Study Focuses on a Different Kind of Liquid Biopsy to Detect Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 08/13/2020
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Because cancer is easier to successfully treat when it’s caught early, a major goal in cancer research is to develop new ways to find tumors at early stages, before they start to spread. One approach that’s being studied are liquid biopsies. These tests aim to find and diagnose cancer anywhere in the body by detecting biomarkers — materials that tumors shed into the bloodstream — in a blood sample.

In a study published August 13, 2020, in Cell by a team of collaborators from Memorial Sloan Kettering and Weill Cornell Medicine, researchers report that tiny packages of materials released by tumors, called EVPs (extracellular vesicles and particles), may serve as biomarkers for detecting a number of different types of cancer in the early stages.

“One of the holy grails in cancer medicine is to diagnose an early cancer in a patient based on a blood test,” says MSK surgeon William Jarnagin, Chief of the Hepatopancreatobiliary Service and co-senior author of the study. “This research is a proof-of-principle study; much more work is needed before it can be used as a screening tool. But ultimately, it would be fantastic if we could use this approach to find cancer in someone before they had symptoms.”

A Different Type of Biomarker

Much of the previous work on liquid biopsies has focused on the detection and analysis of cancer genes that are released by cancer cells into the blood. Some of these liquid biopsies, including MSK-ACCESS, are already approved as a tool for monitoring treatment and matching patients who have cancer with the appropriate targeted therapy. Using liquid biopsies as a screening tool to detect previously undiagnosed cancer is still experimental.

The new study focuses not on analyzing genes but instead examining proteins contained in EVPs. David Lyden, a physician-scientist at Weill Cornell and the paper’s other senior author, studies EVPs in his lab and is a pioneer in the field. He has found that tumors may release EVPs as a way to prepare other parts of the body to receive cancer cells when they spread.

The researchers say that one potential advantage of focusing on proteins in EVPs rather than cancer genes is that it allows them to also characterize different types of cells found in the area around a tumor — called the tumor microenvironment. In addition, it could help them detect changes in other tissues, such as immune organs, which also contribute to EVP proteins that are seen in the blood.

Using Machine Learning to Process Data

The current study looked at whether EVPs might be useful in screening. It employed blood and tissue from people who were known to have cancer as well as some samples from cell lines and mouse models. The research included samples from 18 different cancers, including breastcolon, and lung, which came primarily from MSK. There was a comparison group of samples from people who didn’t have cancer.

A computational biology approach was used to match particular EVP protein signatures with certain types of cancer. “The amount of information that comes from this kind of study is monumental — it’s a huge amount of data,” Dr. Jarnagin says. “You really need high-throughput computer programs and machine learning to be able to sort through it all.”

Once the computing method was established, the team found that the computer could identify different types of cancer from the samples with a sensitivity of 95% (meaning that it found the cancer in 95% of cases) and a specificity of 90% (meaning that 10% of the cancers it identified turned out to be false positives).

“Even if this test became standard, we still would have to do CT and MRI scans to confirm where the tumor was located,” Dr. Jarnagin says. “But if you use a blood test to find who might be at risk of having a certain type of cancer, it would be a huge advance because we could target investigations to these high-risk patients.”

He adds that if this type of liquid biopsy is shown to be effective for clinical use, it’s likely to also be useful in monitoring the treatment response in people already diagnosed with cancer. It may also be a good tool to monitor people after treatment to determine whether their cancer has come back when it’s still too small to show up on a scan.

Next Steps for Validating Findings

Using liquid biopsies to detect cancer is a much bigger challenge than using them to monitor cancers that are already known. For now, the team is focused on the next step: validating that their lab findings with EVPs will work with additional patients. Part of the validation process will involve testing this method in those who don’t have cancer but have an increased risk due to a strong family history or a known mutation in one of the BRCA genes, for example. Standard diagnostic methods will be used as a comparison in the validation process.

Dr. Jarnagin explains that in the future, liquid biopsies are likely to be especially important for diagnosing cancers that don’t currently have established screening methods, including liver and pancreatic cancers.

“These cancers are rarely detected early and treating them as soon as possible could result in better patient outcomes,” says Dr. Lyden, who is a member of the Sandra and Edward Meyer Cancer Center and the Gale and Ira Drukier Institute for Children’s Health at Weill Cornell Medicine.

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.

Imaging and Artificial Intelligence Tools Help Predict Response to Breast Cancer Therapy

Source: Memorial Sloan Kettering - On Cancer
Date: 10/23/2020
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For people with breast cancer, biopsies have long been the gold standard for characterizing the molecular changes in a tumor, which can guide treatment decisions. Biopsies remove a small piece of tissue from the tumor so pathologists can study it under the microscope and make a diagnosis. Thanks to advances in imaging technologies and artificial intelligence (AI), however, experts are now able to use the characteristics of the whole tumor rather than the small sample removed during biopsy to assess tumor characteristics.

In a study published October 8, 2020, in EBioMedicine, a team led by experts from Memorial Sloan Kettering report that — for breast cancers that have high levels of a protein called HER2 — AI-enhanced imaging tools may also be useful for predicting how patients will respond to the targeted chemotherapy given before surgery to shrink the tumor (called neoadjuvant therapy). Ultimately, these tools could help to guide treatment and make it more personalized.

“We’re not aiming to replace biopsies,” says MSK radiologist Katja Pinker, the study’s corresponding author. “But because breast tumors can be heterogeneous, meaning that not all parts of the tumor are the same, a biopsy can’t always give us the full picture.”

Harnessing the Power of Machine Learning

The study looked at data from 311 patients who had already been treated at MSK for early-stage breast cancer. All the patients had HER2-positive tumors — meaning that the tumors had high levels of the protein HER2, which can be targeted with drugs like trastuzumab (Herceptin®). The researchers wanted to see if AI-enhanced magnetic resonance imaging (MRI) could help them learn more about each specific tumor’s HER2 status.

One goal was to look at factors that could predict response to neoadjuvant therapy in people whose tumors were HER2-positive. “Breast cancer experts have generally believed that people with heterogeneous HER2 disease don’t do as well, but recently a study suggested they actually did better,” says senior author Maxine Jochelson, Director of Radiology at MSK’s Breast and Imaging Center. “We wanted to find out if we could use imaging to take a closer look at heterogeneity and then use those findings to study patient outcomes.”

The MSK team took advantage of AI and radiomics analysis, which uses computer algorithms to uncover disease characteristics. The computer helps reveal features on an MRI scan that can’t be seen with the naked eye.

Using an Algorithm to Personalize Treatment

In this study, the researchers used machine learning to combine radiomics analysis of the entire tumor with clinical findings and biopsy results. They took a closer look at the HER2 status of the 311 patients, with the aim of predicting their response to neoadjuvant chemotherapy. By comparing the computer models to actual patient outcomes, they were able to verify that the models were effective.

“Our next step is to conduct a larger multicenter study that includes different patient populations treated at different hospitals and scanned with different machines,” Dr. Pinker says. “I’m confident that our results will be the same, but these larger studies are very important to do before you can apply these findings to patient treatment.”

“Once we’ve confirmed our findings, our goal is to perform risk-adaptive treatment,” Dr. Jochelson says. “That means we could use it to monitor patients during treatment and consider changing their chemotherapy during treatment if their early response is not ideal.”

Dr. Jochelson adds that conducting more frequent scans and using them to guide therapies has improved treatments for people with other cancers, including lymphoma. “We hope that this will get us to the next level of personalized treatment for breast cancer,” she concludes.

Why Do Certain Chemotherapies Increase the Likelihood of Blood Cancer?

Source: Memorial Sloan Kettering - On Cancer
Date: 10/26/2020
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In recent years, improvements in cancer therapy have led to a significant increase in cancer survivorship. Experts estimate that by 2022, the United States will have 18 million cancer survivors, but a subset of those survivors will have long-term health problems to be addressed.

One rare complication of cancer treatment is the development of a secondary blood cancer — therapy-related acute myeloid leukemia or myelodysplastic syndrome. These blood cancers are very aggressive and do not respond well to treatment. Historically, doctors thought that cancer treatments such as chemotherapy and radiation caused an accumulation of mutations in the blood that led to these therapy-related cancers.

In recent years, however, researchers have found that these mutations in the blood can also occur spontaneously with increasing age. This phenomenon is called clonal hematopoiesis (CH), and it’s found in 10 to 20% of all people over age 70. The presence of CH increases the risk of developing a blood cancer. Using data from MSK-IMPACTTM, Memorial Sloan Kettering’s clinical genomic sequencing test, researchers have shown that CH is also frequent in cancer patients.

In a study published in Nature Genetics on October 26, 2020, MSK investigators sought to understand the relationship between CH in cancer patients and the risk of later developing a treatment-related blood cancer. The study included data from 24,000 people treated at MSK. The researchers found CH in about one-third of them.

“Because many people treated at MSK have genetic testing done using MSK-IMPACT, we have this amazing resource that allows us to study CH in cancer patients at a scope that nobody else has been able to do,” says physician-scientist Kelly Bolton, lead author of the study.

Decoding Genetic Changes Specific to Cancer Treatment

Focusing on a subset of patients on whom they had more detailed data, the investigators observed increased rates of CH in people who had already received treatment. They made specific connections between cancer therapies such as radiation therapy and particular chemotherapies — for example certain platinum drugs or agents called topoisomerase II inhibitors — and the presence of CH.

Unlike the CH changes found in the general population, the team found that CH mutations after cancer treatment occur most frequently in the genes whose protein products protect the genome from damage. One of these genes is TP53which is frequently referred to as “the guardian of the genome.”

The work was supported by the Precision Interception and Prevention (PIP) program at MSK, a multidisciplinary research program focused on identifying people who have the highest risk for developing cancer and improving methods for screening, early detection, and risk assessment.

The authors embarked on a three-year study to understand the relationship between CH and cancer therapy. For this part of the research, more than 500 people were screened for CH when they first came to MSK and then at a later point during their treatment. One finding from the study was that people with pre-existing CH whose blood carried mutations related to DNA damage repair such as TP53, were more likely to have those mutations grow after receiving cancer therapies, when compared to people who did not receive treatment.

“This finding provides a direct link between mutation type, specific therapies, and how these cells progress towards becoming a blood cancer,” says Elli Papaemmanuil of MSK’s Center for Computational Oncology, one of the two senior authors of the study. “Our hope is that this research will help us to understand the implications of having CH, and to begin to develop models that predict who with CH is at higher risk for developing a blood cancer.”

For a subset of patients with CH who developed therapy-related blood cancers, the researchers showed that blood cells acquired further mutations with time and progressed to leukemia. “We are now routinely screening our patients for the presence of CH mutations,” adds computational biologist Ahmet Zehir, Director of Clinical Bioinformatics and the study’s co-senior author. “The ability to introduce real-time CH screening for our patient population has allowed us to establish a clinic dedicated to caring for cancer patients with CH. As we continue to study more patients in the clinic, we expect to learn more about how to use these findings to find ways to detect treatment-related blood cancers early when they may be more treatable.”

Applying Findings to Future Treatments

In the future, this research may help to guide therapy by indicating whether some chemotherapy drugs are more appropriate than others in people with CH. People who are at a high risk of developing a treatment-related leukemia also may benefit from a different treatment schedule. “We hope that this research will allow us to ultimately map which CH mutations a person has and use that information to tailor their primary care and also mitigate the long-term risk of developing blood cancer,” Dr. Papaemmanuil says.

“We explored this in collaboration with investigators from the National Cancer Institute, Dana-Farber Cancer Institute, Moffit Cancer Center, and MD Anderson, and showed that such risk-adapted treatment decisions could achieve significant reduction of leukemia risk, without affecting outcomes for the primary cancer,” Dr. Bolton adds.

The investigators also hope to use the data from this study to develop better methods for detecting CH-related blood cancers when they first begin to form — and potentially to develop new interventions that could prevent CH from ever progressing to cancer. “We’re excited about the idea of continuing to grow and expand the CH clinic as part of the integrated vision of PIP,” says physician-scientist Ross Levine, who leads MSK’s CH clinic and is a member of the Human Oncology and Pathogenesis Program.

“In addition to continuing to follow people who are at the highest risk of developing a secondary cancer, we want to continue to use the clinic as a vehicle for studies like this,” he adds. “Our long-term goal is to move toward therapeutic interventions and preventing disease in a way that we’ve never been able to do before.”

Single-Cell Study Sheds Light on Leukemia’s Family Tree

Source: Memorial Sloan Kettering - On Cancer
Date: 10/28/2020
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When Memorial Sloan Kettering postdoctoral fellows Linde Miles and Robert “Bobby” Bowman began working on a new research project in May 2019, they didn’t know how massive a task it would be.

Now, their undertaking — the biggest study ever to examine the genetic causes of leukemia at the level of individual cells — is being published October 28, 2020, in Nature. The findings reveal how a series of mutations in normal blood cells can lead to them eventually becoming cancerous. The study also shows how these mutations accumulate as the disease progresses.

“This single-cell approach gave us new insights into the journey that blood cells take on their path to becoming leukemia,” says physician-scientist Ross Levine, senior author of the paper and a member of the Human Oncology and Pathogenesis Program. “Our hope is that this glimpse into how and why leukemia develops will open up new areas of research in early diagnosis and treatment.”

Learning about Cancer, Cell by Cell

Traditional genomic analysis of cancers — including MSK-IMPACTTM, a test that looks for mutations in 468 genes in patients’ tumors — uses what is called bulk sequencing. That means that it surveys the mutations that are present across all the cells in a tumor sample.

By contrast, the approach used in this study deciphered the mutations found in every single cell. The samples were obtained from 146 people who were treated at MSK for acute myeloid leukemia (AML), as well as those with two blood conditions that can lead to AML: clonal hematopoiesis and a blood cancer called myeloproliferative neoplasms. The analysis yielded data on nearly 750,000 unique blood cells.

“Instead of just broadly profiling all leukemias, we wanted to be able to ask pointed biological questions,” Dr. Bowman explains. “Understanding how these mutations work together will give us insight into their biological function.”

One aspect the study focused on is what’s called the clonal architecture of the cancer. This is the order in which the mutations occur. Dr. Levine compares it to a family tree, with each branch taking the cells in a different direction — some remain healthy and others become aggressive cancer.

“Trying to figure out the clonal architecture is like looking at a maze,” says Dr. Miles, a biochemist who was recently awarded a Marie-Josée Kravis Women in Science Endeavor (WiSE) fellowship. “It required a lot of work to begin to make sense of what we found and begin to detect patterns.”

A United Effort

Dr. Miles spent the summer and fall of 2019 sequencing patient samples. She was able to complete five or six samples a day. When she finished, the amount of data that had been generated was overwhelming.

As a computational biologist, Dr. Bowman’s role was to figure out which mutations occurred together in the same cells and determine the order in which they appeared. At one point, he decided to consult his younger brother, Michael Bowman, a PhD student in mechanical engineering at the Colorado School of Mines.

Michael helped the MSK team develop the right mathematical formulas with an approach he normally uses to study robot behavior. Eventually he came to visit New York City, and spent much of the time that was supposed to be a vacation pouring over data with his brother, Dr. Miles, and Dr. Levine. Michael Bowman is a co-author on the paper.

“This was very much a team effort, and Ross was involved at every step, too,” Dr. Miles says. “It’s probably the most collaborative project I’ve ever worked on.”

Building a New Playbook for Cancer Research

Dr. Levine says the goal of this work is to take the new information about the clonal architecture back to the lab and use it to create more accurate disease models that can then be deployed to develop new diagnostic methods and potentially test new drugs.

“The analogy I like to use is that cancer is like the Death Star in Star Wars,” he says. “You can’t take it apart until you know where the critical nodes are — where the cells are most vulnerable to attack.”

He also explains that, historically, leukemia research has led to methods that can be used to study many other cancers. “Because we can get leukemia samples with a simple blood draw, they’ve always been more accessible,” he says. “Our hope is that similar single-cell studies in solid tumors and other blood cancers will follow and that our work will provide a playbook on how to approach these studies with other kinds of cancer.”

Working It Out: Does Exercise Boost the Effectiveness of Melanoma Treatment?

Source: Memorial Sloan Kettering - On Cancer
Date: 11/05/2020
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Exercise is not just an important part of life for Memorial Sloan Kettering physician-scientist Allison Betof Warner — it’s an important part of her research.

Dr. Betof Warner, a medical oncologist who specializes in treating people with melanoma, is also a member of MSK physician-scientist Jedd Wolchok’s lab. There, she studies the effects of exercise on melanoma and other cancers using mouse models. She hopes to eventually apply her findings to her patients.

In an interview, she talked about her work.

How did you get interested in studying the connection between exercise and cancer outcomes?

I’m a lifelong athlete. I was a competitive gymnast for many years, including as a Division 1 student-athlete in college. When I got to medical school [at Duke University School of Medicine], I became a marathon runner and CrossFit athlete. I competed in the CrossFit Games (the world championships of the sport) and have coached CrossFit since 2010.

I was also working on a PhD in cancer biology. I started out studying the structure of tumor blood vessels. Then I heard a talk from Lee Jones about exercise and cancer. [Dr. Jones, who was then at Duke, now leads MSK’s Exercise Oncology Service, which is studying how exercise affects cancer outcomes through both lab research and clinical trials.]

Lee was using mice to study whether exercise could help improve outcomes in breast cancer. He co-mentored me during my PhD, and we published a study that showed exercise improves the quality of the blood vessels going to a tumor, which, in turn, makes chemotherapy more effective.

How has the view of exercise and cancer changed?

When I started my PhD research about fifteen years ago, some people were concerned that if you improved the structure of the blood vessels in a tumor, it might help the tumor grow faster or make it easier to spread. Our research in mice showed that this is not a concern. We still haven’t shown that patients experience all the benefits we’ve seen in mice, but collectively the data suggest that exercise is not harmful — either in melanoma or any other kind of cancer.

Research has demonstrated that exercise has many benefits for people with cancer, including reducing cancer-related fatigue. It also provides psychological benefits by improving overall mood and sense of well-being.

What are you studying now?

My current research has been looking at mice running on a treadmill to see how it affects the immune system — both the immune cells coming into the tumor and those circulating in the body. We’re still learning, but early work has suggested that exercise slows the growth of melanoma tumors in mice and that it does so by acting on the immune system.

I first became interested in this topic when I was a medical resident, and immunotherapy was becoming an important form of cancer treatment. We’ve known for some time that exercise has effects on the immune system, so it raised interesting questions about the role exercise plays in the effectiveness of immunotherapy. After I came here as a fellow, I joined Jedd’s lab, where they were doing research on how to make immunotherapies more effective.

Does your research influence what you tell your patients?

Currently, we don’t have enough data to recommend one particular type of exercise over another. Several organizations, including the American College of Sports Medicine, have put out recommendations for people with cancer that recommend 150 minutes a week of moderate exercise or 75 minutes a week of more vigorous exercise. I share those guidelines with my patients.

If patients were exercising before their cancer diagnosis, I tell them to maintain what they were doing. For people who were completely sedentary, there is no magic number or exercise prescription for me to give them that’s data driven right now. But we know that getting up, moving around, and being active is good for people with cancer, and I tell them that.

What do you do to stay fit these days?

I exercise six days a week. It not only keeps me healthy, but it keeps me sane.

Before the COVID-19 pandemic, I was teaching CrossFit. I got a Peloton bike right before all the gyms closed, and I’ve become an avid user. My husband and I just bought a house in the suburbs, and I’m putting in a CrossFit gym in our garage. He’s very tolerant!

What are your plans for your research?

In addition to continuing my research in the lab, I’m working with Bill Tap [Chief of the Sarcoma Medical Oncology Service] and Julia Glade Bender [Vice Chair for Clinical Research in the Department of Pediatrics], who are leading the new Adolescent and Young Adult program at MSK. [This program aims to meet both the medical and psychosocial needs of people with cancer who are in their teens, 20s, and 30s.] I’m leading the development of an exercise component. It will focus on research as well as clinical care for patients in the program.

Because of the pandemic, the program will be remote at first, but our goal is to eventually hold in-person classes. One thing that’s important to emphasize about exercise is that it helps to create communities. For adolescent and young adult patients, we expect this program will become part of their support system.

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
Link to original

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.

Taking on New Challenges: 8 Questions with Gilles Salles

Source: Memorial Sloan Kettering - On Cancer
Date: 12/23/2020
Link to original

Gilles Salles recently joined Memorial Sloan Kettering as Chief of the Lymphoma Service within the Division of Hematologic Malignancies. Dr. Salles came to MSK after a long career at Claude Bernard University in Lyon, France.

In an interview conducted in early December just before the annual American Society of Hematology (ASH) meeting, where he presented updates from several studies he’s conducted, Dr. Salles spoke about his decision to join MSK, his research, and his plans for the Lymphoma Service.

Why did you decide to come to MSK?

MSK is a fantastic place in terms of clinical care, clinical research, and basic research. There are not many places in the world that have strengths in all three of these areas. There are so many opportunities here to bring talented scientists together with clinicians who can help them deliver their discoveries to patients.

I’ve been successful in my career, and I’ve been able to bring many improvements in lymphoma care to patients. I asked myself, “Should I just continue here in France and then retire in six or eight years, or should I take on a new challenge?” I decided that this kind of opportunity, to be able to interact more with basic scientists and to build upon translational research projects, doesn’t happen very often. That’s why I took the leap.

What was your relationship with MSK before you came here?

I already knew many members of the Lymphoma Service as well as people in other groups at MSK. I’ve been involved in collaborations with them over the years and have met them at conferences. They are a large part of the reason I decided to join MSK — it’s exciting to work with such talented people.

What was it like moving to a new continent in the middle of a pandemic?

It was strange. I moved to New York over the summer and started working at MSK in mid-August. I haven’t been in the same room with most of my new colleagues yet. We’ve all been meeting on Zoom.

I studied in the United States for my postdoc about 30 years ago in Boston. And I’ve been to New York and other parts of the United States many times since then, both for work and for vacations with my family. This is not the New York I was wishing to rediscover, but I’m hopeful that the pandemic will end soon.

What’s different about MSK’s Lymphoma Service?

We have the SPORE in Lymphoma [Specialized Programs of Research Excellence, a project funded by the National Cancer Institute to help move basic science findings into the clinic]. That was started by my predecessor, Anas Younes, and is now being led by Andrew Zelenetz, a leading physician in the field of B cell malignancies.  

MSK’s Lymphoma Service is quite large, with more than 20 faculty. Because there are so many of us, we can specialize not just in lymphoma but in particular types of lymphoma.

What types of lymphoma do you specialize in treating?

I was very fortunate 20 years ago to be part of the early development of the first monoclonal antibody drug for diffuse large B cell lymphoma (DLBCL), called rituximab. I’m continuing to work on developing new antibody drugs for DLBCL.

I also treat follicular lymphoma. This disease is unusual because some patients who are diagnosed with it don’t require treatment right away, only active surveillance. But it also doesn’t have a cure. Thanks to new treatments, we’ve been able to extend survival for this disease considerably, from an average of eight to ten years to an average of 15 to 20 years. But I think that with the addition of new treatments, especially different kinds of immunotherapy, we will soon be able to offer a cure for some patients.

What are some of the research collaborations you’re planning?

There are many projects I plan to pursue with people here at MSK.

I’m very excited to work with physician-scientist Santosh Vardhana, who recently started his own lab in the Human Oncology and Pathogenesis Program. He has so much knowledge about T cell biology, and we want to apply this to some of the clinical trials we are developing.

I’ve already had the opportunity to work on projects with hematopathologist Ahmet Dogan. To understand lymphoma, we have to really know what’s happening in the tumor, and pathology is the cornerstone of that.

Before I came here, I had met Sloan Kettering Institute cancer biologist Hans-Guido Wendel a few times, and I knew his work. I’ve joined his very innovative project looking at abnormal RNA translation in lymphoma to help bring his findings to the clinic.

In the past, I’ve participated in studies that looked at the ways a person’s genes influence how they respond to treatments for lymphoma. Through this work, I’ve been involved in some consortia with geneticist Vijai Joseph, who studies hereditary cancer. Now that we’re in the same place, we can find time to work more on this project.

What made you interested in pursuing science and medicine as a career — particularly cancer?

I got interested in medicine because I wanted to help people. Medicine is a profession where you bring something to others — health, one of the most precious things we have. I’m also a curious person, so that made science a natural fit.

When I finished medical school, and I had to choose where to focus, the field of oncology was attractive, in part because it was challenging. At that time, there weren’t many options for people with cancer, other than chemotherapy. We in the field were starting to learn more about the biology and immunology of the disease, and it felt like there were many opportunities to improve treatment for cancer patients.

What are you most looking forward to doing in New York once the pandemic is over?

My wife and I are both excited about getting into the jazz music scene. We sometimes hear musicians when we’re walking through Central Park, and it’s so good to hear live music.