of Clinical Oncology Young Investigator Award, an American Association for Cancer Research Lymphoma Research Fellowship, a Mahan Fellowship from the Fred Hutchinson Cancer Research Center, the Pershing Square Sohn Cancer Research Alliance, the Henry and Marilyn Taub Foundation, the Starr Cancer Consortium, National Institutes of Health grants (R01 DK103854 and R01 HL128239), the Evans MDS initiative, and the Department of Defense Bone Marrow Failure Research Program.

Dr. Abdel-Wahab has served as a consultant for H3 Biomedicine, Foundation Medicine, Merck, and Janssen, and has received personal speaking fees from Daiichi Sankyo.

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

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

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

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

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

Targeting a Unique Protein Network

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

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

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

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

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

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

A New Way to Match Drugs to Tumors

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

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

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

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

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

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

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

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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.