An antibody drug that targets part of the bone growth pathway can slow the growth of human osteosarcoma implanted in mice and prevent the tumor from spreading to other parts of the body, according to a study led by Johns Hopkins Kimmel Cancer Center scientists.

David Loeb

David Loeb

Osteosarcoma is one of the most common bone tumors affecting children and adolescents. It is usually treated with surgery and chemotherapy, but the disease spreads in between 25 and 40 percent of patients, and 75 percent of those patients will die of their disease.

These survival rates remain “mostly unchanged” since the 1980s, making it important to uncover new therapeutic options, says David M. Loeb, M.D., Ph.D., an associate professor of oncology and pediatrics and director of the Musculoskeletal Tumor Program at the Kimmel Cancer Center.

As Loeb and colleagues reported earlier this year in Oncotarget, the antibody targets a molecule called DKK-1, which may promote tumor growth in osteosarcoma. DKK-1 blocks part of the Wnt molecular signaling pathway that is key to normal bone development.

Loeb and colleagues implanted tumors grown from human osteosarcoma cells into mice and were able to detect human DKK-1 circulating in the blood shortly afterward. The higher the levels of DKK-1, the faster the tumors grew in the mice, the researchers found. When DKK-1 levels in the mice were high, during the first six weeks of tumor growth, tumors increased in volume at a rate of almost 1 percent every three days, while the rate later slowed to .35 percent when DKK-1 levels were low.

When the mice were treated with a DKK-1 antibody, their human DKK-1 levels became undetectable, and they experienced a substantial slowdown in tumor growth — a .47 percent volume increase every three days, compared to a .95 percent increase in untreated mice.

The researchers then studied the antibody’s effects on metastasis using a mouse model that Loeb and his colleagues developed to more closely mimic osteosarcoma treatment in young patients. They implanted the tumor in a leg bone in the mice, waited for the tumor to grow before doing surgery or amputation to remove the tumor, and then watched to see if the cancer would metastasize.

Only one of 24 mice treated with the DKK-1 antibody developed metastatic disease, compared to six of 18 mice that did not receive the antibody. The one mouse that developed a metastasis appeared to have a local recurrence of its cancer, suggesting that the original surgery to remove the tumor was not completely successful.

“The major limitation to treating patients with osteosarcoma is prevention of metastasis, and I think our major finding is that in the mice who had a good surgery — meaning no local relapse — none of the [antibody]-treated animals developed metastasis,” says Loeb. “I would want to give this to patients early on in their treatment but continue throughout treatment and even up to a year after chemotherapy ended to maximize our chance of preventing metastasis.”

The antibody drug used in the study, called BHQ880 and manufactured by Novartis, also has been tested in clinical trials for the treatment of multiple myeloma. Novartis has discontinued the drug, but Loeb says that comparable antibody drugs could be developed.

It is also possible, Loeb says, that there may be other therapeutic targets to be discovered within the Wnt signaling pathway. “I think we’ve only scratched the surface in terms of understanding how Wnt signaling affects osteosarcoma,” he says.

Other scientists who contributed to the research include Johns Hopkins researchers Seth D. Goldstein, Wendy Bautista Guzman and Masanori Hayashi and Matteo Trucco of the University of Miami Sylvester Cancer Center.

Funding for the study was provided by the National Cancer Institute (1R01CA138212-01, 2P30CA006973), the Pablove Foundation and the Giant Food Children’s Cancer Research Fund.

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“Many lung cancers are not treated with one therapy alone,” says Russell K. Hales, M.D. “Sometimes it takes all three treatments—surgery, radiation, and chemotherapy-- to fully treat the lung cancer. And patients may be anxious after a surgery, about waiting in recovery for other treatments like chemotherapy and radiation.”

Hales, who is a radiation oncologist at the Johns Hopkins Kimmel Cancer Center on the Johns Hopkins Bayview campus, says, “Our goal is to start therapy as quickly as we can, but starting the therapy too quickly after surgery will just result in an unnecessary delay. If a patient starts therapy too quickly after surgery, they may not have fully recovered or healed. Then we may find a month into the next therapy that we need to put it on hold, so that they can recover. There's a balance that has to be maintained between recovering from surgery, and trying to start that therapy as quickly as possible,” he notes.

“At Hopkins, the window we usually use for that time of recovery is somewhere between three and seven weeks, after surgery. But that's going to be individualized, based on how well a patient recovers from surgery,” Hales says.

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The two main categories of lung cancer are small-cell lung cancer, and non-small-cell lung cancer, says Russell K. Hales, M.D. “Non-small cell lung cancer is further divided into adenocarcinoma, and squamous cell carcinoma.

“All lung cancer is aggressive, but all cancer in its early stages can be treated, and patients can have long term control of their disease,” says Hales, a radiation oncologist at the Johns Hopkins Kimmel Cancer Center on the Johns Hopkins Bayview campus. He notes that patients with small cell lung cancer are more likely to have disease that spreads outside of the lung, and although their tumors respond better to therapy, they're more likely to grow back.

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“It's not just smoking that leads to lung cancer,” says Russell K. Hales, M.D. “ We know that environmental exposures and underlying lung disease can increase the likelihood of lung cancer. Unfortunately, in patients with restrictive lung disease, we don't have any information to show that screening those patients will increase the likelihood of finding something.”

Hales, who is a radiation oncologist at the Johns Hopkins Kimmel Cancer Center on the Johns Hopkins Bayview campus, notes, “When people have other risk factors, like family members who have died from lung cancer, or those who have underlying lung problems, we still evaluate them in our pulmonary nodule clinic. On a clinical protocol, we can see if there's a benefit to being screened.” He recommends consulting with a pulmonologist at Hopkins to talk about next steps. Call 410-955-LUNG to set up a consultation.

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“Not everything that arises in the lung is cancer,” says Russell K. Hales, M.D., a radiation oncologist, at the Johns Hopkins Kimmel Cancer Center on the Johns Hopkins Bayview campus. “A nodule in the lung can be from infection, irritation, or inflammation. It can be from other diseases, unrelated to cancer at all.”

Hales notes that a ground glass opacity is a radiologist's characterization of how something may look on the scan. “It’s almost as if you were to describe a car as a red car. Well, that tells us it's red, but it doesn't tell us what type of car it is,” he says. Many factors go into determining how likely the opacity is to be cancer, including the size of the lesion, or whether it's growing.

“At the Hopkins Kimmel Cancer Center, we evaluate carefully whether a ground glass opacity is cancerous or not,” Hales notes. “We have a solitary pulmonary nodule clinic to evaluate patients with ground glass opacities. If you're a patient who was recently told you have something like this, you can certainly call 410-955-LUNG, so that we can specifically evaluate the ground glass opacity that you may have.”

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Eric Raabe

Eric Raabe

A rare cell line developed by Johns Hopkins researchers is giving scientists their first chance in decades to test new therapies for a lethal pediatric brain cancer that has few treatments.

Kimmel Cancer Center scientist Eric H. Raabe, M.D., Ph.D., helped to develop the diffuse intrinsic pontine glioma (DIPG) cell line, grown from tumor tissue donated by parents whose children died from the cancer. In two studies, Raabe and his colleagues used this DIPG cell line and others to identify the drug panobinostat (Farydak), along with an experimental inhibitor drug called MRK003, as possible treatments for DIPG.

In their report published online last May in the journal Nature Medicine, the researchers tested the impact of 83 different potential drugs on 16 DIPG cell lines, including the one developed at Johns Hopkins. They found that panobinostat was the most effective compound against the cancer cells, significantly shrinking DIPG tumors in five mice. The tumors were 6.5-fold larger in untreated mice, compared with tumors in mice treated with a single dose of panobinostat.

Panobinostat has been approved for use in some adult cancers, and Raabe said that plans for a phase 1 clinical trial to test the drug’s safety in children are now underway, thanks to the promising results of the Nature Medicine study.

DIPG, which accounts for about 10 percent of all pediatric brain tumors, is usually diagnosed between the ages of 5 and 10. The cancer is invasive and infiltrates itself among healthy cells in the brainstem, making surgical removal impossible. Patients receive radiation to treat their symptoms, but most live only six months to two years after their diagnosis.

Because the cancer is located in the brainstem, the part of the brain that controls breathing and heart rate, the tumor is rarely biopsied, and for a long time scientists had no living cell lines with which to test treatments.

“But there was a big change that happened about five years ago, when families began to advocate and ask what they could do to help learn more about DIPG,” Raabe explained. Some families began giving permission for their children to undergo “rapid autopsies,” which removed some of the tumor tissue within six hours of the children’s deaths.

The generosity of these parents helped Raabe and others at Johns Hopkins grow one of the first and most robust DIPG cell lines, giving researchers an opportunity to explore the molecular makeup of DIPG and to grow DIPG-like tumors in mice.

“Before this, we were shooting in the dark, and we had no models with which to test drugs until the last three or four years. With these cell lines, we’re part of a group that decided to try something different,” Raabe said. “And we went in a few years from having no drugs with any activity against DIPG to having a drug like panobinostat that at least in tissue culture and mouse models appears to have activity against DIPG.”

In a second study published in the Journal of Neuropathology and Experimental Neurology, Raabe and colleagues tested compounds that block the NOTCH molecular pathway in DIPG cells, since these tumors have been shown to have high levels of NOTCH pathway proteins. They found that an inhibitor compound called MRK003 shrank the number of DIPG cells by 75 percent over seven days of treatment, stopping the cells’ proliferation and triggering cell death. By combining MRK003 with radiation treatment, the researchers were able to boost the percentage of cell death in one DIPG line to 16.6 percent, compared with just 6 percent in cells treated with radiation alone.

Raabe said that it will important to explore the possibilities of both panobinostat and NOTCH inhibitors, since each type of drug comes with its own advantages. For instance, MRK003 can be targeted to brain tissue, but it’s unclear yet whether panobinostat can reach brain tissue as well. And while researchers wait for safety trials of panobinostat in children, “the phase 1 clinical study for NOTCH inhibitors has already been done in children, so we have a dose that we know,” Raabe noted.

Raabe added that none of this research—and the studies yet to come—would have been possible without the parents of DIPG patients making a difficult decision to donate tumor tissue. “The cell lines from these autopsies, and the amount of information that we have learned about DIPG in the last five or so years is remarkable, and it’s all due to the generosity of the families during very difficult times, and their consideration for the next generation of patients with DIPG.”

Other researchers on the Nature Medicine study include Catherine S. Grasso, Michael J. Quist, Nicholas Wang, Paul T. Spellman, Lara E. Davis, Elaine C. Huang, Charles Keller, Jinu Abraham, and Matthew N. Svalina of Oregon Health & Science University; Yujie Tang, Lining Liu, Pamelyn J. Woo, Anitha Ponnuswami, Spenser Chen, Tessa B. Johung, Michelle Monje, and Wenchao Sun of Stanford University; Nathalene Truffaux, Marie-Anne Debily, Ludivine Le Dret, and Jacques Grill of CNRS; Noah E Berlow and Ranadip Pal of Texas Tech University; Mari Kogiso, Yuchen Du, Lin Qi, Yulun Huang, Hua Mao, and Xiao-Nan Li of Baylor College of Medicine; Marianne Hütt-Cabezas of Johns Hopkins University; Katherine E. Warren, Paul S. Meltzer, and Martha Quezado of National Cancer Institute; Dannis G. van Vuurden and Esther Hulleman of VU University Medical Center, Amsterdam; Maryam Fouladi of Cincinnati Children’s Hospital Medical Center; Cynthia Hawkins of University of Toronto; Javad Nazarian at Children’s National Health Systems; and Marta M. Alonso of University Hospital of Navarra.

Scientists who contributed to the Journal of Neuropathology study include Kimmel Cancer Center scientists Isabella C. Taylor, Marianne Hütt-Cabezas, William D. Brandt, and Charles G. Eberhart; Madhuri Kambhampati and Javad Nazarian of George Washington University School of Medicine and Health Sciences; Howard T. Chang of Michigan State University; and Katherine E. Warren of the National Cancer Institute.

The research was supported by the Matthew Larson Foundation; the National Cancer Institute (P30 CA006973); Lyla Nsouli Foundation, the Children’s Oncology Group (COG) Central Nervous System Committee, the DIPG Collaborative (The Cure Starts Now Foundation, Reflections of Grace Foundation, Smiles for Sophie Foundation, Cancer-Free Kids Foundation, Carly’s Crusade Foundation, Jeffrey Thomas Hayden Foundation, Soar with Grace Foundation), the Accelerate Brain Cancer Cures Foundation (ABC2), CureSearch for Childhood Cancer, the Team Julian Foundation and the COG Chair’s Grant (5UOCA098543), the National Institutes of Health (K08NS070926), Alex’s Lemonade Stand Foundation, the McKenna Claire Foundation, the Connor Johnson Memorial Fund, the Dylan Jewett Memorial Fund, the Elizabeth Stein Memorial Fund, the Dylan Frick Memorial Fund, the Abigail Jensen Memorial Fund, the Zoey Ganesh Memorial Fund, the Wayland Villars DIPG Foundation, the Jennifer Kranz Memorial Fund, Unravel Pediatric Cancer, the Virginia & D.K. Ludwig Fund for Cancer Research, the Price Family Charitable Fund, the Godfrey Family Fund in Memory of Fiona Penelope, the Child Health Research Institute at Stanford, the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases, Etoile de Martin, Fondation Lemos and Le Défi de Fortunée, the Scott Carter Foundation, the Semmy Foundation, the Department of Defense, National Science Foundation (CCF0953366), Marie Curie grant (IRG270459), the Spanish Ministry of Health grant (PI13/0125), and the St. Baldrick’s Foundation and Iron Matt Foundation.

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--This post was written by freelance writer Becky Ham.

A compound made from the tree’s bark shows promise against tumors spurred by the leptin hormone.

Southern magnolia

Southern magnolia

Stand under the glossy green canopy of a southern magnolia in full bloom, and you’ll be dazzled by this queen tree’s show of hundreds of highly perfumed ivory blossoms, each the size of a teacup. It’s a stunning sight, but for centuries, Magnolia grandiflora has been known for more than its pretty face. The tree contains a pharmacopeia of sorts, yielding chemical compounds that have been used to treat everything from anxiety to heart attack.

Dipali Sharma, M.S., Ph.D., an associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center, thinks it may be time to add some breast cancers to this list of ailments. With her team at Johns Hopkins, Sharma is testing a magnolia compound called honokiol that seems to slow the growth of breast cancers fueled by an excess of leptin, a hormone closely connected with obesity.

Dipali and her colleagues have turned to honokiol after many years of studying the complicated role that leptin plays in breast cancer—and the role of obesity as a risk factor in many cancers. The well-known Million Woman study conducted through the University of Oxford suggested that about half the cancers in postmenopausal women in the United Kingdom can be attributed to obesity. Other studies have found that women at the highest body-mass index (BMI) levels have double the death rate from breast cancer, compared to those in the lowest BMI tier.

With nearly two-thirds of U.S. adults overweight or obese, according to U.S. Centers for Disease Control and Prevention, it’s a cancer risk factor that is poised to become “a very significant medical problem,” Sharma says. “Developing a preventive and therapeutic strategy for cancer in the obese state is extremely important.”

A Hormone’s Hyperactive Signals

Dipali Sharma

Dipali Sharma

Leptin is sometimes called the “starvation hormone,” although its role in the body is much more complicated. It is made by fat cells, and helps to regulate the body’s energy stores by suppressing hunger. People who are obese make more leptin because they have a higher percentage of body fat, but their bodies appear to be resistant to this hunger-inhibiting signal.

Unfortunately, the abnormal increased flow of leptin can trigger a variety of other changes in the body. Sharma and others have shown that leptin and its latch-like receptors on the surfaces of cells are overabundant in breast cancer cells, compared to normal breast cells. Their studies demonstrate that hyperactive leptin signaling by these cells causes the cancer cells to multiply and invade tissue, and spurs the growth of the blood vessels that feed tumors.

“We learned that leptin-induced tumors quickly learn to evade all the usual biological checkpoints that have been put in place to keep the tumors from growing and spreading fast,” says Sharma. Leptin helps the tumor cells make a critical change in their shape and mobility, she explains, “and after achieving this state, a tumor cell becomes poised to migrate and invade and transition from a primary, non-invasive tumor to an invasive tumor.”

The Johns Hopkins scientists realized that their results could help explain why advanced grade and stage cancers, including those that spread to the lymph nodes, are more prevalent in obese women with invasive breast cancer. So they set out to find a way to quiet leptin’s hyperactive signaling in these tumors.

The Magnolia Medicine Cabinet

Magnolia’s medical record is a long one, especially in places like China, Japan and the Korean peninsula. Records from China show that magnolia bark, called houpu, was used as early as 100 A.D. to treat digestion problems and breathing ailments such as asthma. The bark, cones and leaves from a variety of Magnolia species are taken in their whole form, as extracts or powders, or most often brewed into a herbal tea. In traditional Asian medicine, magnolia is prescribed as an anti-inflammatory drug, an anti-anxiety medicine, a blood thinner, and yes—an anticancer agent.

The chemical compound called honokiol, extracted from magnolia seed cones, appears to be one of a handful of biologically active ingredients in the magnolia plant. Researchers have tested honokiol in cells grown in the lab and in animals, and confirmed that the compound does have an array of medicinal properties. In the 1990s, the Emory University lab of cancer specialist Jack Arbiser developed new ways to purify the compound, leading to a flurry of studies in his lab testing honokiol’s anticancer properties against lymphocytic leukemia and myeloma, melanoma, breast and prostate cancers.

When Sharma and her colleagues began the search for a biologically active compound that would have anticancer activity and could shut down the leptin signaling network, honokiol leapt to the top of their list. It’s a small molecule, which makes it easier for the body’s cells to interact with and absorb. It doesn’t appear to be toxic except in very high doses, and it isn’t part of the hormone family that includes estrogen. This last point is important, says Sharma, because it means honokiol could “be used to treat estrogen-receptor (ER) positive as well as estrogen-receptor negative breast cancers.”

How Honokiol Works

In two studies (here and here) published last year in the journal Oncotarget, Sharma and her colleagues put honokiol under renewed scrutiny, first examining the effects of the compound on breast cancer cells grown in the lab. They discovered that honokiol can block the transformation and activation of some of the key molecules within leptin’s signaling network in these cells—most notably a signaling pathway that includes some well-known cancer-related proteins.

The researchers uncovered an especially intriguing role for a microRNA regulator called miR-34a. MicroRNAs are tiny snippets of genetic material that help to regulate how certain protein-coding genes are turned on and off. In a handful of other studies of miR-34a, scientists have identified the microRNA as an important tumor suppressor that is weakened in aggressive breast tumors. Now, for the first time the Johns Hopkins research team has shown that honokiol helps to keep miR-34a active and able to suppress some of the other cancer-linked proteins in the leptin network.

Sharma and her colleagues then fed some mice a high fat diet and watched their leptin levels rise, compared to those in mice on a normal diet. Breast tumors grown in the obese, hyper-leptin mice had low levels of the protective miR-34a, they soon discovered, but these levels rose when the mice were fed doses of honokiol. Over four weeks of treatment, these tumors grew to be significantly smaller in obese mice treated with honokiol, to about the half the size of the tumors in untreated obese mice.

The link between obesity, leptin and breast cancer has been strengthened by these and other studies. But Sharma says the findings haven’t yet changed how breast cancer patients are diagnosed or treated. “Currently, clinicians do not distinguish between leptin-induced or non-induced breast cancers,” she explains. “It’s not the usual clinical practice to check a patient for leptin or leptin receptor levels.”

She thinks the data collected by her lab and others will alter this practice in the future, especially since leptin signaling could affect how well standard breast cancer therapies work. Some studies suggest, for instance, that breast cancer cells that have exposed to high levels of leptin over several years might be less sensitive to treatments like tamoxifen.

The next steps would be to begin a clinical trial of honokiol in breast cancer patients who are obese, “and then move toward tests of all patients who have this high-leptin state,” Sharma says.

This research was funded by the Breast Cancer Research Foundation and The Fetting Fund.

Learn more about Dipali Sharma’s research, and the work of our other nationally-recognized physician-scientists in developing new ways to diagnose, treat and support breast cancer patients, at the Kimmel Cancer Center’s Breast Cancer Program’s website.

 

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Julie Brahmer

Julie Brahmer, M.D., is interviewed at the ASCO 2016 meeting.

Julie Brahmer, M.D., director of the Thoracic Oncology Program, began treating patients with immunotherapy drugs nearly a decade ago. She led one of the first large studies of the popular drugs, which was reported in 2012. Since then, Brahmer has become an expert in identifying and managing side effects that come with taking the drugs. “Patients can experience side effects that include anything that ends in –itis,” says Brahmer. They are typically ones that involve inflammation, such as colitis (inflammation of the colon) and the worst of them, pneumonitis (inflammation of the lungs). These types of side effects aren’t unexpected, says Brahmer, when taking medicines that tinker with the immune system, and inflammation is considered an immune-related biochemical process. Aside from inflammation-related side effects, fatigue often tops the list of the drugs’ side effects, says Brahmer. She says some patients also experience low thyroid hormone levels. A new study of patients receiving immunotherapy at the Kimmel Cancer Center may reveal a connection between the drugs and the development of inflammatory arthritis.

“Patients are concerned about drugs’ side effects,” says Brahmer. “So, we need to educate clinicians and learn to recognize and treat side effects early.” The toxic effects of the drugs can occur anytime during a patient’s regimen, she says, even after patients stop taking the drugs. If side effects occur, they are typically at low grade levels, but some have more severe effects. Treatment includes oral corticosteroids, and, for severe problems, hospitalizations may be necessary.

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Dr. Tom Smith at #ASCO16.

Dr. Tom Smith at #ASCO16.

Tom Smith, M.D., wants cancer patients to live well. Fewer side effects, better quality of life, more joyful time with family…these are among the primary goals, he says, of palliative medicine. Researchers have studied the impact of palliative medicine programs on patients’ outcomes, and results show that patients benefit, says Smith. “A lot of aggressive chemotherapy is given in the last six months of life, and only about 18 percent of these patients ever use hospice, so they are missing an important part of good cancer care.” says Smith, director of Palliative Medicine at Johns Hopkins Medicine and the Harry J. Duffey Family Professor of Palliative Care at the Johns Hopkins Kimmel Cancer Center. Professional organizations, including the American Society of Clinical Oncology (ASCO), have pointed to better treatment outcomes among patients who have six months or less to live and are in hospice programs. “They have better quality of life, better caregiver support and at least two studies have shown that cancer patients who use hospice live longer than those who don’t. There are multiple studies that show cancer patients who get palliative care alongside their usual care have better quality of life, fewer symptoms, can plan better, and live longer, too,” says Smith, who discussed an #ASCO16 presentation  by researchers at the University of North Carolina, Chapel Hill.

So, how can more patients access palliative medicine programs? Smith says the concept of palliative medicine should be introduced early in cancer care -- for every patient -- through consultations with palliative medicine teams, apart from the primary oncologist. Smith suggests GetPalliativeCare.org for more information and PrepareForyourCare.org for tips on how to manage serious illness. He also says that doctors should encourage the concept of “prognostic awareness” sooner than later with their patients, by having specific and honest discussions about prognosis throughout their care.

Watch Smith discuss end of life care in this MedPage Today video and read his comments on the American Association for Cancer Research blog.

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IMG_0625

Suzanne Topalian

Immunotherapy expert, Suzanne Topalian, M.D., delivered a presentation to a standing room only crowd at the 2016 American Society of Clinical Oncology (#ASCO16) regarding new directions in scientists’ search for biomarkers that identify patients and tumor types most likely to respond to immunotherapy drugs. Among the approaches is an immunohistochemistry test for the protein PD-L1, which is found on the surface of cancer cells. PD-L1 binds with its partner, PD-1, a protein found on immune cells, to create a chemical “handshake” that blocks the immune system from identifying and killing cancer cells. Several immunotherapy drugs against PD-1 or PD-L1, called “immune checkpoint blockers,” aim to disrupt this chemical connection. A chemical test performed on biopsy specimens identifies patients whose tumor cells are studded with the PD-L1 protein and may be more likely to respond to checkpoint blocking drugs.  However, there are still many patients whose tumor test for the PD-L1 protein are negative and can respond to the drugs. “This is a complex biomarker,” said Topalian, associate director for the Bloomberg-Kimmel Institute for Cancer Immunotherapy. “There are different interpretations and scoring of the commercially available tests and other tests in development, and more study is needed.”

Another response-predicting biomarker targets mutations in DNA mismatch repair genes found in cancer cells. The connection between the mismatch repair gene mutations and response to the immunotherapy drug pembrolizumab (anti-PD-1) was first described at last year’s ASCO meeting. From that research, scientists at the Kimmel Cancer Center showed that patients whose tumors have these mutations (about 10-15 percent of colorectal cancers and 2-4 percent of other cancer types) are more likely to respond to pembrolizumab. Topalian said last year’s data are holding up and tumor responses occur in about 50 percent or more of patients with these mutations.

Finally, scientists have some of the first evidence, based on data presented earlier this year by Topalian and colleagues at the Fred Hutchinson Cancer Research Center, that patients who have virus-linked skin cancer called Merkel cell carcinoma may also respond well to receiving the immunotherapy drug pembrolizumab (anti-PD-1) as their first therapy. Additional data presented by Howard Kaufman from Rutgers at #ASCO16, showed that among 88 patients with this rare but aggressive form of skin cancer, 32 percent of them had significant tumor regressions after receiving an immunotherapy drug called avelumab (anti-PD-L1), and most of the responses were ongoing at the point of the data’s analysis. Patients who had had two or more previous therapies did not respond as well as those who had only one round of chemotherapy. Taking this and the previous study into context, Topalian noted that these two immunotherapy drugs target the same pathway and seem to mediate regressions in advanced Merkel cell cancers. She said there may be more of an advantage in using these drugs in the first line of therapy for these cancers, however, more observation of patients and additional studies will be needed to provide evidence. For Merkel cell carcinoma, a rare cancer that is classified as an orphan disease, Topalian added, “these two national and global studies highlight the importance of networking centers.”

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