Dr. Mark Souweidane today treated the final patient in his Phase I clinical trial of convection-enhanced delivery (CED) for diffuse intrinsic pontine glioma (DIPG). The trial, which had enrolled 31 patients over the past four years, was designed to test the safety of CED as a means of delivering a cancer-fighting drug directly to the site of a DIPG tumor. (More about the DIPG trial.)
The trial received FDA approval in late 2011, and the first patient was treated in May 2012. (Read “Cheering for Caitlin,” a profile of the first patient.) Since then, 30 children have received infusions of a therapeutic agent called 124I-8H9, which consists of the 8H9 antibody (produced by mice and effective against many kinds of tumors) combined with the radioactive substance 124I. The dosage of the drug was increased over the course of the trial, also testing safety, but no dose-limiting side effects occurred in any patient.
The infusions, which were done at Memorial Sloan Kettering Cancer Center, were able to deliver the drug directly to the brain stem tumor and were not blocked by the body’s protective blood-brain barrier, which normally prevents chemotherapy drugs from crossing from the bloodstream into the brain in sufficient concentrations to attack a tumor. In this trial, Dr. Souweidane was able to achieve concentrations of 1,000 times or more than what can be achieved with IV chemotherapy. He was also able to design and test new ways to measure those concentrations at the tumor site and monitor how long the drug stayed in the tumor.
Dr. Souweidane and his team will spend the next several months evaluating the data and preparing the results for publication. In the meantime, researchers in the Children’s Brain Tumor Project laboratory have been working to pave the road for the next stages of the trial. Other drugs and drug combinations are being tested to determine what the best agents are to infuse, and at what dose levels. DIPG cell lines are also being grown in the lab, providing a rich source of information about how the tumor mutates over time and responds to different treatments in vitro as well as in animal models. (More about the Children’s Brain Tumor Project.)
The Children’s Brain Tumor Project (CBTP) has been given the opportunity to add another researcher to our ambitious “Summer Sprint.” Carlos Colon, a committee member of the Cristian Rivera Foundation, has pledged $5,000 to support this additional summer research position to supplement our already ambitious effort.
Thanks to our generous supporters, the CBTP lab had already hired six summer researchers to work on testing new drugs and drug combinations against DIPG, GC, and other rare brain tumors; using PET imaging to evaluate these drugs; studying the transformation of low-grade gliomas into malignancies; and procuring samples of thalamic gliomas from other labs around the country. (See more about these projects.) The seventh researcher, Fatima Nathalia Morales, will be working on the team supporting Dr. Souweidane’s DIPG clinical trial, validating the method for monitoring brain tumor and distribution volumes in patients enrolled in the trial.
Fatima, an undergraduate student at Columbia University majoring in biology with a minor in mathematics, is spending the summer in the CBTP lab as part of the Travelers Summer Research Fellowship Program. The support from Carlos Colon and the Cristian Rivera Foundation makes it possible for us to provide her with the equipment and supplies she needs to do her work.
We are extremely grateful to Carlos Colon for the gift, and to John Rivera and the Cristian Rivera Foundation for the tireless efforts on our behalf.
Clinical Trial Update: Now treating patients at its seventh and final dose level, the trial of convection-enhanced delivery (CED) should conclude this summer. Fatima will be helping to evaluate data from more than four years of that trial.
The Cristian Rivera Foundation who is one of the top donors of The Children’s Brain Tumor Project is proud to attend the Children’s Brain Tumor Project Second Annual Family Council Meeting Today Tuesday April 28th, 2015. It’s an honor to come together with other families and foundations who all share the same passion towards helping fund Dr. Mark Souweidane and all the other Doctors who work tirelessly towards finding a cure for inoperable brain tumors.
Philanthropists, celebrity guests and more came together in support of the Cristian Rivera Foundation last night for the foundation’s first-ever New Jersey fundraiser at Zylo Tuscan Steak House in Hoboken. All proceeds from the event went towards the Cristian Rivera Foundation’s goal of curing rare, inoperable pediatric brain stem tumor Diffuse Intrinsic Pontine Glioma (DIPG).
Cristian Rivera Foundation Committee Member Andy Epstein and Zylo manager Kevin Hayes organized the event, which featured entertainment from Sinatra Idol winner Eric DeLauro (www.SinatraIdol.com) and hot new singing sensations Tyler Reid and Stevie G (www.youtube.com/tylernstevie). Guests also enjoyed three hours of passed hors d’oeuvres, as well as specialty cocktails from Stoli Vodka and first-class tastings provided by Artesa Winery and Macallan Scotch.
Many esteemed and noteworthy guests were on hand at the sold-out event, including Real Housewives of New Jersey star Danielle Staub and Saturday Night Live Star and Cristian Rivera Foundation Committee Member Kenan Thompson. Some of Thompson’s fellow Committee Members who attended the event included actress and founder of the Puerto Rican Traveling Theatre Miriam Colon, founder and CEO of AM PM Entertainment Concepts Vito Bruno, Information Technology manager Steve Cox, founder of Bronx Base Builders William Padilla, interior decorator Solange Osorio, concert impresario Ralph Mercado, businessman Elis Pacheco, and Celebrity Chefs Alex Garcia and Ricardo Cardona.
Fresh off the Stanley Cup Finals, New Jersey Devils Captain Zach Parise made a surprise appearance to auction off an autographed hockey stick and jersey, as well as once-in-a-lifetime photo opportunities with guests. The auction also included rare autographed items from Cake Boss Buddy Valastro and home-catered meals provided by Chefs Garcia and Cardona, among other items.
In all, the Cristian Rivera Foundation raised $55,000 to help fund the groundbreaking clinical trials led by Dr. Mark Souweidane at Memorial Sloan Kettering and Weill Cornell Medical Center. Dr. Souweidane operated on the first patient in his trial—a beautiful 4-year-old girl—on May 1, 2012, the first day of Brain Tumor Awareness Month. Dr. Jeff Greenfield, who works alongside Dr. Souweidane in his quest to cure DIPG, attended the event and gladly accepted the $55,000 check from Epstein, Hayes and Cristian Rivera Foundation founder John “Gungie” Rivera.
Since October of 2010, the Cristian Rivera Foundation has donated more than $200,000 to Dr. Souweidane’s pioneering research.
May 1, 2012—New York, NY—Doctors at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center took a major step towards finding a cure for inoperable pediatric brain stem tumor Diffuse Intrinsic Pontine Glioma (DIPG) on Tuesday, May 1, 2012 as work began on the first patient in a pioneering clinical trial spearheaded by Dr. Mark Souweidane. Through the innovative use of convection-enhanced delivery (CED), Dr. Souweidane’s clinical trials will be the first of its kind to administer radio immunotherapy to children with an otherwise incurable tumor.
Denise Pflaumer Downing is the patient’s mother and a Facebook follower of The Cristian Rivera Foundation. She expressed her gratitude for the efforts of the Foundation when she sent this message: “I am sitting at MSKCC in NYC. Right now, my 4 year old daughter is in surgery with Dr Mark Souweidane and his team as they perform the first surgery in a new clinical trial on my daughter. I am so thankful to your foundation for all you have done to support this research and make this trial possible. We must find a cure for DIPG, not only for my child but for all children. Thank you Cristian Rivera Foundation!”
Another sentiment soon followed, this time from Dr. Souwedaine himself.“Today, the first day of Brain Tumor Awareness month, we treated our first patient on our trial using local delivery of a radioimmunotherpeutic agent. The beautiful 4-year-old girl did fantastic and tolerated her surgery like a true champion. Today marks a day of hope for her family, an entry into a new treatment approach for these children, and the culmination of over 12 years of translational research.”
Through this groundbreaking work, Dr. Souweidane and his team aim to ultimately save the lives of approximately 200-300 children who are diagnosed with DIPG each year in the United States. DIPG is typically found in children between the ages of 1 and 9, who are given a bleak prognosis after the tumor is discovered. Median survival is less than one year and the two-year survival rate is less than 20 percent. Currently, there are no recorded survivors and all children diagnosed with the disease typically pass away within 3-18 months.
Helping make these landmark trials possible were donations from top cancer charities with the common goal of making DIPG a thing of the past, including New York City-based not-for-profit 501(c)(3) The Cristian Rivera Foundation, which, to date, has donated approximately $150,000 to Dr. Souweidane’s promising research. John “Gungie” Rivera started the foundation in 2009, months after his 6-year-old son Cristian lost a more than two-year battle with the disease. The Cristian Rivera Foundation is committed to supporting DIPG families and finding a cure for DIPG through education and program funding.
“When my son Cristian was first diagnosed with DIPG, it seemed very unlikely, in fact almost impossible, that a cure would be found in my lifetime,” said Rivera. “Thanks to the amazing courage and interminable spirit of Dr. Souweidane and everyone at the Weill Cornell Pediatric Brain and Spine Center, I firmly believe a cure is within our grasp. Dr. Souweidane gives the DIPG community the hope they so desperately need and I am proud to give him the full support of the Cristian Rivera Foundation as he works toward a cure.”
Four Organizations Fund International Research Consortium to Improve Lives of Children Suffering From Diffuse Intrinsic Pontine Glioma (DIPG)
Accelerate Brain Cancer Cure (ABC2), CureSearch for Children’s Cancer, The Cure Starts Now Foundation and The Lyla Nsouli Foundation for Children’s Brain Cancer Research today announced their collaborative funding to support groundbreaking research aimed at dramatically improving the lives of children suffering from Diffuse Intrinsic Pontine Glioma (DIPG) – one of the most devastating pediatric cancers.
Together, the four organizations have committed $229,000 to support the work of the DIPG Preclinical Consortium, the only international scientific group focused on preclinical development of targeted therapy combinations for DIPG. The goal of the research is to test and then move the most effective therapy forward to early phase clinical trials in the next 18 – 24 months.
Children with DIPG have a uniformly dismal prognosis with a median survival of 9 months. A DIPG tumor grows amidst the nerves in the pons (middle) of the brain stem, and therefore cannot be surgically removed. Radiotherapy provides only temporary improvement of symptoms. No chemotherapy has ever proven effective. Novel therapies are desperately needed. “The scientific community has truly rallied around this cause. The mandate for a novel therapeutic approach was born in the Children’s Oncology Group brain tumor committee under the bold leadership of Dr. Amar Gajjar. With the consortium co-leadership of clinical trialist Maryam Fouladi and the accountability to DIPG patients and their family, this program is moving unexpectedly quickly towards its goal,” says Charles Keller, MD, Associate Professor and leader of the Pediatric Cancer Biology Program, Pape’ Family Pediatric Research Institute in the Department of Pediatrics at Oregon Health & Science University.
“If we succeed, it will be because families that have donated their children’s tumor gave us this opportunity. We are reminded every day that the cultures we study are parent-directed Legacy Gifts of the most selfless kind from children who current therapy could not save (the brain stem being vital to life; therefore, tumor donation can only occur at autopsy). What ABC2 , CureSearch for Children’s Cancer, the Lyla Nsouli Foundation, and The Cure Starts Now have done to make our consortium possible, and so quickly, is unprecedented – and greatly appreciated,” adds Dr. Keller.
The research project entitled, “Rapid Preclinical Development of a Targeted Therapy Combination for DIPG” was launched with initial support from The Cure Starts Now Foundation. Two additional European labs were added to the project with funding from The Lyla Nsouli Foundation for Children’s Brain Cancer Research (based in London, UK).
The funding from ABC2 and CureSearch for Children’s Cancer added a cutting-edge functional genomics component that will prioritize potential new drug targets. “We are proud to support this multi-national team of researchers in their efforts to rapidly develop effective drugs to treat children suffering from DIPG,” said Max Wallace, CEO of ABC2. “By combining forces with our non-profit partners, ABC2 looks forward to leveraging the resources and expertise of all the organizations to improve the lives of children with cancer.” John Lehr, president and CEO of CureSearch for Children’s Cancer echoed Wallace’s comments saying that “developing new drug targets is an integral step to providing children with DIPG a better prognosis. CureSearch is committed to funding research in rare cancer types so that one day, all children will be guaranteed a cure.” Keith Desserich, Chairman and Co-Founder of The Cure Starts Now Foundation added, “innovative strategies such as Dr. Keller’s and his collaborators will help lead to a revolution in cancer care for all. Not only by focusing on rare cancers like DIPG can we offer hope to children fighting this disease, but we also learn vital skills that may ultimately lead to a cure for all cancers; and in this way, this may be the start of a truly homerun strategy in cancer cures.”
About the DIPG Preclinical Consortium
The multi-national consortium is identifying potentially important biological pathways in DIPGs that are readily targetable with currently available molecularly-targeted agents. In addition, the consortium has successfully grown human DIPG tumors from autopsy materials in the petri dish and has developed mouse models of DIPG – a key resource to functionally testing potential therapies.
Since the number of children with this unfortunate disease is limited, and the number of available targeted agents is quite large, the consortiumhypothesizes that it can identify a promising combination of molecularly-targeted agents using functional genomics to prioritize targets. The ultimate goal is to move the most effective single agent or combination therapy forward to early phase clinical trials in the next 18-24 months.
The DIPG Preclinical Consortium team includes:
Charles Keller MD, Kellie Nazemi MD and Nate Selden MD, PhD at Oregon Health & Science University
Oren Becher MD, Duke University Medical Center
Michelle Monje MD, PhD, Stanford University
Maryam Fouladi MD, Cincinnati Children’s Hospital Medical Center
Cynthia Hawkins, MD, PhD, University of Toronto
Xiao-Nan Li MD, PhD, Baylor College of Medicine
Dannis G. van Vuurden MD, MSc, & Esther Hulleman, VU Cancer Center Amsterdam
Jacques Grill, Institut Gustave-Roussy, Villejuif, France
For More Information about the Research Funding Partners:
Neurooncol. 2012 Jan 10. [Epub ahead of print] An experimental xenograft mouse model of diffuse pontine glioma designed for therapeutic testing. Aoki Y Hashizume R, Ozawa T, Banerjee A, Prados M, James CD, Gupta N. Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, 505 Parnassus Ave., Rm M779, San Francisco, CA, 94143-0112, USA.
The prognosis for diffuse infiltrating pontine gliomas (DIPG) remains extremely poor, with the majority of patients surviving less than 2 years. Here, we have adapted standard xenograft techniques to study glioma growth in the mouse brainstem, and have utilized the mouse model for studying a relevant therapeutic for treating DIPGs. bioluminescence imaging monitoring revealed a progressive increase in signal following the injection of either of two tumor cell types into the brainstem. Mice with orthotopic GS2 tumors, and receiving a single 100 mg/kg dose of temozolomide showed a lengthy period of decreased tumor luminescence, with substantially increased survival relative to untreated mice (P < 0.001). A small molecule inhibitor that targets cdk4/6 was used to test AM-38 brainstem xenograft response to treatment. Drug treatment resulted in delayed tumor growth, and significantly extended survival. Our results demonstrate the feasibility of using an orthotopic brainstem tumor model in athymic mice, and for application to testing therapeutic agents in treating DIPG.
“It’s been almost two years since Sam was diagnosed in December 2006. The only improvement that I’ve seen during this time is that we have this wonderful site!” [the DIPG Internet Yahoo support list and discussion group]
So said “Sheila” (in December 2008), whose young grandson had died in February 2008 from a diffuse intrinsic pontine glioma.
A diffuse intrinsic pontine glioma, known as DIPG, is perhaps the most feared pediatric brain tumor because of the dismal survival statistics and devastating clinical course. This tumor tends to strike four to ten year olds with approximately half of these young children dying in the first year and 80-90% by the end of the second.
Despite more than 200 trials, no treatment has been found to be effective for long term survival in DIPG. For some children, steroids and radiation allow for a ‘honeymoon’ with relief of symptoms. But this is often followed by a relentless advancing of the disease and tragically, death months later.
Basic science research into this tumor has been frustratingly difficult. A significant hurdle has been the lack of tumor tissue on which to carry out tests.
In 1993, the standard of care for DIPG in the United States changed, as biopsy provided no improvement in survival over neuro-imaging in typical pediatric diffuse pontine tumors. Since that time, biopsies of pediatric DIPG have been uncommon resulting in the scarcity of tumor material for research. At the time “Sheila” wrote, there were no published reports on cell lines, no animal models and no molecular/genetic studies.
The changes in the medical community’s approach to a disease are often evident much before the patient community is aware of them because the time from concept to study to publication of a research paper can take years. In 2008, change was beginning in DIPG research. The heart-wrenching post from grandmother “Sheila” launched an effort towards earlier awareness of research endeavors as well as international advocacy collaboration.
In 2005 the biopsy debate had heated up again. St Jude Children’s Research Hospital in Memphis, Tennessee (USA) responded with a concerted effort to approach families for post-mortem tumor donation for research resulting in more molecular information on DIPG. Since many children die at home, far from St Jude, the emotional and logistical challenges were numerous.
A family responded to the financial issues raised by these challenges by establishing a foundation called Tyler’s Treehouse (established in 2006), specifically started to fund the logistical aspects of this study.
Over the ensuing years, many families with DIPG children have provided the ultimate gift to the research community involved with these studies of their child’s tumour tissue. Some families as far away as Australia and South America have donated their child’s tissue. The St. Jude efforts haven’t lead to publication yet, however, The Hospital for Sick Children (“Sick Kids”) in Toronto, Canada published the first whole genomic analysis of DIPG tumors in February 2010.
Their French colleagues took a different approach, with a clinical trial including upfront stereotactic biopsy of pediatric DIPG. In the July 2007 issue of the Journal of Neurosurgery the surgical results were published. With 33 children there was no mortality and only two children had transient morbidity.
The combined effect of the French stereotactic biopsy results and the molecular analysis studies from “Sick Kids” in Toronto has lead to renewed efforts for future clinical trials to include molecular analysis from stereotactic biopsy samples.
The development of animal models is also emerging.
At the 2008 ISPNO (International Symposium on Pediatric Neuro-Oncology) conference in Chicago (USA), Dr. Oren Becher won the best basic science presentation award for his genetically engineered mouse model of brainstem glioma. The excitement of potentially being able to study this tumor in a mouse model has resulted in requests for Dr Becher’s mice from several others interested in studying brainstem glioma.
For some time, the non-availability of resected tumor tissue for the development of cell lines has met with failure, even to the point of new researchers being discouraged from pursing this direction.
In the summer of 2009, Stanford University in California revealed that Dr. Michelle Monje had been able to culture neurospheres from post-mortem pediatric DIPG tissue using a stem cell technique. This breakthrough in DIPG research at Stanford has lead to an EGFRviii vaccine being introduced to the pediatric brain tumor community for the first time as well as other research. Some of this has been funded through the Kyle O’Connell Foundation.
Truly exciting events have been two international meetings of researchers and clinicians to discuss DIPG. The Fondo Alicia Pueyo hosted the first conference in Barcelona, Spain in February 2009. The second event was hosted by The Hospital for Sick Children in Toronto with funding support by Just One More Day and B.R.A.I.N.child.
We are now seeing a change in DIPG research – and the international collaboration of parents, advocates, clinicians and researchers that is making this happen.