Cancer and Blood Disorders Center
Cancer and Blood Disorders Center
News Article | May 13, 2017
The 35th annual Jimmy Fund Scooper Bowl®, presented by Valvoline Instant Oil Change SM, will take place at Boston’s City Hall Plaza on June 6, 7 and 8 from noon to 8 p.m. Dozens of flavors will be served by top ice cream and frozen yogurt companies in the nation’s largest all-you-can-eat ice cream festival. All proceeds support adult and pediatric cancer care and research at Dana-Farber Cancer Institute. “We’re thrilled to partner with Dana Farber to sponsor The Jimmy Fund Scooper Bowl for the 2nd consecutive year,” said Don Smith, CEO of Henley Enterprises, Inc., an independent licensee of Valvoline Instant Oil Change Franchising, Inc. “What better way to celebrate the summer than by bringing a family-fun event to Boston that also raises money to find cures for cancer?” Jimmy Fund Scooper Bowl has raised more than $5 million for Dana-Farber’s lifesaving mission. This year participants can cut the lines by purchasing the Valvoline Instant Oil Change ‘Speedy Pass’ for $25. Pre-event tickets are $5 for children ages 3-9 and $10 for adults. Event day ticket prices are $10 for children and $15 for adults. Children 2-years-old and under are free. A three-day Scooper Pass is $20. Tickets are available online at http://www.scooperbowl.org. About Valvoline Instant Oil Change℠ Valvoline™, a leading supplier of premium branded lubricants and automotive services, has been serving American motorists for more than 150 years. Its operating segment, Valvoline Instant Oil Change℠, ranks as the #2 quick-lube chain by number of stores, with more than 1,070 company-owned and franchised locations in the U.S. Its industry-leading model is built to deliver a quick, easy and trusted experience to every customer, every day. Visit http://www.vioc.com to learn more. ™ Trademark, Valvoline or its subsidiaries, registered in various countries ℠ Service mark, Valvoline or its subsidiaries, registered in various countries About the Jimmy Fund The Jimmy Fund (http://www.JimmyFund.org) solely supports Boston’s Dana-Farber Cancer Institute, raising funds for adult and pediatric cancer care and research to improve the chances of survival for cancer patients around the world. The Jimmy Fund is the official charity of the Boston Red Sox, Massachusetts Chiefs of Police Association, the Pan-Massachusetts Challenge, and the Variety Children's Charity of New England. Since 1948, the generosity of millions of people has helped the Jimmy Fund save countless lives and reduce the burden of cancer for patients and families worldwide. Follow the Jimmy Fund on Facebook: http://www.facebook.com/thejimmyfund and on Twitter: @TheJimmyFund. About Dana-Farber Cancer Institute From achieving the first remissions in cancer with chemotherapy in 1948, to developing the very latest new therapies, Dana-Farber Cancer Institute is one of the world’s leading centers of cancer research and treatment. It is the only center ranked in the top 4 of U.S. News and World Report’s Best Hospitals for both adult and pediatric cancer care. Dana-Farber sits at the center of a wide range of collaborative efforts to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. Dana-Farber/Brigham and Women’s Cancer Center provides the latest in cancer care for adults; Dana-Farber/Boston Children's Cancer and Blood Disorders Center for children. The Dana-Farber/Harvard Cancer Center unites the cancer research efforts of five Harvard academic medical centers and two graduate schools, while Dana-Farber Community Cancer Care provides high quality cancer treatment in communities outside Boston’s Longwood Medical Area. Dana-Farber is dedicated to a unique 50/50 balance between cancer research and care, and much of the Institute’s work is dedicated to translating the results of its discovery into new treatments for patients locally, and around the world. About Henley Enterprises, Inc. Henley Enterprises, Inc. founded in 1989, is the largest Valvoline Instant Oil Change franchisee. They operate over 200 service centers across twelve states including: California, Delaware, Florida, Michigan, Massachusetts, Maryland, New Hampshire, New Jersey, Ohio, Pennsylvania, Rhode Island, and Virginia.
News Article | May 12, 2017
Researchers find key molecule that could lead to new therapies for anemia and other iron disorders "Without iron, life itself wouldn't be feasible," says Barry Paw, MD, PhD. "Iron transport is very important because of the role it plays in oxygen transport in blood, key metabolic processes and DNA replication." New findings reported in Science by a multi-institutional team, including researchers from University of Illinois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Brigham and Women's Hospital and Northeastern University, could impact a whole slew of iron disorders, ranging from iron-deficiency anemia to iron-overload liver disease. The team has discovered a small molecule found naturally in Japanese cypress tree leaves, hinokitiol, can bypass iron disorders in animals. Paw, co-senior author on the new Science paper and physician at Dana-Farber/Boston Children's, and members of his lab demonstrated that hinokitiol can successfully reverse iron deficiency and iron overload in zebrafish disease models. Although iron is crucial to many aspects of health, it can't transport itself without the help of the body's iron-transporting proteins. Many human diseases of iron deficiency or overload result from hereditary or acquired loss of the protein function that is responsible ferrying iron across cellular membranes, subcellular compartments and mitochondrial membranes. "Like most things in life, too much or too little of a good thing is bad for you; the body seeks homeostasis and balance," says Paw. "Amazingly, we observed in zebrafish that hinokitiol can bind and transport iron inside or out of cell membranes to where it is needed most." For example, iron is a necessary co-factor in the body's production of hemoglobin, a protein that carries oxygen in the blood of vertebrates. But if iron-transporting proteins are absent, iron can't get across cell membranes and inside the cells' mitochondria, blocking an essential step of hemoglobin production. "Red blood cells are the number one type of tissue in the body that need iron, so if iron-transporting proteins are missing, anemia can result," says Paw. "Iron-deficiency anemia is the most common nutritional problem in the world." On the flip side, it's not good if too much iron builds up inside cells either. Iron overload can cause tissue damage, DNA damage and life-threatening organ dysfunction across the heart, liver and pancreas. This can be caused by a hereditary lack of iron-transporting proteins or from receiving frequent blood transfusions, which are often necessary over the course of treatment for many different medical conditions. "If you're sick because you have too much protein function, in many cases we can do something about it. But if you're sick because you're missing a protein that does an essential function, we struggle to do anything other than treat the symptoms. It's a huge unmet medical need," said the paper's co-senior author Martin Burke, MD, PhD, who led team members from University of Illinois. Burke's team initially found that hinokitiol could transport iron across cell membranes in vitro before reaching out to Paw and other collaborators to test its efficacy in animal models. A stain reveals hemoglobin production in a healthy zebrafish (left), an anemic zebrafish (middle) and an anemic zebrafish treated with hinokitiol (right).¬¬ Paw and collaborators observed that hinokitiol molecules can bind to iron atoms and move them across cell membranes and into/out of mitochondria, despite an absence of the native proteins that would usually carry out these functions. "If there is a genetic error, cell membranes won't open for iron to come across," says Paw. "But when you administer hinokitiol, it combines with iron and ferries it into, within or out of the cells and mitochondria where iron is needed. "Therefore, it's a very interesting small molecule that has a lot of therapeutic potential!" Paw concludes. The National Institutes of Health and the Howard Hughes Medical Institute supported this work.
News Article | May 12, 2017
A new molecule could help researchers find a bevy of new therapy options to help treat patients with anemia and other iron disorders. Researchers from several institutions including the University of Illinois, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Brigham and Women’s Hospital and Northeastern University, have pinpointed hinokitiol—a small molecule found in Japanese cypress tree leaves could lead to treatments for a range of iron disorders including iron-deficiency anemia and iron-overload liver disease. “Without iron, life itself wouldn't be feasible,” Dr. Barry Paw, Ph.D., said in a statement. “Iron transport is very important because of the role it plays in oxygen transport in blood, key metabolic processes and DNA replication.” The researchers successfully reversed iron deficiency and iron overload in zebrafish disease models using the molecule. “Like most things in life, too much or too little of a good thing is bad for you; the body seeks homeostasis and balance,” Paw said. “Amazingly, we observed in zebrafish that hinokitiol can bind and transport iron inside or out of cell membranes to where it is needed most.” The researchers discovered that the molecules can bind to iron atoms and move them across cell membranes and into and out of mitochondria, despite an absence of the native proteins that normally perform these functions. “If there is a genetic error, cell membranes won't open for iron to come across,” Paw said. “But when you administer hinokitiol, it combines with iron and ferries it into, within or out of the cells and mitochondria where iron is needed. “Therefore, it's a very interesting small molecule that has a lot of therapeutic potential,” he added. They also found that hinokitiol could transport iron across cell membranes in vitro prior to testing it on animals. Iron-related diseases are often hereditary or caused by an acquired loss of the protein function that is responsible for ferrying iron across cellular membranes subcellular compartments and mitochondrial membranes. Iron is necessary for the body to produce hemoglobin—a protein that carries oxygen in the blood of vertebrates. However, when the proteins are missing, iron can’t get across cell membranes and inside the cells’ mitochondria, blocking a crucial step in hemoglobin production. It is also problematic if too much iron builds up inside cells, causing tissue damage, DNA damage and life-threatening organ dysfunction across the heart, liver and pancreas. This is caused by a hereditary lack of iron-transporting proteins or from receiving frequent blood transfusions. “If you're sick because you have too much protein function, in many cases we can do something about it,” Dr. Martin Burke, Ph.D., the paper’s co-senior author, who led team members from the University of Illinois, said in a statement. “But if you're sick because you're missing a protein that does an essential function, we struggle to do anything other than treat the symptoms. It's a huge unmet medical need.”
News Article | December 6, 2016
SAN DIEGO, CA ¬- An immunotherapy drug able to induce lasting remissions in classical Hodgkin lymphoma may be equally effective in patients with either of two rare, aggressive forms of non-Hodgkin lymphoma, results from a small case series indicate. Dana-Farber Cancer Institute investigators who treated the patients will report their findings at the 58th annual meeting of the American Society of Hematology (ASH) on Monday, December 5, 2016. The research involved five patients with recurrent or refractory primary central nervous system lymphoma (PCNSL) or primary testicular lymphoma (PTL) who were treated with nivolumab, a drug that blocks a key protein, PD-1, on immune system T cells. The blocking allows the T cells to ignore signals that would dampen their attack on the lymphoma cells. Four of the patients had a complete response to the drug - showing no evidence of tumor on brain imaging - and one had a partial response. Both PCNSL and PTL are aggressive non-Hodgkin's lymphomas that occur outside the lymph nodes and respond poorly to conventional therapy. Nearly half of patients with PCNSL relapse within two years of diagnosis, and almost half of patients with PTL have their disease worsen after initial chemotherapy. For patients whose disease recurs or resists frontline therapy, there are few treatment options. Nivolumab has had striking success in clinical trials involving patients with classical Hodgkin lymphoma. Results from phase 1 and 2 trials show that approximately 70 percent of patients, all with drug-resistant forms of the disease, had full or partial remissions after treatment with the drug. Researchers in the lab of senior author Margaret Shipp, MD, of Dana-Farber discovered that PCNSL and PTL share a key molecular abnormality with classic Hodgkin lymphoma, leading them to hypothesize that nivolumab could be effective against these diseases as well. "There have been major advances in treatment of PCNSL, including high-dose chemotherapy and autologous stem cell transplant, particularly for young and healthy patients," said study lead author Lakshmi Nayak, MD, of Dana-Farber. "But because the median age at which patients are diagnosed is 65, transplant is often not an option. Our findings are very encouraging, particularly as the responses to nivolumab in our patients have been durable for more than 10 months." Based on their laboratory findings and clinical results, investigators have now opened a phase 2 trial of nivolumab in patients with relapsed or treatment-resistant PCNSL and PTL. Co-authors are Ann LaCasce, MD, Margaretha Roemer, Bjoern Chapuy, MD, PhD, Philippe Armand, MD, PhD, and Scott Rodig, of Dana-Farber; Fabio Iwamoto, MD, of Columbia University; and Srinivasan Mukundan Jr., of Brigham and Women's Hospital. From achieving the first remissions in childhood cancer with chemotherapy in 1948, to developing the very latest new therapies, Dana-Farber Cancer Institute is one of the world's leading centers of cancer research and treatment. It is the only center ranked in the top 4 of U.S. News and World Report's Best Hospitals for both adult and pediatric cancer care. Dana-Farber sits at the center of a wide range of collaborative efforts to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. Dana-Farber/Brigham and Women's Cancer Center provides the latest in cancer care for adults; Dana-Farber/Boston Children's Cancer and Blood Disorders Center for children. The Dana-Farber/Harvard Cancer Center unites the cancer research efforts of five Harvard academic medical centers and two graduate schools, while Dana-Farber Community Cancer Care provides high quality cancer treatment in communities outside Boston's Longwood Medical Area. Dana-Farber is dedicated to a unique, 50/50 balance between cancer research and care, and much of the Institute's work is dedicated to translating the results of its discovery into new treatments for patients locally and around the world.
News Article | September 15, 2016
Although targeted drugs like Gleevec have revolutionized the treatment of chronic myelogenous leukemia (CML), patients generally must take them for the rest of their lives and may cease benefiting from them over time. In new research that could suggest a road to a cure, scientists at Harvard-affiliated Dana-Farber Cancer Institute and Boston Children’s Hospital have found that CML stem cells die when a protein called Ezh2 is inhibited. Drugs that target the protein are currently in clinical trials for other cancers. The findings, reported online today in the journal Cancer Discovery, raise the prospect that Ezh2 blockers, in combination with Gleevec and similar drugs, could eradicate the disease in some patients relatively rapidly or could be an effective therapy for those who become resistant to Gleevec-like agents, the authors write. In a paper published simultaneously by Cancer Discovery, a team of Scottish scientists report similar findings using a different research approach. “The vast majority of patients with CML do remarkably well on imatinib [Gleevec] and similar drugs: The disease is well-controlled and side effects are tolerable,” said Stuart Orkin, the study’s senior author and a pediatric hematologist/oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “In only 10-20 percent of patients, however, are the leukemia cells fully cleared from the body. The other 90 percent retain a reservoir of leukemic stem cells — which initiate the disease — and must stay on the drugs permanently.” CML is a slowly progressing type of blood cancer that develops in the bone marrow. Primarily occurring in adults, it is rare in children. Over time, some patients develop resistance to Gleevec and other drugs that block BCR-ABL, the misbegotten “fusion” protein that drives CML growth. Although second- and third-line targeted therapies can often return the disease to remission, some patients don’t benefit from these drugs or develop severe side effects. The new study grew out of efforts to discover whether different types of cancer are susceptible to Ezh2 inhibitors. In laboratory experiments, the Dana-Farber/Boston Children’s researchers found that not only is Ezh2 overabundant in leukemia stem cells, but it helps them survive and give rise to full-fledged CML cells. Follow-up studies in mice showed that inactivating Ezh2 through gene-editing techniques caused CML stem cells to die, halting the disease at its source. “The stem cells’ dependence on Ezh2 suggests they will be especially vulnerable to drugs that target the protein,” Orkin said. “Such drugs are already in clinical trials for other diseases, including lymphoma and some solid tumors.” Epizyme, a biopharmaceutical company based in Cambridge, Mass., recently opened a pediatric trial of an Ezh2 inhibitor for children with rhabdoid and other tumors. Dana-Farber/Boston Children’s is a site in the multicenter Phase 1 trial. Although adding Ezh2-targeting agents to the standard drug regimen for CML has the potential to dramatically shorten the treatment period for many patients, ethical considerations may lead to the agents’ first being tested in patients who don’t respond to Gleevec and similar drugs, either initially or after drug resistance develops, Orkin said. “Our findings suggest inhibition of Ezh2 should be considered as a way to eradicate CML when used in combination with current targeted therapies. It offers a promising approach to shortening the duration of therapy in order to achieve a cure. If successful, the cost savings of such an approach could also be significant.” The study was funded in part by the National Institutes of Health and Hyundai Hope on Wheels.
News Article | November 21, 2016
BOSTON -- In a new study, a group of Boston scientists, including researchers at Dana-Farber Cancer Institute, offer a genetic explanation for the age-old conundrum of why cancer is more common in males than females. Females, it turns out, carry an extra copy of certain protective genes in their cells - an additional line of defense against the cells growing out of control - the investigators report in a paper published online today by Nature Genetics. Though not solely responsible for cancer's "bias" toward males, the duplicate copies likely account for some of the imbalance, including up to 80 percent of the excess male cases in some tumor types, report the study authors, based at Dana-Farber, the Broad Institute of Harvard and MIT, and Massachusetts General Hospital. "Across virtually every type of cancer, occurrence rates are higher in males than in females. In some cases, the difference might be very small - just a few percent - but in certain cancers, incidence is two or three times higher in males," said Andrew Lane, MD, PhD, of Dana-Farber, the co-senior author of the study with Gad Getz, PhD, of the Broad Institute and Massachusetts General Hospital. "Data from the National Cancer Institute show that males carry about a 20 percent higher risk than females of developing cancer. That translates into 150,000 additional new cases of cancer in men every year." Despite the size of the gap, the reasons for this divergence have been difficult to discern. The historic explanation - that men were more likely to smoke cigarettes and be exposed to hazardous chemicals in the work environment - has proven inadequate, because even as smoking rates have dropped and occupational patterns changed, men still outpace women in developing many cancers, including some associated with tobacco use such as kidney, renal, bladder, and oral cancers, Lane said. The disparity is present among boys and girls, as well as men and women. Previous research found that in one form of leukemia, the cancer cells often carried a mutation in a gene called KDM6A, located on the X chromosome - one of the sex chromosomes that determine whether an individual is male or female. (Females cells carry two X chromosomes; males carry an X chromosome and a shorter, smaller Y chromosome.) If KDM6A is a tumor-suppressor gene - responsible for preventing cell division from spinning out of control - the mutation could lead to cancer by crippling that restraint system. One might expect female cells to be just as vulnerable to the mutation. During embryo formation, one of the X chromosomes in female cells shuts down and remains off-line for life. A mutation in KDM6A on the active X chromosome, therefore, should lead to the same cell-division havoc as it does in males. Unexpectedly, KDM6A mutations were detected more often in male cancers. It turns out that some genes on the inactivated X chromosome in female cells "escape" that dormant state and function normally. One of those awakened genes happens to be a working copy of KDM6A. The "good" copy of the gene is sufficient to prevent the cell from turning cancerous. The new study explored whether this phenomenon - fully functional tumor-suppressor genes on an otherwise idle X chromosome - underlies the broader phenomenon of cancer's partiality toward male cells. The researchers dubbed such genes "EXITS," for Escape from X-Inactivation Tumor Suppressors. "Under this theory, one of the reasons cancer is more common in males is that male cells would need a harmful mutation in only one copy of an EXITS gene to turn cancerous," Lane said. "Female cells, by contrast, would need mutations in both copies." To test this hypothesis, researchers at the Broad Institute scanned the genomes of more than 4,000 tumor samples, representing 21 different types of cancer, looking for various types of abnormalities, including mutations. They then examined whether any of the irregularities they found were more common in male cells or female cells. The results were striking. Of nearly 800 genes found solely on the X chromosome, six were more frequently mutated - and incapacitated - in males than females. Of more than 18,000 other genes, none showed a gender imbalance in mutation rates. Of the six genes more likely to be mutated in males, five were known to escape X chromosome inactivation, making them strong candidates to be EXITS genes. "The fact that the very genes which are more often mutated in males are found exclusively on the X chromosome - and that several of them are known to be tumor-suppressors and escape X-inactivation - is compelling evidence of our theory," Lane remarked. "The protection afforded by the working copies of these genes in female cells may help explain the lower incidence of many cancers in women and girls." One of the implications of the finding is that many cancers may arise through different molecular pathways in men and women. To circumvent the added genetic safeguards against cancer in female cells, tumors in women may employ alternate genetic circuits than in men. To explore this possibility, the study authors recommend that future clinical studies of cancer treatments be "statistically powered" ¬- that is, involve enough patients and tumor tissue samples - to understand whether men and women respond differently to treatment because of genetic differences in their tumors. The lead authors of the study are Andrew Dunford, of the Broad Institute and David M. Weinstock, MD, of Dana-Farber and the Broad Institute. Co-authors are Virginia Savova, PhD, John P. Cleary, Akinori Yoda, PhD, and Alexander A. Gimelbrant, PhD, of Dana-Farber; Steven E. Schumacher, MS, and Rameen Beroukhim, MD, PhD, of Dana-Farber and the Broad Institute; Timothy J. Sullivan, Julian M. Hess of the Broad Institute; and Michael S. Lawrence, PhD, of Massachusetts General. Financial support for the research was provided by the National Cancer Institute (grant K08CA181340); an American Society of Hematology Scholar Award; a V Foundation Scholar Award and a Stand Up to Cancer Innovative Research Grant. From achieving the first remissions in childhood cancer with chemotherapy in 1948, to developing the very latest new therapies, Dana-Farber Cancer Institute is one of the world's leading centers of cancer research and treatment. It is the only center ranked in the top 4 of U.S. News and World Report's Best Hospitals for both adult and pediatric cancer care. Dana-Farber sits at the center of a wide range of collaborative efforts to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. Dana-Farber/Brigham and Women's Cancer Center provides the latest in cancer care for adults; Dana-Farber/Boston Children's Cancer and Blood Disorders Center for children. The Dana-Farber/Harvard Cancer Center unites the cancer research efforts of five Harvard academic medical centers and two graduate schools, while Dana-Farber Community Cancer Care provides high quality cancer treatment in communities outside Boston's Longwood Medical Area. Dana-Farber is dedicated to a unique, 50/50 balance between cancer research and care, and much of the Institute's work is dedicated to translating the results of its discovery into new treatments for patients locally and around the world.
News Article | October 28, 2016
Nine years ago on a Monday afternoon, Sandra Smith, a pastor’s wife and mother of three in DeWitt, Mich., learned she had an aggressive form of breast cancer. The real bad news, however, would hit the family later that week. At first they thought their youngest, six-year-old Andrew, was just battling the flu. Then he started vomiting. He’d also developed a facial droop, and his gait seemed off. Smith remembers wondering if they were “making a big deal out of nothing,” even as they rushed to the emergency room. Nothing could be further from the truth. An MRI scan revealed a large area of swelling in Andrew’s brain stem—clear evidence of a fatal childhood cancer that typically strikes between the ages of four and 10 and kills most within a year of diagnosis. Unlike the cells dividing uncontrollably in Smith’s breast, her son’s cancer, called diffuse intrinsic pontine glioma (DIPG), could not be fought with surgery or conventional chemotherapy. In DIPG the malignant cells entwine with normal brain tissue in a region that controls critical functions such as breathing and heart rate, making it impossible for a surgeon to remove. In more than 200 drug trials nothing has worked better than radiation therapy, which itself can only extend life a few short months in kids with DIPG. Andrew outlived the “typical” DIPG patient by surviving just over two years after his diagnosis, passing away at the end of 2009. DIPG accounts for about 10 percent of childhood brain and spinal cord tumors. It is the second-most common pediatric brain tumor and the leading cause of cancer death in kids. Treatment options and survival rate for DIPG have not changed in 40 years—a predicament that likely helped nudge brain cancer past leukemia as the deadliest childhood malignancy in the nation, according to a recent report from the U.S. Centers for Disease Control and Prevention. Today, however, the outlook for DIPG and other childhood brain cancers looks more promising, thanks to a surge of new research made possible by advances in gene-sequencing methods and tumor tissue donations from families who have lost children, such as Andrew, to these diseases. In recent years researchers around the world have used patients’ tumor tissue to generate dozens of cell lines and mouse models to study the basic biology of pediatric brain cancers. The time is ripe. In the dawn of precision medicine, which aims to customize disease treatment to the individual patient, genetics and basic science findings suggest why past trials may have failed and are guiding future and ongoing efforts to identify effective therapeutics for these devastating diseases. Michelle Monje, an assistant professor of neurology at Stanford University, first encountered DIPG around 2002 as an MD/PhD student there. Working with her clinical mentor to care for a nine-year-old girl dying of DIPG, it was “the first time I’d come upon a disease we had no idea how to treat,” Monje says. “I felt so close to this patient and was devastated by my inability to help her.” Back then there was little molecular data on DIPG. No animal models. No cell cultures. Generating such research tools requires tumor samples from patients. Yet since MRI scans can reliably diagnose typical DIPG and getting brain stem tissue is not trivial, biopsies were rarely done. With precious little tumor tissue to study in the lab, Monje says, research progress on DIPG had stalled for decades. The tide started turning by 2007, when a team of surgeons in France reported safely obtaining biopsy samples from 24 children with DIPG using stereotactic techniques that use computer imaging to guide needle placement. That study invigorated longstanding efforts by a pediatric neuro-oncologist Mark Kieran, clinical director of the Brain Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, who had spent years pushing for DIPG biopsies in the U.S., initially without success. By that time technological advances had made it possible to read DNA sequences from tiny bits of tissue, giving further impetus for a tricky surgical procedure now shown to be safe in trained hands. The Boston team began offering patients genomic sequencing of their tumors biopsied at diagnosis and relapse, to “see how the tumor is evolving and redirect the appropriate drugs to it,” Kieran says. Tumor profiles could help determine which patients might benefit from a newer class of drugs called targeted therapies, which hit specific proteins in the tumor rather than just kill off any dividing cell. Targeted therapies are a cornerstone of precision medicine. Since 2009 researchers at Dana–Farber have sequenced brain tumors in nearly 1,000 children. Among kids with tumors classified as a low-grade glioma, up to 10 percent have a mutation in a gene called BRAF that is seen in some adult skin tumors. A few years ago, 32 children from Europe and North America with BRAF-positive gliomas entered a clinical trial of dabrafenib, a targeted therapy approved for melanoma patients with this mutation. At a conference in Copenhagen earlier this month, Kieran reported that 23 of the 32 kids improved on the BRAF-inhibiting drug—a response rate high enough that his team is offering continued therapy to trial participants with the mutation. In 2012 Kieran and collaborators launched a clinical trial to biopsy tumors of children with DIPG, test them for several molecular markers and, based on the results, assign one of four treatment strategies. Two years ago a team led by Sabine Mueller, a pediatric neuro-oncologist at the University of California, San Francisco, initiated another DIPG trial. This study probes patient tumors using a more sophisticated technique, whole exome sequencing, which scours the entire protein-encoding portion of the genome rather than just checking for pre-specified markers. Based on each patient’s tumor profile the U.C. San Francisco team proposed up to four drugs that seem appropriate. It will take another one to two years to see if the drugs help. Although helpful for some individuals, precision medicine is expensive, and some scientists suspect it may only modestly improve the lives of cancer patients in general. Cells within a single tumor can acquire different mutations, such that “even if there is an effective agent, it is likely to have limited benefit because molecular pathways that are active in other parts of the tumor will lead to tumor growth from different clones of tumor cells,” researchers wrote in a New England Journal of Medicine commentary published in September. And without specific drugs approved for DIPG, there is ongoing debate about whether biopsies offer real benefit to these patients. Some labs have taken a less controversial route to DIPG samples—obtaining them as legacy gifts from families who agree to donate tumor tissue once their child passes. Smith, the Michigan mom, learned about legacy gifts through an online DIPG support group in spring of 2008, a half year after her son Andrew was diagnosed. Reading that post about removing the brain after death and donating the tissue “was horrifying to me,” Smith recalls. “But I understood [that without patient samples] there was no way for researchers to look at this tumor.” She shared the idea on a Yahoo group for DIPG families that she and her friend moderate. In November 2008, a mother from the Yahoo list called Smith in a panic. Her daughter was in her final hours, and the family wanted her tumor tissue donated but hadn’t made arrangements. Autopsy tissue donations are logistically challenging. Once a child passes, the brain needs to be removed, with tumor tissue placed into sterile tubes, within six hours. Yet patients tend to die at home, far from the medical center, sometimes in the middle of the night or during a snowstorm on a holiday weekend. Some labs book on-call service from a tissue recovery team close to where the child lives. To have the biggest impact, samples should go to labs that can receive and process them the same day. As Smith helped other families arrange tumor donations, she got to know some of the leading DIPG researchers, including Monje, who had just worked out a way to culture cells from autopsy tissue and use those cells to create mouse models of DIPG. In July 2011 Smith learned of a seven-year-old girl named McKenna, who was battling DIPG. Smith and Monje worked with the family and “made sure we had the required documents when the time came,” says McKenna’s mother, Kristine Wetzel, a high school teacher in Huntington Beach, Calif. McKenna faded suddenly, and the family decided to donate her tumor tissue within an hour of her death. Although painful, the decision was “surprisingly comforting,” Wetzel says. “It was a way to fight back against the monster that had stolen our daughter.” The Wetzels have since helped other DIPG families with tumor donations and created a foundation to raise awareness and fund research in pediatric brain cancer. The foundation covers the cost of tissue donations to Monje’s lab and pays for a technician who maintains the lab’s DIPG cultures and has shipped samples to some 80 labs around the world. Support varies but usually amounts to about $100,000 per year, Monje says. Autopsy tissue donations have “transformed the research landscape from an unapproachable problem, due to lack of material for research, to an unprecedented analysis of the DIPG genome,” says neurobiologist Suzanne Baker, who helps lead the Neurobiology and Brain Tumor Program at St. Jude Children’s Research Hospital. A wave of papers by Baker, Kiernan and others at Washington University School of Medicine in St. Louis and elsewhere, revealed a surprise. Although DIPG has a gene signature distinct from other brain cancers, the rare childhood tumors share one striking feature: Nearly 80 percent of them have mutations in a gene that codes for a protein called histone H3. Histone proteins are like spools around which DNA wraps. A key player in epigenetics—the study of biological mechanisms that turn genes on or off—histones influence how easily DNA is accessed by enzymes that translate genetic code into working proteins. “Histone H3 is so fundamental…I would think lots of cancers would have these mutations,” Baker says. Yet they seem to be unique to DIPG and about a third of non–brain stem tumors in kids. The genetic insights could not have come at a better time. Whereas some labs were busy plumbing whole genome sequencing data from DIPG tumor cells, others were testing potential drugs in cell cultures and mouse models generated from patient brain tumor samples. The idea was to carefully vet compounds in the lab before choosing which ones to test in a longer, costlier clinical trial. The approach is not revolutionary. Generally it is “the way you do medical research,” Monje says. But for DIPG, “we’d been unable to do this” for decades because there had been no cell cultures or experimental mice modeling the disease. The situation improved in 2010 when Charles Keller, then at Oregon Health & Science University, organized a global screening effort. By then many labs were creating cell cultures from DIPG tumor tissue. As co-chair of a committee proposing drugs for DIPG clinical trials, Keller rallied the Monje lab and 12 other groups to pool resources for a collaborative study. His group dispensed 83 potential drugs onto well plates and sent them to the other labs for testing. At these far-flung labs researchers loaded the plates with DIPG cell cultures and looked for wells that turned blue—a chemical indication that the drug was killing tumor cells. Top drug candidates also improved survival in mice with implanted DIPG tumors. In addition, the labs purified genetic material from their DIPG cell lines and sent DNA and RNA samples to Oregon for sequencing to establish a clear tie between the cells’ gene glitch and drug response. Checking for these connections is key, Keller says, because many drugs that looked promising based on mutations in the DIPG cells showed no effect in the cellular assays. But there emerged a winner—a drug called panobinostat, which inhibits enzymes that chemically modify histone proteins. Coincidentally, the U.S. Food and Drug Administration approved panobinostat as a treatment for another cancer, multiple myeloma, as the global screening manuscript went to press in Nature Medicine. The results helped launch a clinical trial of panobinostat that opened for enrollment in May. Led by Monje, this trial will measure side effects and determine the best doses of the drug for treating children with DIPG. Panobinostat is not going to be a silver bullet, however. The lab data showed some DIPG cells develop resistance to the drug, suggesting it will need to be combined with other therapies to achieve a survival benefit in patients, Monje says. One challenge with panobinostat is shared by many brain cancer therapies—delivering them effectively into the brain. “Many drugs don’t cross the blood–brain barrier so they are not getting to the tumor,” says U.C. San Francisco’s Mueller. Some researchers are using a procedure called convection-enhanced delivery to place drugs through small catheters directly into the brain tumor. Others are using nanotechnology to reformulate drugs so they can be more specific and durable—for example, by inserting molecular tags that direct the drug to molecules found uniquely on the tumor. It is possible that good drugs for DIPG already exist, Mueller says, but “we just don’t know how to deliver them correctly.” She is planning a future trial using convection-enhanced delivery of panobinostat in kids with DIPG. In the meantime Monje’s lab and other groups are doing additional drug screens with epigenetic agents and combination regimens, and Keller founded a nonprofit cancer biotech to speed the movement of candidate drugs from basic science research to clinical testing. Each year his team organizes a weeklong crash course to teach families about pediatric brain cancers and explain how tumor tissue donations are driving research. Some families make regular visits to the lab to see their child’s cells under the microscope. Wetzel’s family visited Monje’s lab eight to nine months after their daughter died of DIPG. “The first time I saw McKenna’s cells, I started crying uncontrollably,” Wetzel says. “I wanted to take every petri dish…and throw it against the wall, to the destroy the cell line like it had destroyed my daughter.” Now, after trips to the lab about once a year, Wetzel feels differently. “I see it as McKenna’s last stand…her gift to the world and to children who will follow her. If McKenna can’t be here, let her make the world a better place in the one way she now can. It helps us to think there was some purpose to her death.”
News Article | September 19, 2016
Leukemia is no longer the No. 1 cause of cancer deaths in children, but brain cancer has taken it's place, according to a new report. All pediatric cancer death rates have been dropping since the mid-1970s, according to the report released today (Sept. 16) from the National Center for Health Statistics. The report details changes in cancer death rates among children and teens ages 1 to 19, from 1999 to 2014. "The shift from leukemia to brain cancer as the leading site of cancer death is a noteworthy development in the history of childhood cancer as it was always leukemia until quite recently," said lead author Sally Curtin, demographer and statistician at the NCHS, which is part of the Centers for Disease Control and Prevention (CDC), in an email interview with Live Science. [Top 10 Cancer-Fighting Foods] There were still 1,785 cancer deaths in children and adolescents in 2014, Curtin said. Brain cancer and leukemia accounted for more than half of those. In 1999, six out of 20 cancer deaths among children were due to leukemia, and about five in 20 were due to brain cancer, according to the numbers in the report. By 2014, those numbers had reversed. "Major therapeutic advances" in the treatment of cancers, particularly leukemia, has likely resulted in the increases in survivorship, the researchers wrote in their report. Overall, the cancer death rate for children and teens dropped 20 percent over the 15 years included in the study. Among females, the overall cancer death rate dropped 22 percent. Among males, it dropped 18 percent. Throughout the study period, the rate of cancer deaths among males outpaced that of females, according to the report. "The leukemia specialists have done a really great job of stratifying these patients to give them appropriate therapy based on whether they feel their tumors are more aggressive or not," said Dr. Peter Manley, pediatric neuro-oncologist at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center, who was not involved in the new report. But survival of rates among children with brain tumors has not changed much, Manley said. Still, the survival rates related to certain subtypes of brain tumors, such as low-grade gliomas, are improving and that current research is very promising, he said. "There's some really interesting information that's coming out," Manley said. New research on brain cancer is focusing on cancer genomics, and on using molecular analysis and genome sequencing to learn what makes the tumors abnormal and what causes them to grow, he said. Researchers have also been developing drugs that target the molecules involved in cancer growth and spread. "The information coming from this [research] is so impressive that my feeling is that we will continue to see a decline in deaths," Manley told Live Science. Pediatric cancer doesn't receive nearly as much national funding as adult cancers, he noted. "Overall, the important thing to take from this [report] is that, across the board, there are significantly [fewer] cancer deaths just in the last 15 years," Manley said. "So the hope is, in the next 15 years, we'll continue to see that decline." Copyright 2016 LiveScience, a Purch company. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
News Article | October 28, 2016
In people with chronic infections or cancer, disease-fighting T cells tend to behave like an overworked militia — wheezing, ill-prepared, tentative, in a state of “exhaustion” that allows disease to persist. In a paper posted online today by the journal Science, researchers at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center report that, in mice with chronic viral infection, exhausted T cells are controlled by a fundamentally different set of molecular circuits than T cells effectively battling infections or cancer. This finding suggests a way to increase the staying power of CAR T cells, a promising form of immunotherapy for cancer. An accompanying study, led by researchers at the University of Pennsylvania and co-authored by Dana-Farber scientists, reports that these differences in circuitry remain largely unchanged by a type of cancer immunotherapy known as checkpoint inhibition, potentially closing off one avenue of improving this technique. The studies bring renewed focus to the epigenetics of T cells — the multilayered system of molecular switches, accelerators, and throttles that controls the activity of genes. Scientists have known for years that the pattern of genes is different in exhausted T cells than in functional T cells that are fully engaged in fighting disease, but the actual extent of these differences has been uncertain. One difference that is clear is that exhausted T cells express the programmed cell death protein-1 (PD-1), which commands them not to attack normal, healthy cells, but can also prevent them from striking at cancerous or chronically infected cells. Blocking PD-1 with checkpoint-inhibiting drugs — and thereby restoring the cancer-killing zeal of T cells — has become one of the most successful new approaches to cancer treatment in nearly a decade. However, it has shown effectiveness in only about a quarter of cases. “Exhausted T cells display a variety of functional defects,” said Nicholas Haining of Dana-Farber/Boston Children’s, the senior author of the new paper. “They are paralyzed and don’t have the firepower to destroy cancer or virally infected cells. For us, the question in this study was, do exhausted cells represent a distinct type of T cell or are they merely a ‘groggy’ version of functional T cells?” With chronically infected mice as their model, the researchers used a new technology called ATAC-seq to map the regulatory regions of the genome — the sections of DNA involved in switching genes on and off — in the animals’ exhausted and functional CD8+ T cells. (CD8+ T cells are programmed to identify and eliminate cancerous and infected cells.) “We found the landscape of regulatory regions to be fundamentally different in exhausted and functional T cells,” Haining said. “There were thousands of instances where a regulatory region appeared in exhausted T cells but not in their functional counterparts, and vice versa. This tells us that the two types of cells use very different wiring diagrams to control their gene activity.” The researchers then tested whether removing a regulatory stretch of DNA that spurs the production of PD-1 would drive down expression of the protein. Using CRISPR/Cas9 technology, they snipped out that region and indeed, PD-1 expression dropped. The success of this experiment may offer the key to improving CAR T cell therapy. CAR T cells are T cells that are removed from a patient, genetically engineered to grow a protein “sensor” that targets them to tumor cells, and then reinjected into the patient. Although the retrofitted T cells have demonstrated effectiveness at tracking down cancer cells, particularly in leukemia, one of the shortcomings of CAR T cells is that they tend to become exhausted. The work described in the new study suggests that while T cells are being engineered to produce the sensor, they could also be retooled to delete the genetic wiring that causes them to express excessive levels of PD-1 or other exhaustion genes. The resulting CAR T cells not only would be better at stalking cancer, but also more aggressive about attacking it. In the companion paper, researchers explored whether blocking the PD-1 checkpoint rewired exhausted T cells to make them, from an epigenetic standpoint, more like functional T cells. Using chronically infected mouse models, as in the first study, the investigators found that while such gain of function does occur briefly, the epigenetic switches from its previous, exhausted state remain largely unchanged. “This suggests that the benefits achieved by checkpoint blockade result from a transient revving up of exhausted T cells, not a permanent reshaping of their state,” Haining said. The findings of the two studies point to the need for a comprehensive atlas of the regulatory regions that are active in exhausted and functional T cells, he continued. Such a guide would provide targets for rewiring T cells with genetic engineering or epigenetic drugs to make them more effective cancer killers.
News Article | December 5, 2016
SAN DIEGO, CA - Despite an elevated risk of toxicity from chemotherapy, children with Down syndrome and acute lymphoblastic leukemia (ALL) did not experience higher rates of relapse or treatment-related mortality compared with other children treated on Dana-Farber Cancer Institute ALL Consortium Protocols, according to research presented at the 58th annual meeting of the American Society of Hematology, December 5, 2016. "Without dose reductions or modifications, the Down syndrome patients did just as well as the non-Down syndrome patients," said Lewis B. Silverman, MD, senior author of the abstract and clinical director of the Hematologic Malignancy Center at Dana-Farber/Boston Children's Cancer and Blood Disorders Center. "They were able to tolerate full-dose chemotherapy based on their risk group and did well despite biologic differences in their disease compared with other children's disease." Children with Down syndrome are at increased risk for developing ALL, but the optimal therapy for this group of patients has not been established. Silverman notes that previous studies have shown that children with Down syndrome have an increased risk of complications of treatment. Some studies have also reported that they have higher rates of relapse and/or treatment-related mortality, resulting in lower rates of long-term cure. While the Dana-Farber protocol has never modified treatment for children with Down syndrome, Silverman added, other protocols have made dose-adjustments to minimize side effects. "There has been controversy in the field regarding how Down syndrome children do in terms of their prognosis compared with children who don't have Down syndrome," Silverman said. "We found that with our particular treatment approach, we're not running into problems that others have reported." Researchers studied 1286 diagnosed children and adolescents with ALL treated on the Dana-Farber Consortium protocols between 2000 and 2011 at 11 institutions in the United States, Canada, and Puerto Rico. Of these patients, 38 (3 percent) had Down syndrome. Among the findings: As has been reported in other studies, researchers found that the Down syndrome patients were less likely than other patients to present with T-cell ALL (none in the DS group vs 11.7 percent in non-DS patients) and high hyperdiploidy (8.8 percent vs 25.1 percent). The former is considered a higher-risk form of ALL, while the latter is associated with a more favorable prognosis, Silverman said. "The target toxicities that one needs to think about are infections and mucositis," Silverman said. "With supportive care to try to prevent these complications, our overall recommendation is that you can treat children with Down syndrome the same as other children with ALL." Uma H. Athale, MD, MSc, of McMaster Children's Hospital, in Hamilton, Ontario, Canada, is lead author of the abstract. Dana-Farber/Boston Children's Cancer and Blood Disorders Center - the nation's top pediatric cancer center, according to U.S. News & World Report - brings together two internationally known research and teaching institutions that have provided comprehensive care for pediatric oncology and hematology patients since 1947. The Harvard Medical School affiliates share a clinical staff that delivers inpatient care at Boston Children's Hospital and most outpatient care at Dana-Farber Cancer Institute.