Promising Results from the First-Ever Trial of a Drug that Blocks Cancer Gene KRAS

Source: Memorial Sloan Kettering - On Cancer
Date: 09/20/2020
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Targeted therapies aim to block the activity of genes that cause cancer, providing a direct attack on tumors while sparing healthy cells. Identifying genes that trigger tumor growth is only the first hurdle to developing targeted drugs — just because investigators know a gene may cause cancer doesn’t mean they can prevent it from wreaking havoc.

The cancer gene KRAS (pronounced “kay-rass”) is a case in point. It’s been studied for about 40 years and is known to be responsible for many of the most common cancers. This includes about one-quarter of lung cancers and between one-third and one-half of colon and rectal cancers. Until recently, however, the KRAS protein was considered an “undruggable” target.

On September 20, 2020, in the New England Journal of Medicine (NEJM), investigators reported results from CodeBreak 100, the first-ever clinical study of a drug that directly targets KRAS. In this international phase 1 trial, researchers found that a drug called sotorasib (AMG 510) slowed or stopped cancer growth in many people with advanced cancer that had a KRAS mutation. The investigators say much more research is needed to determine how to best use this drug, but this trial is a significant first step.

“Sotorasib is not a cure, but this study is the first to crack KRAS in a clinically meaningful way,” says Memorial Sloan Kettering medical oncologist Bob Li, a senior investigator and corresponding author of the study. “It’s an important step forward, but it’s not yet a home run.”

Shutting Down Cancer Growth

The challenge in targeting the KRAS gene comes from the uncommon shape of the KRAS protein. Most proteins have a lumpy, irregular shape, with many clefts and pockets where a drug can wedge in. When this happens, a drug can act as a key, locking up a protein and shutting down its activity. “By contrast, the KRAS protein is quite round and smooth,” Dr. Li explains. “There’s no lock-and-key approach.”

In 2013, researchers at the University of California, San Francisco, reported there may be a way in: They found a small pocket in a version of the mutant KRAS protein, called KRAS-G12C, and designed a drug to fit into this pocket when it was open.

In 2016, MSK physician-scientists Piro Lito and Neal Rosen published a study that built on this work. They described the trapping mechanism that enables the new class of drugs to shut down the growth of cancer cells driven by the KRAS-G12C mutation.

“When one of these drugs goes in the protein’s pocket, it traps KRAS-G12C in its ‘off’ state,” says Dr. Lito, who is also a senior author on the new NEJM paper. “The protein can’t wake up, and the tumor cell cannot grow.”

Sotorasib, which was developed by investigators at the biopharmaceutical company Amgen, is an improved and more potent KRAS-G12C inhibitor. Combining their respective strengths in phase 1 clinical trial development and translational science, Drs. Li and Lito partnered with Amgen to bring the first-in-class KRAS-G12C inhibitor sotorasib to patients.

Promising Findings from an International Trial

In the trial for sotorasib, 129 people whose tumors had KRAS-G12C received the drug, which is taken as a pill. Fifty-nine of them had non-small cell lung cancer, 42 had colorectal cancer, and 28 had other types of tumors. All of the study participants had disease that spread to other parts of the body; they already had received an average of three previous treatments. The trial included people treated at more than two dozen hospitals around the world.

Among those 59 people with lung cancer, seven patients did not respond and 52 experienced disease control (which means that their tumors either stopped growing or shrank). In that group of 52, 19 patients had their tumors shrink substantially. The average time until the disease got worse was about six months. “That level of response is significant for this population of patients because most of them have exhausted other treatment options.” Dr. Li explains.

A little more than half of the people in the trial (73 patients) had some side effects, but only 15 of them had significant side effects. All but one patient were able to safely continue the drug when the side effects resolved, and no one died from side effects. “Because the drug is selective for this specific KRAS mutation, it was well tolerated by patients,” Dr. Lito says. “It only binds to and inhibits the mutated form of the protein in cancer cells. This is important because it enables high doses of the drug to be safely administered.”

Next Steps for Research

Responses for other types of cancer — including colorectal cancer, as well as pancreaticendometrial (uterine), and appendiceal cancers and melanoma — were not as good as they were for lung cancer. But some patients with those other cancers did benefit with substantial tumor shrinkage. The investigators plan to study why sotorasib appears to work better in some types of cancer than it does in others, even when the cancers have the same mutated protein. Additional trials are already underway to continue studying sotorasib, both alone and in combination with other drugs.

Research on how to block KRAS is continuing in the laboratory as well. In January 2020, Dr. Lito’s lab published a study that looked at new approaches for combining KRAS inhibitors with other drugs. “We’re taking what we’ve learned in patients back to the bench to continue developing new treatments,” Dr. Lito says. “We’re already thinking one step ahead about how to use this drug for the greatest benefit of people who need it.”

The results from this clinical trial are also being presented at the European Society for Medical Oncology 2020 Virtual Congress.

T Cell Therapies Offer a New Way to Treat Gynecologic Cancers

Source: Memorial Sloan Kettering - On Cancer
Date: 09/30/2020
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The American Cancer Society estimates that more than 113,000 people in the United States are diagnosed with a gynecologic cancer every year. Memorial Sloan Kettering is a leader in treating people with these cancers, which include tumors of the cervixovaries, and uterus.

Among the new treatments being developed for gynecologic cancers are a type of immunotherapy called T cell therapies. These are treatments in which a patient’s own immune cells are modified to recognize and attack cancer cells. MSK doctors and scientists were the first to develop these treatments for leukemia and lymphoma. Now, many researchers are focused on further advancing this approach to make it effective against solid tumors.

“For certain blood cancers, cellular therapy can be remarkably potent, perhaps even curative,” says physician-scientist Christopher Klebanoff, whose lab is focused on developing new cell therapy approaches. One challenge of immunotherapy is directing the immune cells only to tumors so they don’t cause injury to healthy tissues.

Treating Cancer with CARs and TRUCKs

The most well-known cell therapy is chimeric antigen receptor (CAR) T therapy, which has shown success in treating certain blood cancers. CAR T modifies a patient’s immune cells (T cells) so they can recognize a protein (called an antigen) on the outer surface of cancerous cells. These supercharged T cells then seek out and destroy the cancer. For many cancers, especially cancers originating from a solid organ, the antigen isn’t quite as easy for the T cell to find, making cell therapies more challenging to develop.

This has led to a related tactic called T cell receptor (TCR) therapy, in which T cells are engineered to detect antigens on the inside of the cancer cell. “The ability to do this is one of the greatest tricks in biology,” Dr. Klebanoff says. “That is, how can you allow an immune cell to look inside other cells to detect if the proteins inside are normal or abnormal?”

As it turns out, the way this “looking” works is actually indirect: As part of normal cellular operations, proteins eventually get broken down and recycled to make new proteins. One step in this recycling process displays protein fragments on the surface of cells — allowing them to be seen by engineered T cells. TCR therapies are designed to take advantage of this natural process that the immune system uses to survey tissues in the body.

Some of the newest cell therapies known as TRUCKs — T cells redirected for antigen‐unrestricted cytokine‐initiated killing — work by combining the antitumor abilities of CAR T or TCR therapy with a molecule called a cytokine. The cytokine recruits another wave of immune cells to the tumor.

A Personalized Approach to Cancer Care

Medical oncologist Roisin O’Cearbhaill is the research director for the Gynecologic Medical Oncology Service and a leader in studying new cell therapies and immunotherapy approaches for treating gynecologic cancers, including a treatment for cervical cancer and other tumors caused by the human papillomavirus (HPV). “We’re building up our clinical trial program at MSK so that we will be able to offer more cellular therapies for patients with gynecologic cancers,” she says.

“With cell therapies, we use our knowledge about specific molecular and genomic properties of the patient’s cancer,” Dr. O’Cearbhaill explains. “And we may also use certain markers on their blood cells in order to get the best possible match for a targeted therapy for that individual patient.”

“For each of our patients, we take a very personalized approach to match the best possible medicines, including experimental medicines offered in clinical trials, with the patient’s disease,” Dr. Klebanoff says. “I’m a big believer in the concept of partnership and shared purpose, and this is how we work in collaboration with our patients. We have a shared purpose to try to improve things both for them and for others with similar diseases in the future.”

Clinical Trials Offering Cell Therapies for Gynecologic Cancers

MSK currently has a number of clinical trials that are examining this approach.

  • Dr. O’Cearbhaill is co-leading a phase I study with Dr. Klebanoff that is assessing the safety and effectiveness of using a TCR therapy called KITE-439 to treat cancers caused by a strain of HPV called HPV 16. The majority of cervical cancers as well as many cancers of the mouth, throat, vagina, vulva, penis, and anus are associated with HPV 16. In this study, a patients’ immune cells are modified to recognize and attack tumor cells that contain HPV 16.
  • The doctors are also co-leading a phase I trial for a cell therapy called KITE-718, which targets cancers containing MAGE-A3/A6, a protein found in some ovarian and cervical cancers as well as other kinds of cancer.
  • To study another treatment for ovarian cancer and cancers of the fallopian tubes and the peritoneal cavity (the lower abdomen), Dr. O’Cearbhaill is leading a phase I trial for a CAR T therapy that targets a protein called MUC16, which is made by many of these tumors. MUC16, also called CA125, is best known as a biomarker used to monitor treatment for ovarian cancer.
  • Dr. O’Cearbhaill is also leading a phase I/II trial for a TRUCK drug called TC-210, which is being tested in combination with chemotherapy. This cell therapy targets tumors that make a protein called mesothelin, which is found in several cancers, including some ovarian tumors.

A Perfect Match: Molecular Tests Developed at MSK Guide Personalized Treatment for Lung Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 11/25/2020
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EGFRALKBRAF. MET. NTRK. RET. ROS1. This may seem like what you see when you dump a box of Scrabble tiles on a table, but these letter combinations are actually the names of genes that — when mutated — drive the formation, growth, and spread of lung cancer.

In aggregate, mutations in these seven genes cause about one-third of all non-small cell lung cancers. And each of them has at least one drug designed to counteract them that’s been approved by the US Food and Drug Administration. For patients who are matched with one of these drugs, treatment tends to be much more effective than it is with chemotherapy, which kills not just cancer but all fast-growing cells. Additionally, targeted drugs usually have fewer side effects than other forms of treatment.

“Our goal is always to find the best treatment for every patient,” says Memorial Sloan Kettering medical oncologist Helena Yu, who specializes in evaluating targeted therapies for lung cancer. “But you don’t know what the best treatment is until you look at all the options, and you won’t know all the options until you do molecular testing.”

A History of Developing Molecular Tests

Nearly two decades ago — when the first drugs for EGFR mutations were being evaluated — researchers at MSK recognized that targeted therapy would be an especially important approach for people with lung cancer. This was because the drugs worked extremely well in a subset of patients. Also, many people stood to benefit because lung cancer is so common. Targeted drugs work by zeroing in on the activities of mutated proteins in cancer cells and shutting down the cells’ growth, mostly sparing healthy cells.

MSK researchers also understood how vital it was to examine tumor tissue and determine whether it contained the mutations that were being targeted. Studies had shown that EGFR drugs were quite effective in people whose tumors had EGFR mutations. Those whose tumors had other mutations would not benefit. (What happened is not uncommon in cancer drug development — when the trials of drugs targeting EGFR began, investigators didn’t know who would most benefit from them.)

In 2004, MSK was one of the first hospitals in the world to begin regularly testing people with non-small cell lung cancer for EGFR mutations. The development of this clinical test was led by molecular pathologist Marc Ladanyi.

In the years after that test was created, Dr. Ladanyi and his team in MSK’s Molecular Diagnostics Service have continued to roll out new molecular tests, including MSK-IMPACTTM, which expanded the benefits of molecular testing to all solid tumors. Today, this test can detect alterations in 505 cancer-related genes while requiring only one small piece of tissue. MSK-IMPACT was cleared as a tumor genetic profiling assay by the FDA in 2017. In 2019, MSK began using MSK-ACCESS, a tool that can detect mutations in 129 genes by analyzing just a small amount of blood. MSK-IMPACT and MSK-ACCESS enable doctors to match patients with drugs designed to target their tumors and provide them with many other details about a tumor’s genetics as well.

“When a patient comes to me with newly diagnosed, metastatic lung cancer, the first thing I do is order an MSK-ACCESS test for them,” Dr. Yu says. “We get the results within two weeks, and if their cancer cells contain one of these mutations, we can start them on a targeted therapy right away.” Because MSK-IMPACT requires a tissue sample, it may not be available to patients who received their biopsy and diagnosis at another hospital. But if enough tissue is left over from earlier tests, MSK-IMPACT can be used to confirm the diagnosis and provide further detail. “MSK-IMPACT is still the gold standard for molecular testing,” she adds.

Clinical Trials Lead to New Therapies

As leader of MSK’s Early Drug Development Service, medical oncologist Alexander Drilon has been at the helm of several clinical trials for targeted therapies that are now used to treat lung and other cancers. Recently, he led the clinical trial that resulted in the FDA’s approval of selpercatinib (RetevmoTM), which treats lung and thyroid cancers driven by a mutation called a RET fusion. Studies showed that among patients who had stopped responding to other drugs, 64% had their tumors shrink when treated with selpercatinib. For those who had never received chemotherapy or another treatment, the response was even higher — 85%.

“As more targeted therapies are developed, tests like MSK-IMPACT that look for many mutations at the same time have become so important,” Dr. Drilon said. “If you run individual tests for each mutation separately, you’ll exhaust the amount of the patient’s tumor tissue that’s available for analysis.”

Selpercatinib and other targeted therapies were initially approved to treat stage IV disease that could not be operated on — cancers that had spread beyond the lungs to other parts of the body. Investigators at MSK are now conducting studies to determine whether they can help people with less-advanced cancers. The drugs may be given before surgery, to shrink tumors and make them easier to remove, or after surgery, to destroy any cancer that may be left behind.

Unfortunately, many people can develop resistance to these drugs, and MSK researchers are now focused on developing new drugs that can take over when one targeted therapy stops working. MSK-ACCESS plays an important role here, too: Doctors can use blood tests to monitor the cancer and determine whether it has acquired additional mutations without having to conduct a surgical or needle biopsy to get another tissue sample.

Advancing the Search for New Drugs and New Targets

MSK investigators are also leading the way in the search for drugs that target mutations in other genes. In September 2020, medical oncologists Bob Li and Piro Lito published results from the first-ever trial for sotorasib, a drug that targets a mutation called KRAS-G12C. This mutation is found in about 10% of non-small cell lung cancers, most often in former or current smokers.

Dr. Li and Dr. Drilon are also conducting a trial to determine whether the drug trastuzumab deruxtecan (Enhertu®), which was approved for breast cancer in December 2019, is effective in treating lung cancers driven by genetic changes in a gene called HER2.

“You need really good sequencing tests to find all these mutations,” Dr. Drilon says. “As testing becomes cheaper and more and more drugs become available, the medical community needs to move toward a paradigm where every person with lung cancer receives molecular testing.”

Unexpected Finding Reveals New Target for Aggressive Form of Lung Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 12/01/2020
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Targeted therapies are currently available for about one-third of people with lung adenocarcinoma, the most common kind of lung cancer. These drugs inhibit cancer cells by thwarting the molecular changes that drive them to grow while largely sparing healthy tissues. But for the other two-thirds of people with this type of cancer, there are fewer treatment options.

A team from Memorial Sloan Kettering is reporting new findings about a particularly aggressive subset of lung adenocarcinomas that are driven by two mutations that frequently occur together, in genes called KEAP1 and STK11. The molecular changes characteristic of these tumors were surprising to the investigators who discovered them: they block a type of cell death called ferroptosis. Cancers with these changes require this blockade to stay alive and grow. The study was published December 1, 2020, in Cell Reports.

Ferroptosis is a type of programmed cell death that is dependent on iron. Ferroptosis was discovered less than a decade ago, but it has already emerged as an important target for cancer therapies as well as drug treatments for other diseases. When ferroptosis fails to occur when it should, cells can grow uncontrollably. 

“We really didn’t know what particular vulnerabilities we would find in these cancer cells,” says MSK physician-scientist Charles Rudin, Chief of the Thoracic Oncology Service, Co-Director of the Fiona and Stanley Druckenmiller Center for Lung Cancer Research, and the paper’s senior author. “But all of the work we report in this study pointed toward ferroptosis as a key player.”

Two Mutations Working Together

The genetic change that allows the cancer cells to block ferroptosis is called a co-mutation: alterations in two genes called STK11 and KEAP1 work together to create an environment in which tumor cells are able to grow even when they are receiving signals that would otherwise induce cell death. The combination of mutations in these two genes is found in more than 10% of lung adenocarcinomas, so a drug that could successfully target this alteration would have a meaningful impact.

MSK biostatistician Ronglai Shen was the first to discover that the STK11/KEAP1 co-mutation is often found in lung adenocarcinomas that are very aggressive and hard to treat. She made the discovery when doing an analysis of lung cancer using data from MSK-IMPACTTM, a test that looks for hundreds of mutations in tumors at the same time. Dr. Shen is a co-author on the new study.

The connection to ferroptosis was unexpected. “Our findings suggest that targeting certain proteins that play a role in the regulation of ferroptosis could lead to new treatments for this cancer,” Dr. Rudin says.

CRISPR Helps Create Useful Lab Models

In the current study, first author Corrin Wohlhieter, a graduate student in the lab that’s co-led by Dr. Rudin and Triparna Sen, used the gene editing tool CRISPR — which allows researchers to make very specific changes to the genetic code — to create three types of cells: some of these cells had the gene STK11 knocked out, some had KEAP1 knocked out, and some had both genes knocked out. She then isolated each of the three cell types and studied them in the lab, including in mouse models. By analyzing the cells’ behaviors, she was able to figure out which other genes were activated when STK11 and KEAP1 were lost.

“Lung cancers tend to be very heterogeneous, so if you don’t do these kinds of controlled experiments it’s hard to isolate changes attributable to a particular gene or set of genes,” Dr. Rudin says. “By creating these knockouts, it allows us to really focus on cells with these mutations and to link any behaviors we observe to the presence or absence of these factors.”

The team’s observations helped them make the connection to ferroptosis. They found that cells with both the STK11 and KEAP1 mutations also had high levels of proteins already known to make cells resistant to ferroptosis. Dr. Rudin and his colleagues pinpointed one of these proteins, called SCD1, as a particularly good target for these tumors.

“Although the current SCD1 inhibitors that we have are not likely to make good drugs,” he explains, “there are many labs at MSK that are actively investigating strategies for targeting ferroptosis in cancer cells.”

Dr. Rudin says he plans to work with other researchers to learn more about these interactions and to look for compounds that could be developed into drugs. “We hope to find drugs that inhibit the pathways in these tumor cells, ultimately developing a targeted therapy strategy for these particularly difficult cancers,” he concludes.

Targeted therapies are currently available for about one-third of people with lung adenocarcinoma, the most common kind of lung cancer. These drugs inhibit cancer cells by thwarting the molecular changes that drive them to grow while largely sparing healthy tissues. But for the other two-thirds of people with this type of cancer, there are fewer treatment options.

Ferroptosis is a type of programmed cell death that is dependent on iron. Ferroptosis was discovered less than a decade ago, but it has already emerged as an important target for cancer therapies as well as drug treatments for other diseases. When ferroptosis fails to occur when it should, cells can grow uncontrollably. 

“We really didn’t know what particular vulnerabilities we would find in these cancer cells,” says MSK physician-scientist Charles Rudin, Chief of the Thoracic Oncology Service, Co-Director of the Fiona and Stanley Druckenmiller Center for Lung Cancer Research, and the paper’s senior author. “But all of the work we report in this study pointed toward ferroptosis as a key player.”

Two Mutations Working Together

The genetic change that allows the cancer cells to block ferroptosis is called a co-mutation: alterations in two genes called STK11 and KEAP1 work together to create an environment in which tumor cells are able to grow even when they are receiving signals that would otherwise induce cell death. The combination of mutations in these two genes is found in more than 10% of lung adenocarcinomas, so a drug that could successfully target this alteration would have a meaningful impact.

MSK biostatistician Ronglai Shen was the first to discover that the STK11/KEAP1 co-mutation is often found in lung adenocarcinomas that are very aggressive and hard to treat. She made the discovery when doing an analysis of lung cancer using data from MSK-IMPACTTM, a test that looks for hundreds of mutations in tumors at the same time. Dr. Shen is a co-author on the new study.

The connection to ferroptosis was unexpected. “Our findings suggest that targeting certain proteins that play a role in the regulation of ferroptosis could lead to new treatments for this cancer,” Dr. Rudin says.O

CRISPR Helps Create Useful Lab Models

In the current study, first author Corrin Wohlhieter, a graduate student in the lab that’s co-led by Dr. Rudin and Triparna Sen, used the gene editing tool CRISPR — which allows researchers to make very specific changes to the genetic code — to create three types of cells: some of these cells had the gene STK11 knocked out, some had KEAP1 knocked out, and some had both genes knocked out. She then isolated each of the three cell types and studied them in the lab, including in mouse models. By analyzing the cells’ behaviors, she was able to figure out which other genes were activated when STK11 and KEAP1 were lost.

“Lung cancers tend to be very heterogeneous, so if you don’t do these kinds of controlled experiments it’s hard to isolate changes attributable to a particular gene or set of genes,” Dr. Rudin says. “By creating these knockouts, it allows us to really focus on cells with these mutations and to link any behaviors we observe to the presence or absence of these factors.”

The team’s observations helped them make the connection to ferroptosis. They found that cells with both the STK11 and KEAP1 mutations also had high levels of proteins already known to make cells resistant to ferroptosis. Dr. Rudin and his colleagues pinpointed one of these proteins, called SCD1, as a particularly good target for these tumors.

“Although the current SCD1 inhibitors that we have are not likely to make good drugs,” he explains, “there are many labs at MSK that are actively investigating strategies for targeting ferroptosis in cancer cells.”

Dr. Rudin says he plans to work with other researchers to learn more about these interactions and to look for compounds that could be developed into drugs. “We hope to find drugs that inhibit the pathways in these tumor cells, ultimately developing a targeted therapy strategy for these particularly difficult cancers,” he concludes.

Building a Safer Opioid: MSK Research Seeks to Develop New Ways to Relieve Pain

Source: Memorial Sloan Kettering - On Cancer
Date: 01/04/2018
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The United States is in the midst of an opioid epidemic. According to the Centers for Disease Control and Prevention, 91 Americans die every day from opioid overdoses, and that figure is rising.

Researchers are working to combat this epidemic. Economics, psychology, and medicine all play a role. Chemistry also can be a factor by contributing to the development of safer opioid drugs that effectively treat pain but are less likely to lead to addiction or abuse.

Memorial Sloan Kettering medicinal chemist Susruta Majumdar has focused on this effort for more than a decade. He is part of a multicenter group of researchers publishing a paper in Cell that reports an inventive approach for developing safer opioid drugs. We spoke with Dr. Majumdar recently about this research.

Why are opioid drugs so likely to cause addiction and abuse?

All of the opioid drugs that are currently available target what is called the mu opioid receptor. These drugs include morphine, oxycodone, and fentanyl. When they bind to this receptor, which is found in nerve cells all over the body, they block the pathways that transmit pain signals to the brain.

But targeting the mu receptor has another effect on the nervous system. It gives you a feeling of euphoria, a high. It’s the same thing you feel when you have sex or eat chocolate or take some other drugs, like cocaine. One of the reasons people become addicted to opioids is because they’re constantly seeking that high.

How does your research address the issue of opioid addiction and abuse?

In addition to mu, there are two other opioid receptors that also block pain signals. They are called the kappa receptor and the delta receptor. In my research, we’re looking for ways to activate the kappa receptor. We think this approach has great potential. Drugs that target the kappa receptor can block pain signals without giving the feeling of euphoria that leads to abuse.

Unfortunately, kappa drugs that have been studied in the lab also have unwanted side effects, like frequent urination. But more importantly, they cause hallucinations and dysphoria, or feelings of unhappiness. Our goal is to design kappa drugs that will provide effective pain relief while avoiding these other effects.

How are you investigating this?

We’re using an approach called structure-based drug design. It’s built on the idea that once we know the shape of a protein, we can design a molecule that will fit into it exactly the way we want it to, like a key fitting into a lock.

In this case, that protein is the kappa opioid receptor. We have determined its shape, so now we can design drugs that bind to it in just the right way.

What does the new Cell study add to this area of research?

In 2015, our team at MSK reported that we had created a compound that binds very effectively to the kappa opioid receptor. We called the compound MP1104. We showed this molecule had the ability to reduce pain without the other negative effects associated with kappa opioids. We also showed that it blocked cocaine addiction in mice.

A team led by pharmacologist Bryan Roth at the University of North Carolina (UNC) at Chapel Hill then used our molecule to crystalize the kappa opioid receptor and determine its structure. Once they did that, our lab at MSK developed a library of other molecules that are related to MP1104 using structure-based drug design.

The new compounds were synthesized by MSK research scholar Rajendra Uprety and tested by postdoctoral researcher Tao Che at UNC. At least one of the molecules we made shows an ability to bind selectively to the kappa receptor over other opioid receptors.

To summarize our findings, MP1104 has made it possible to understand how kappa receptors are activated. In addition, having the crystal structure available will allow us and others to discover new kappa drugs that can relieve pain without causing the unhappy feelings that the current kappa drugs can cause.

What’s next for this research collaboration?

We now have several promising compounds that we can begin to test in animals in the lab. Our goal is to find the best candidates to eventually test in people.

An Unlikely Treatment for Triple-Negative Breast Cancer: Prostate Cancer Drugs

Source: Memorial Sloan Kettering - On Cancer
Date: 01/29/2018
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For many people with breast cancer, drugs that target proteins driving the cancer’s growth have made a huge difference in fighting the disease. But for those with triple-negative breast cancer — a subtype defined by what it lacks rather than by its own characteristics — there are fewer good options.

Now doctors are finding an unlikely therapy for treating some of these tumors: drugs that were originally developed to treat prostate cancer. Results from a new multicenter trial published in the Journal of Clinical Oncology (JCO) report success with this approach. Memorial Sloan Kettering is at the forefront of this research.

“There is a great unmet need for novel, active therapies for patients with triple-negative breast cancer,” says MSK Breast Medicine Service medical oncologist Tiffany A. Traina, who is leading many of these efforts and was first author of the new study. “We have many women with advanced triple-negative breast cancer looking for clinical trials because standard chemotherapy options aren’t always enough for them.”

Different Breast Cancer Subtypes, Different Treatments

The three most common proteins known to fuel breast cancer growth are the estrogen receptor, the progesterone receptor, and the HER2 receptor. Estrogen and progesterone are female hormones that help regulate the menstrual cycle, among other functions. Drugs that block estrogen, such as tamoxifen and the class of drugs called aromatase inhibitors, can slow or stop the growth of tumors with these receptors.

Breast cancers with growth driven by the HER2 receptor can be treated with drugs that block this receptor, such as trastuzumab (Herceptin®) and others.

About 15% of breast cancers, however, are defined as triple negative. This means they don’t have any of these receptors. It also means they don’t respond to drugs that target them. These cancers do respond to chemotherapy, and some studies have suggested they actually may respond better to chemotherapy than other subtypes. But chemotherapy has more side effects than these other, targeted drugs.

Triple-negative disease is more common in African Americans, younger women, and those whose cancer results from inherited mutations in the BRCA genes.

Finding an Unlikely Target for Triple-Negative Breast Cancer Treatment

It turns out that about half of triple-negative breast cancers carry another hormone receptor — the one for the male hormone androgen. In a landmark study more than ten years ago, the late MSK pathologist William Gerald was the first to report that some breast cancers could carry the androgen receptor. His research also found the androgen receptor was responsible for growth of the cancer. This opened up a possible new option for treating breast cancer with this type of hormone therapy. (Although estrogen and progesterone are considered female hormones and androgens are regarded as male ones, both types of hormones are found in people of both genders.)

In 2013, Dr. Traina was the first to lead a multicenter study showing that this approach may be effective in treating triple-negative breast cancer. That study used another androgen-targeting drug, called bicalutamide (Casodex®).

The recent JCO study reported results from 78 women with advanced triple-negative breast cancer that expressed the androgen receptor. The purpose of the phase II trial was to evaluate the safety and efficacy of the prostate cancer drug enzalutamide (Xtandi®). All participants were treated with the drug, which is given as a pill, once a day. The investigators found that 33% of people benefited from the drug. Survival also appeared longer than expected for triple-negative breast cancer. The only serious side effect was fatigue.

Enzalutamide was co-invented by physician-scientist Charles Sawyers, Chair of MSK’s Human Oncology and Pathogenesis Program. The drug targets multiple steps in the androgen receptor signaling pathway, making it more effective in treating prostate cancer than some other androgen-blocking drugs.

“What’s so exciting is that this research started at MSK,” Dr. Traina says. “It’s a true bench-to-bedside story that begins with a discovery in the lab and has led to many trials that may offer a new, effective treatment for patients with this highest-risk subset of breast cancer.”

Further Expanding Uses of Enzalutamide

“The findings from this study support the continued development of enzalutamide for the treatment of advanced triple-negative breast cancer,” Dr. Traina adds. Another recent study that Dr. Traina participated in also found that enzalutamide can provide benefit when added to an aromatase inhibitor called exemestane (Aromasin) in people whose breast cancer carries both estrogen and androgen receptors. The findings were presented at the recent San Antonio Breast Cancer Symposium.

In addition, she and her colleagues are studying enzalutamide in early-stage triple negative breast cancer. They are also looking at several other prostate cancer drugs that block the androgen receptor, both alone and in combination with other novel targeted therapies.

Dr. Traina and MSK breast medical oncologist Ayca Gucalp are also recruiting people for a new trial that would test androgen receptor–blocking drugs specifically in men with breast cancer. About 90% of male breast cancers carry the receptors for estrogen or progesterone, and studies suggest that most of them also carry the androgen receptor.

Experimental Cancer Drug Developed at MSK Leads to New Approach for Treating Alzheimer’s Disease

Source: Memorial Sloan Kettering - On Cancer
Date: 03/01/2018
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Like cancer, Alzheimer’s disease involves changes in proteins. When functioning normally, proteins are important for cells to work properly. Also like cancer, Alzheimer’s occurs more commonly in older people, reflecting the idea that it usually takes a long time for these kinds of cellular changes to build up to a point that they cause real damage.

So although it may be a bit surprising, it’s not an impossible stretch to think that a drug developed to treat cancer may also work against Alzheimer’s disease. A family of these drugs has its origins at Memorial Sloan Kettering.

MSK chemical biologist Gabriela Chiosis has developed compounds for both cancer and Alzheimer’s. This week she spoke about her work at the National Institutes of Health’s Alzheimer’s Disease Research Summit. Dr. Chiosis was among top researchers from around the world who were invited to present their research on the biology of Alzheimer’s.

“Of Dr. Chiosis’s many intriguing discoveries, one that stands out is that Alzheimer’s disease shares a common cellular abnormality with many cancers,” says Larry Norton, Deputy Physician-in-Chief for Breast Cancer Programs at MSK, who has collaborated with Dr. Chiosis on the development of drugs. “The fact that there is a common mechanism raises the possibility of a common therapy. So her research could have profound implications for many human diseases, particularly those associated with aging.”

Targeting the Disease Process

Dr. Chiosis’s current work is focused on a type of regulatory network found inside cells called epichaperomes. “Epichaperomes form under conditions of chronic stress, something that is found in both cancer and Alzheimer’s disease,” she says. “One of the roles of these networks is to enhance the processes that become disrupted in diseased cells. These processes include defective signaling, increased production of certain proteins, and inflammation.”

In 2005, Dr. Chiosis and her colleagues developed a drug called PU-H71 for the treatment of cancer. PU-H71 is now in a phase I/II trial for people with metastatic breast cancer. Based on their discoveries about PU-H71, she and her team later developed a related drug, which they called PU-AD, for Alzheimer’s disease.

Both drugs bind to a protein called Hsp90 but only when it’s incorporated into the epichaperome network. Hsp90 is a protein found in essentially every cell in the human body. Its normal role is to help with proper protein folding. But when it becomes part of the epichaperome, Hsp90 contributes to stabilizing the proteins inside cells that let the disease develop.

“The formation of the epichaperome keeps damaged cells alive while they remain dysfunctional,” Dr. Norton explains. “Dr. Chiosis’s discoveries about epichaperomes are important because they are so overarching and could apply to many diseases.”

Taking a Look Inside Cells

Dr. Chiosis’s research has also led to imaging methods for detecting epichaperomes in cancer and Alzheimer’s, called PU-PET and PU-AD PET, respectively. She has collaborated with other investigators at MSK, including radiochemists Jason Lewis and Naga Vara Kishore Pillarsetty and radiologists Mark Dunphy and Steven Larson, on their development.

The approach involves attaching a weak radioactive label to PU-H71 or PU-AD, which then can be imaged with PET scanning. For cancer, PU-PET allows doctors to identify who is most likely to benefit from PU-H71 treatment. It can also help doctors monitor how well the drug is working.

In her presentation at the NIH summit, Dr. Chiosis discussed how an understanding of the epichaperome network can be used to identify some of the changes that occur in a number of different pathways in brain cells. These pathways can lead to Alzheimer’s disease, and learning more about them could suggest possibilities for the development of new targeted drugs.

She also talked about how PU-AD PET can be used to visualize Alzheimer’s disease in the brain. “The negative effects on memory, behavior, and the ability to think clearly that are commonly witnessed in people with Alzheimer’s are due to accumulation of toxic proteins called amyloid and tau in the brain,” Dr. Chiosis says. “But toxic changes in the neuron may begin 20 years before these deposits or the clinical symptoms of the disease develop. As such, we believe that using PU-AD PET to detect Alzheimer’s during this long preclinical phase may provide a promising window of opportunity for treatment.”

Both the PU-PET and PU-AD PET scans are now being tested in clinical trials at MSK. Dr. Norton and Dr. Chiosis have established a company called Samus Therapeutics that is focused on developing these scans as well as new therapies that target the epichaperome.

Immunotherapy Combination Is Better than Chemotherapy for Non-Small Cell Lung Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 04/16/2018
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A treatment that combines two specific immunotherapy drugs has already had success in some people with advanced melanoma and kidney cancer. A phase III study has now shown that the same combination was also effective for people with lung cancer. The international research team that conducted the trial was led by Memorial Sloan Kettering medical oncologist Matthew Hellmann. The findings are being presented at the 2018 American Association for Cancer Research (AACR) annual meeting. They are being published online in the New England Journal of Medicine as well.

The clinical trial was called CheckMate -227. It looked at combining nivolumab (Opdivo®) and ipilimumab (Yervoy®) to treat people with advanced non-small cell lung cancer, the most common type of lung cancer. The analysis being presented focused on people with a molecular marker indicating that there were many mutations in their tumors. Previous studies from MSK have suggested that tumors with many mutations are likely to respond to immunotherapy. After a minimum follow-up of nearly a year, those whose tumors had many mutations who received the immunotherapy combination were 42% less likely to have their cancer progress compared with those in the control group, who got standard-of-care chemotherapy.

“This trial had two important findings,” says Dr. Hellmann, who is a member of the Parker Institute for Cancer Immunotherapy at MSK. “First, it showed us that the combination of these immunotherapies together control lung cancer better than chemotherapy. Second, it showed that molecular markers are effective in helping to predict which people will benefit from immunotherapy.

“The results of this study highlight the importance of molecular profiling to identify the best treatment options for each patient,” he adds. “We are already doing this type of testing routinely for people with lung cancer, for example, with MSK-IMPACT™.”

Leading the Way in Clinical Trials

Ipilimumab and nivolumab are both in the class of drugs called immune checkpoint inhibitors. These drugs help control cancer by taking the brakes off the immune system. This allows the white blood cells called T cells to attack tumors. MSK physician-scientist Jedd Wolchok led the clinical research that resulted in the approval of ipilimumab in 2011 by the US Food and Drug Administration for the treatment of advanced melanoma.

Dr. Wolchok also led the pivotal clinical trial that resulted in FDA approval for the combination of ipilimumab and nivolumab in melanoma in 2015. Because that combination has worked well for melanoma, researchers decided to evaluate it for other cancers as well, including non-small cell lung cancer. Nivolumab on its own is already approved for this type of lung cancer, as well as for a number of other cancers.

Importance of Mutational Burden

Despite the striking success of checkpoint inhibitors at stopping cancer growth and even eliminating tumors in some people, these drugs don’t work for everyone. Research at MSK has focused on why that’s the case and looked for ways to predict beforehand who is most likely to benefit.

One important discovery that’s been made in many types of cancer is that tumors with a greater number of mutations tend to respond better to checkpoint inhibitor drugs than those with fewer mutations. This characteristic is called a high tumor mutation burden (TMB). In a related study, published online April 12, 2018, in the journal Cancer Cell, Dr. Hellmann and colleagues at MSK and elsewhere focused on the role of TMB in people with non-small cell lung cancer who were treated with nivolumab plus ipilimumab. The goal of study was to examine was to link the molecular features of the tumors to the patients’ outcomes after treatment with nivolumab plus ipilimumab in a phase I trial called CheckMate-012.

Based on their analysis, the researchers found that a high TMB was a good way to predict the effectiveness of combination immunotherapy in people with non-small cell lung cancer. The findings were used to guide the testing that was later done in the CheckMate -227 trial. TMB is already part of the results obtained from the MSK-IMPACT test.

A New Treatment Option for Non-Small Cell Lung Cancer

In CheckMate -227, among people whose tumors had a high TMB, the response rate was much better for those who got immunotherapy rather than chemotherapy. After getting the combination, 45% had their tumors shrink compared with 27% of those who got chemotherapy. And responses were distinctly durable with immunotherapy, where 68% were still responding to the immunotherapy combination one year after treatment started compared with only one-quarter of those who got chemotherapy.

The researchers say that immunotherapy is an important addition to the roster of treatment options for people with advanced non-small cell lung cancer. “This drug combination shows that some people can be spared treatment with chemotherapy,” Dr. Hellmann says. “And if a person stops responding to immunotherapy, they can still be given chemotherapy for additional benefit.”

Findings from Two Patients Shed New Light on Drug Resistance in AML

Source: Memorial Sloan Kettering - On Cancer
Date: 06/27/2018
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Last summer, the US Food and Drug Administration approved enasidenib (Idhifa®) for the treatment of acute myeloid leukemia (AML). Enasidenib works differently than most cancer drugs. Rather than killing leukemia cells, it turns them into normal blood cells. Memorial Sloan Kettering hematologist-oncologist Eytan Stein led the pivotal clinical trial that resulted in the drug’s approval.

Now, a collaborative team of researchers is reporting that people who take enasidenib can develop resistance to it — and in a way never seen before. The findings are being reported in Nature.

“Everyone who studies precision medicine spends a lot of time thinking about why some people respond to certain drugs and why some stop responding or never respond at all,” says physician-scientist Ross Levine, who was one of the paper’s senior authors, along with Dr. Stein. “MSK has been one of the leaders in figuring this out.”

The discovery was made by a team of doctors, laboratory researchers, and pharmaceutical company scientists. They used cells from people who were being treated with enasidenib to uncover why the drug sometimes stops working. 

Targeting a Mutation Found in Several Different Cancer Types

Enasidenib is approved for people with AML that is driven by a mutation in a gene called IDH2. About 15% of people with AML have this mutation. IDH2 mutations and mutations in the related gene IDH1 are found in other types of leukemia as well as myelodysplastic syndromes, glioblastoma, and bile-duct cancer.

The proteins made from mutated IDH genes can drive cells to become cancerous. MSK President and CEO Craig Thompson conducted much of the fundamental research on IDH mutations and their relationship to cancer. He is one of the co-authors of the Nature paper.

Researchers had previously shown that only one of the two copies of the IDH2 gene needs to be mutated to drive cancer. The other one is usually normal. In the new paper, the investigators report that when cells developed resistance to enasidenib, the additional mutations that allowed the cells to resist the drug occurred on the normal copy of IDH2.

This stands in contrast to how resistance develops against most targeted cancer therapies. In those cases, an already mutated gene develops an additional mutation that allows the cancer cell to fend off the drug’s effects. “The finding about IDH2 suggests that genetic resistance is more complicated than we thought,” says Dr. Levine, who is a member of MSK’s Human Oncology and Pathogenesis Program (HOPP).

Just two patients were in the study, but the investigators learned a great deal. Experiments with laboratory models allowed them to study how the mutations work. The findings suggest that some people may develop resistance to IDH inhibitors due to a mutation on the same copy of the gene that carries the cancer-causing mutation.

Dr. Levine says that this prediction was confirmed when the researchers identified a third patient being treated with a similar drug that targets a mutation in IDH1. The IDH inhibitor stopped working in this person when a resistance mutation appeared on the copy of the IDH1 gene with the cancer-causing mutation. This suggests that the process may be universal to all IDH-blocking drugs. “It’s a small number of people, but we’re quite confident that we’ll see this same mechanism in others moving forward,” he adds.

Targeting IDH mutations is a growing area of cancer drug development. Earlier this month, Dr. Stein was a co-first author of a paper published in the New England Journal of Medicinethat looked at another drug that targets the IDH1 mutation in people with AML. The multicenter phase I trial reported data on 125 people whose cancer had stopped responding to other treatments. The researchers found that of those treated with the drug, ivosidenib, almost 42% responded. Nearly 22% had a complete remission, meaning that their cancer was no longer detectable. The overall survival was longer than what would be expected in people with this stage of AML and severe side effects were rare. The researchers plan to continue studying the drug in larger, placebo-controlled trials.

A New Biomarker for Drug Resistance

After the people in the study developed resistance, their tumors started growing again. Doctors were able to switch them to other drugs that worked in a different way, however, so they were not affected by the additional mutation. There are a number of other treatment options for people with AML. These include both FDA-approved therapies and experimental drugs being tested in clinical trials. Many people with AML ultimately receive stem cell or bone marrow transplants, which offer the opportunity for a cure. However, many people are not able to undergo transplants, which makes developing new drugs an important focus.

“Now that we know resistance to enasidenib can develop, we can start to monitor people for it by conducting blood tests,” says first author Andrew Intlekofer, who is also a physician-scientist in HOPP. “Over the course of therapy, we can use the protein as a biomarker for the formation of resistance. Then we’ll know we need to offer a different treatment.”

Far-Reaching Implications for Other Cancers

Understanding how resistance to enasidenib develops could lead to the development of additional drugs. Although, Dr. Intlekofer adds, more research is needed before new drugs can be identified. He also notes that the new discoveries about enasidenib could apply to other drugs that work in a similar way. Treatment of other cancers that are characterized by IDH1 and IDH2 mutations could be affected as well.

Dr. Levine highlights the importance of collaboration when conducting this kind of research. Working closely with scientists from Agios, the company that makes enasidenib, was of particular importance, he says. “To do this kind of work, it requires a great team. Everyone who worked on this study made important contributions. This work was one of the most satisfying research experiences I’ve ever had.”

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

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

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

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

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

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

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

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

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

Ivosidenib and enasidenib are both made by Agios Pharmaceuticals.