DIPG Discussion -- brought to you by Just One More Day for Love, Hope & a Cure

Biomarkers for DIPG?

2012-01-02T21:50:00.000-06:00

So far it has been difficult to predicatively monitor DIPG tumor. MRI’s have not been found to be predictive. Other advanced imaging techniques are and have bee studied. The issue of biomarkers has also been approached. Unfortunately with DIPG, tissue analysis is something that is rarely done because of the infrequency of biopsies with this tumor. However there has been some investigation of urinary and blood biomarkers.

The recent publication from the NIH regarding a pegylated inteferon for DIPG had a small subsection on the evaluation of urinary VEGF (vascular endothelial growth factor) and serum bFGF (basic fibroblast growth factor) and MMP-9(matrix metalloproteinases). Interestingly what was found in the small number of patient that had low urine VEGF, low serum bFGF) and a non-rising level of MMP-9 were more likely to survive longer than 2 years. On the other hand, none of those with high urine VEGF, high serum bFGF and a rising level of MMP-9 were long-term survivors.

This is not a new concept for cancer or brain tumors. In fact in 2008 Boston Children’s reported on a panel of urinary biomarkers that predicted presence and response to therapy. The issue that is evolving is the study of serum and urine biomarkers for DIPG.

Conventional MRI cannot predict survival in childhood diffuse intrinsic pontine glioma
J Neurooncol. Feb;86(3):313-9. Epub 2007 Oct 2.
http://www.ncbi.nlm.nih.gov/pubmed/17909941

A phase 2 study of pegylated interferon α-2b (PEG-Intron®) in children with diffuse intrinsic pontine glioma. Cancer. 2011 Nov 15. doi: 10.1002/cncr.26659. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/22086404

Urinary biomarkers predict brain tumor presence and response to therapy.
Clin Cancer Res. 2008 Apr 15;14(8):2378-86.
http://www.ncbi.nlm.nih.gov/pubmed/18413828

A new Preclinical DIPG Consortium

2011-12-21T11:27:00.000-06:00

A new Preclinical DIPG Consortium has been unveiled at-
http://pptiohsu.blogspot.com/2011/12/open-science-forum-dipg-preclinical.html

One of the spectacular things is that this clearly identifies some of the researchers that are truly placing significant emphasis is trying to unravel DIPG. There are 5 US sites and one each in Canada, France and Amsterdam. A main requirement to be a site currently seems to have a cell line as well as a funding source.

The DIPG Consortium includes:

Oregon Health and Science University- Charles Keller MD, Kellie Nazemi MD, Nate Selden MD, PhD and Dan Guillaume MD, PhD

Duke University- Oren Becher MD

Stanford- Michelle Monje, MD, PhD

Cincinnati Children’s Hospital Medical Center- Maryam Fouladi, DM

Baylor College of Medicine- Xiao Nan Li, MD,PhD

University of Toronto- Cynthia Hawkins, MD, PhD

VU Cancer Center of Amsterdam- Dannis G. van Vuuren, ND MSc and Ester Hulleman

Institut Gustave-Roussy, Villejuif France- Jacques Grill

The current study is called "Rapid Preclinical Development of a Targeted Therapy Combination for DIPG" which has a goal of attempting rapidly to test agents against cell lines and then animal models to hopefully rapidly translate into clinical trials over the next two years.

It does seem that this trial is a novel approach in that it will treat DIPG specifically and not rely on adult models or cell lines. This is important in that pediatric DIPG is molecularly distinct from adult gliomas.

Another interesting thing is that the high throughput screening of agents seems like it is to be limited specifically to 60 already available drugs. This sounds quite reasonable as why test against agents that might not be available for some time.

In addition, combinations of agents will also be tested. This also seems to be significant as many researchers have said that a single agent is unlikely to be effective against DIPG.

It seems that after the best agents and combinations are found in vitro (against cells alone) that they will be tested in animal models- likely both xenografts and Oren Becher’s GEMM (genetically engineered mouse model).

Note- Xenografts are made when human cells lines are injected into animal to create a tumor. GEMMs make tumors on their own and are not from human cell lines

People can check back to the website at that entry to check the progress of the study (mid page)-

http://pptiohsu.blogspot.com/2011/12/open-science-forum-dipg-preclinical.html

Funding for this study has been through parent founded organizations. The Cure Starts Now provided $100,000 for the North American Institutions. Also listed were those involved in the DIPG Symposium Collaboration including Reflections of Grace Foundation, The Jeffrey Thomas Hayden Foundation, Cancerfree Kids, Carly’s Crusaders, The Max Lacewell Foundation, Smiles for Sophie Forever Foundation and Benny’s World Foundation for making our project possible.

http://kellerlabblog.blogspot.com/2011/11/thecurestartsnow-funds-dipg.html

Additionally, a $28,000 grant from The Lyla Nsouli Foundation for Children’s Brain Cancer Research in the UK allowed for expansion for the two participating European collaborators.

http://kellerlabblog.blogspot.com/2011/11/lyla-nsouli-foundation-funds-supplement.html

A phase 2 study of pegylated interferon α-2b (PEG-Intron®) in children with diffuse intrinsic pontine glioma

2011-12-09T20:46:00.000-06:00

The NIH based study lead by Kathy Warren utilizing low dose pegylated interferon for children with newly diagnosed DIPGs recently was published on line ahead of print in the journal Cancer. The rationale behind this study was the finding that low dose administration of interferon alfa produced” more significant inhibition of angiogenesis-regulating genes, tumor vascularization, and tumor growth compared with the higher intermittent dose schedule. These effects were lost at higher doses, suggesting that metronomic administration of IFNs may have a more robust antitumor effect.”

In this study, 32 children between the ages of 1.8 and 14.8 years (mean 5.3 years) were given pegylated interferon subcutaneously (a shot under the skin) weekly starting 2-10 weeks after radiation until disease progression or unacceptable toxicity. The idea was to try to have a continuous low dose of inferferon.

There were no grade 4 toxicities and no child stopped interferon because of toxicity.

The overall survival at 2 years was 14.3% The median time to progression from diagnosis was 235 days, and the median OS from diagnosis was 351 days.

The authors concluded, “Although low-dose PEG-Intron therapy did not significantly improve 2-year survival in children with DIPG compared with an historic control population, it did delay the time to progression.”

The narrowness of the eligibility criteria in this study is particularly interesting as it shows the advancement in understanding that not all brainstem tumors are the same. This stricter eligibility criterion seems to be trying to eliminate those tumors that might have an underlying aspect giving it a better prognosis and thus skew the data. The eligibility criteria defined as:

Age less than 21 years
Diffuse intrinsic tumor with epicenter presumed in the pons
Signal abnormality involving 50% or more of the pons on T2-weighed sequence at diagnosis
Involvement of the ventral pons
No expophytic component
No patients with known or suspected neurofibromatosis type 1

The paper pointed out that the increasing delineation of a DIPG tumor can make it very difficult to compare results with past papers that did not define the patient population in this way. Those that previously included focal tumors and those with exophytic components might have mistakenly high overall survival statistics. For those interested in comparing studies analysis of the eligibility criteria is going to be important.

A phase 2 study of pegylated interferon α-2b (PEG-Intron®) in children with diffuse intrinsic pontine glioma Cancer. 2011 Nov 15. doi: 10.1002/cncr.26659. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/22086404

Call To Action: Criminals Stealing From Our Families Whose Children have Died

2011-11-27T14:18:00.001-06:00

This is shocking….. There are criminals out there just looking around for kids who have died and then claim them as dependents before some families can file. Those families that have been targeted must then have to prove that their child was actually their child.

How can something so appalling happen? How can people get the social security number?

Well, actually for those in the know it is very easy.   It is the government who made it mandatory for this data to be rapidly available after an individual’s death. The thought was not bad or evil.   The Death Master File (yes, that is what is called) was meant particularly for financial institutions to try to prevent others from using a dead person’s SSN to gain credit.   In addition, there was a movement toward more transparency.   What wasn’t considered at that time was the ease of information transfer that would come years later with the internet.   Likely it wasn’t considered how genealogy sites would used the Death Master File.

So, how easily available is this Death Master File available?   Well, one can even get it as a app- http://itunes.apple.com/us/app/ssdmf/id453279465?ls=1&mt=8

Or if you don’t want to go to all that trouble one can just use one of the genealogy sites.

It seems that the DIPG community has been particularly hard hit with a dozen or more families being hit this year.   Here is an article from Nov 17 the Huffington Post….. http://www.huffingtonpost.com/2011/11/17/why-thieves-are-stealing-childhood-cancer-victims-identities_n_1093481.html

On Nov 18, Representative Sam Johnson (R- TX) along with seven co-sponsors introduced a bill to try to curtail this fraud perpetrated on our grieving families.:

H.R.3475 -- Keeping IDs Safe Act of 2011
http://thomas.loc.gov/cgi-bin/query/z?c112:H.R.3475:

Please consider calling and writing your Representative to bring awareness to this issue.
http://www.house.gov/

Unfortunately, it might not be possible to close this loophole before the next tax cycle in 2012 so it is likely that many families will continue to be vulnerable to this fraud.

Clinical Trials for the Newly Diagnosed Child with DIPG

2011-11-13T12:55:00.001-06:00

A review of www.clinicaltrials.gov was done on October 20, 2011 to identify which therapeutic trials are currently listed as open for the newly diagnosed child with DIPG. The following is information on the ten (10) listed trials that were listed as accruing patients as well as one vaccine trial that is yet to open. Clinicaltrials.gov seems to be often not be up to date on trial status. If you have interest or questions it might be wise to contact the primary investigator. Contact information is listed at the bottom of each clinical trial site. Most

clinical trials for DIPG can be found with the key word “pontine glioma” but some are still listed under “brainstem glioma”.

*Note- many, if not most clinical trials will not allow you to enter a trial if you have already started treatment.

PDGFR Inhibitor Crenolanib in Children/Young Adults With Diffuse Intrinsic Pontine Glioma or Recurrent High-Grade Glioma

Phase 1
ligible age- 18 months- 21 years
Study Chair- Cynthia Wetmore
Location- St Jude (Memphis, TN)
http://clinicaltrial.gov/ct2/show/NCT01393912?term=pontine+glioma&recr=Open&rank=1

Molecularly Determined Treatment of Diffuse Intrinsic Pontine Glioma

Phase 2
Eligible age- 3-18 years
Study Chair- Mark Kieran
Location- when open up to 20 locations- only Boston open on 10/20/11
http://clinicaltrial.gov/ct2/show/NCT01182350?term=pontine+glioma&recr=Open&rank=3

Lenalidomide and Radiation Therapy in High Grade Gliomas or Diffuse Intrinsic Pontine Gliomas

Phase 1
Eligible age- 1-18 years
Location- NIH (Bethesda, MD)
http://clinicaltrial.gov/ct2/show/NCT01222754?term=pontine+glioma&recr=Open&rank=4

A Study of Bevacizumab Therapy in Patients With Newly Diagnosed High-Grade Gliomas and Diffuse Intrinsic Pontine Glioma
Phase- not listed
Eligible age- 3-30 years
Study Chair- Maryam Fouladi
Location- Cincinnati and Chicago
http://clinicaltrial.gov/ct2/show/NCT00890786?term=pontine+glioma&recr=Open&rank=5

Cilengitide in Combination With Irradiation in Children With Diffuse Intrinsic Pontine Glioma

Phase 1
Eligible age- 6 months-21 years
Study Chair. Pierre Leblond
Location-

France

http://clinicaltrial.gov/ct2/show/NCT01165333?term=pontine+glioma&recr=Open&rank=7

Phase I Rindopepimut After Conventional Radiation in Children w/ Diffuse Intrinsic Pontine Gliomas

Phase 1
Eligible age- 3 to 18
Study Chair- Paul Fisher
Location- Stanford (Palo Alto, CA)
http://clinicaltrial.gov/ct2/show/NCT01058850?term=pontine+glioma&recr=Open&rank=8

Vorinostat and Radiation Therapy Followed By Maintenance Therapy With Vorinostat in Treating Younger Patients With Newly Diagnosed Pontine Glioma

Phase 1/2
Eligible age- 3 to 21 years
Study Chair- Jack Su
Location- COG trial- multiple locations
http://clinicaltrial.gov/ct2/show/NCT01189266?term=pontine+glioma&recr=Open&rank=11

Pilot Study of Glioma Associated Antigen Vaccines in Conjunction With Poly-ICLC in Pediatric Gliomas
Phase- none listed (listed as a pilot)
Eligible age- 19 months – 20 years
Study Chair- Regina Jakacki
Location- Pittsburgh
http://clinicaltrial.gov/ct2/show/NCT01130077?term=pontine+glioma&recr=Open&rank=13

External Beam Radiation Therapy and Cetuximab Followed by Irinotecan and Cetuximab for Children and Young Adults With Newly Diagnosed Diffuse Pontine Tumors and High-Grade Astrocytomas

Phase
Eligible age-
Study Chair-
Location-
http://clinicaltrial.gov/ct2/show/NCT01012609?term=pontine+glioma&recr=Open&rank=15

Valproic Acid and Radiation Followed by Maintenance Valproic Acid and Bevacizumab in Children With High Grade Gliomas
Phase 2
Eligible age- 3-21 years
Study Chair- Ira Dunkel
Location- POETIC study- several locations
http://clinicaltrial.gov/ct2/show/NCT00879437?term=brainstem+glioma&recr=Open&rank=9

Not Yet Open-

Imiquimod/Brain Tumor Initiating Cell (BTIC) Vaccine in Brain Glioma

Phase 1
Eligible age- 3 to 25 years
Study Chair- Christopher Moetel
Location- Minneapolis. MN
http://clinicaltrial.gov/ct2/show/NCT01400672?term=pontine+glioma&recr=Open&rank=6

DIPG - Current Status and Future Strategies

2011-11-03T07:59:00.001-05:00

The September 27^th issue of journal Child’s Nervous System included a review article evaluating where we are with the treatment and research of diffuse intrinsic pontine gliomas. These authors performed an extensive literature review particularly looking at clinical trials, evolving molecular biology and new therapeutics.

In their review they found-

Radiation is the only treatment that has consistently shown clinical and radiographic improvement. Approximately 70% of the children receiving radiation will have clinical improvement and 30-70% will have radiographic improvement.
Multiple studies using a combination of radiation and another agent with generally unimpressive results. Such agents have included RMP-7/carboplatin, topetecan/cisplatin, tamoxifen, vincristine/vp-16, cisplatin, temozolomide, vandetanib, and tipifarnib. However, the vandetanib study showed that those patients that had a higher plasma VEGF level to start had a longer progression free survival whereas those patients that has increasing levels of VEGF with treatment had a shorter progression free survival. (Original vandetanib study- http://www.ncbi.nlm.nih.gov/pubmed/20921456 )
“No single chemotherapeutic agent alone or in combination, either in a neoadjuvant oradjuvant setting, has proven to increase disease-free survival or alter overall survival in these children with primary or progressive disease.” This has included avastin and irinotecan which has had some success in adults.

The prognosis has remained dismal for more than two decades. This ‘virtual standstill’ for improved prognosis is leveled at:

The lack of biologic knowledge about these tumors.
Assumptions that adult and pediatric high grade gliomas are the same.
The poor drug access to the tumor because of the blood brain barrier.
The lack of experimental models.

Recommendations included:

A shift in treatment paradigm to include a diagnostic biopsy to “identify key molecules of unique signaling pathways which could provide clues to potential targets.
Development of preclinical (i.e., mouse) models.
“The need to design phase I study with routine sampling along with CED of therapeutic agents is imperative in these fatal tumors.”
“Further exploration of these different imaging modalities needs to be continued, and should facilitate better understanding of tumor architecture and metabolic profile as well as to provide more accurate prediction of extent and duration of response following radiation and adjuvant therapies.”
Evaluation of immunotherapy, gene therapy and other innovative techniques.

Diffuse intrinsic pontine glioma-current status and future strategies.

Childs Nerv Syst. 2011 Sep;27(9):1391-7. Epub 2011 Apr 30.
http://www.ncbi.nlm.nih.gov/pubmed/21533575

Prados Predicted Paradigm Shift for DIPG (diffuse intrinsic pontine glioma)

2011-10-19T10:48:00.001-05:00

Three years ago, Dr. Michael Prados was interviewed by Accelerated Brain Cancer Cure on his thoughts of advancements coming for pediatric brain tumors. Dr Prados immediately focused on the paradigm shift occurring in the medical community to develop unique strategies to fight DIPG though analysis of individual biopsy samples predicting things may change quickly for DIPG.

Why did that paradigm shift occur in the prior year? Well, French physicians published in the Journal of Neurosurgery 4 years of biopsy results for diffuse pontine lesions. All 24 children survived the procedure and only 2 suffered some sequela from the intervention developing transient cranial nerve palsies. One of the two has a worsening of a previous hemiparesis. Two children had their treatment plan altered because of the biopsy results.

Stereotactic biopsy of diffuse pontine lesions in children

http://www.ncbi.nlm.nih.gov/pubmed/17647306

Neurosurgeon Stefanie Puget has come to North America several times to discuss there ongoing work. It appears she was just at the Bethesda Consensus Conference earlier this month.

However, it seems that events have moved beyond the discussion stage. The new multi-institution, 4-armed molecular stratification study is listed as open on clinicaltrials.gov opening first at Dana Farber Boston. The other institutions slated to collaborate in this trial include -

University of California, San Francisco
Children's Hospital Boston
Children's Memorial Hospital
Children's Hospital Los Angeles
University of Utah
Memorial Sloan-Kettering Cancer Center
Seattle Children's Hospital
The Children's Hospital, Denver
Doernbecher Children's Hospital
Washington University Children's Hospital
Miami Children's Hospital
Johns Hopkins University
University of Florida
Children's Hospitals and Clinics of Minnesota
Southwestern Regional Medical Center
New York University
University of Rochester
University of Mississippi Medical Center
Louisville Children's Hospital
Children's Healthcare of Atlanta

http://clinicaltrials.gov/ct2/show/NCT01182350?term=pontine+glioma&rank=4

Accelerate Brain Cancer Cure (ABC²) is a U.S. brain tumor foundation started in 2001 by Dan and Steve Case with the mission to accelerate a cure for brain cancer by increasing the number of potential therapies and moving them rapidly into the clinic for patients. Since inception, ABC² has raised more than 16 million dollars investing in each stage of the development pipeline in pushing for a cure. It is worth taking a look at the diversity of funding they have engaged in striving for a cure.
http://www.abc2.org/smarter-research

PBTC Phase 2 Study Results for Temozolomide/06-Benzylguanine

2011-10-15T14:12:00.000-05:00

An abstract was released ahead of print for a phase 2 Pediatric Brain Tumor Consortium study on recurrent/progressive high-grade gliomas and brainstem gliomas utilizing the combination of temozolomide and 06-benzylguanine (06 BG). The study was initially put up on clinicaltrials.gov in January 2006.

O6-Benzylguanine and Temozolomide in Treating Young Patients With Recurrent or Progressive Gliomas or Brain Stem Tumors

http://clinicaltrial.gov/ct2/show/NCT00275002?term=06+temozolomide&rank=10

The thought was that the two agents may work differently to stop tumor growth and that combined chemotherapy might kill more cells. Temozolomide is an alkylating agent that interferes with DNA replication. This mechanism of action has seemed dependant on the ability to methylate DNA primarily at the N7 of 0-6 position on guanine. Some cells were found to be able to repair this DNA damage. The hope that O6 BG might overcome some of that repair issue.

Of the 41 children evaluated, 16 had brainstem gliomas. There were no sustained objective responses with any in the brainstem glioma group, however, one patient had long term stable disease of more than 6 courses (28 day course).

It was concluded that this combination “did not achieve target response rate for pediatric patients with recurrent or progressive high grade glioma or brainstem glioma.”

A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study
http://www.ncbi.nlm.nih.gov/pubmed/21968943

Columbia’s new treatment for DIPG - CED Topotecan

2011-10-13T14:29:00.002-05:00

In September, Columbia University announced that neurosurgeons Richard Anderson and Jeffrey Bruce have successfully used convection enhanced delivery (CED) with the agent topotecan for two pediatric DIPG patients.
http://www.columbianeurosurgery.org/2011/09/anderson-and-bruce-beating-the-odds-with-new-cancer-treatment/

CED requires fine catheters to be placed directly into the tumor. This approach allows for therapy to be placed directly in the tumor avoiding systemic toxicity and higher dosages.

Dr Bruce has worked for more than a decade in development of CED for malignant gliomas. His initial publications were in 2000 with a rat glioma model. In 2011, Bruce has authored three publications regarding CED with topotecan for malignant glioma.

Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model
http://www.ncbi.nlm.nih.gov/pubmed/11126910

Convection-enhanced delivery of topotecan into a PDGF-driven model of glioblastoma prolongs survival and ablates both tumor-initiating cells and recruited glial progenitors
www.ncbi.nlm.nih.gov/pubmed/21464045

Regression of Recurrent Malignant Gliomas with Convection-Enhanced Delivery of Topotecan
http://www.ncbi.nlm.nih.gov/pubmed/21562434

Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump
http://www.ncbi.nlm.nih.gov/pubmed/21750007

In addition to Columbia, the NIH also has a CED trial open for recurrent DIPG children utilizing a different agent -
An Open Label Dose Escalation Safety Study of Convection-Enhanced Delivery of IL13-PE38QQR in Patients With Progressive Pediatric Diffuse Infiltrating Brainstem Glioma and Supratentorial High-grade Glioma
http://clinicaltrial.gov/ct2/show/NCT00880061?term=pontine+glioma&rank=20

The NIH has piloted CED in the brainstem not only for DIPG but also for other issues. In 2007, the NIH published technical notes on two children that received CED therapy. One of these children had a DIPG and the other had Gaucher’s Disease.
Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note.
http://www.ncbi.nlm.nih.gov/pubmed/17639894

Nimotuzumab and Vinorelbine Concomitantly to Radiation and as Maintenance for Diffuse Pontine Glioma in Childhood

2011-10-11T19:11:00.001-05:00

On September 25^th, YM Bioscience presented a poster presentation at the ECCO-EMSO meeting in Stockholm, Sweden regarding the combined use of Nimotuzamab and vinorelbine with radiation in pediatric DIPG entitled:
"Nimotuzumab and Vinorelbine Concomitantly to Radiation and as Maintenance for Diffuse Pontine Glioma in Childhood: Promising Results on a Series of 13 Patients"
http://www.news-medical.net/news/20110927/Data-from-YM-BioSciences-nimotuzumab-clinical-trials-to-be-reported-at-ECCO-ESMO-2011.aspx

This appears to a companion to the 2011 ASCO presentation in Chicago. In this study, the Italian researchers reported on a series of 12 children. They noted that all children were treated on an outpatient basis and none had suffered significant treatment related side effects. For the 12 children (ages from 3-13), the progression free survival at 9 months was 69 ± 21% and the 12 month overall survival was 81.5 ± 12 %. The researchers believed this combination shows promise for DIPG

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=77258

Many researchers feel that combination therapy is going to be important in combating DIPG. It is exciting to see the combination therapy research.

DIPG Consensus Conference

2011-10-10T15:53:00.000-05:00

On October 6 and 7^th in Bethesda, a potentially pivotal meeting took place.
http://web.ncifcrf.gov/events/DIPG/default.asp

This invitation-only conference brought together physicians that care for children with diffuse intrinsic pontine gliomas to talk about several key current issues facing DIPG research. Some of the presentation titles include:

A Death Sentence Without Tissue Diagnosis
Translating Genomics Into Novel Therapeutic Strategies in Pediatric DIPG
Using A Genetically Engineered Mouse Model of Brainstem Glioma as a Preclinical Tool
Development of an International DIPG Registry
Personalized Medicine in Translation: From the Tissue to Treatment in a Single trial
Rapid Preclinical Development of Targeted Therapy Combinations for DIPG

Hopefully a Consensus Statement or White Paper will be issued as was done with the Toronto DIPG Think Tank.

http://www.ncbi.nlm.nih.gov/pubmed/21901544

The agenda and presenters can be found in the following link-
http://web.ncifcrf.gov/events/DIPG/agenda.pdf

JCO Releases St Jude DIPG Study Ahead of Print

2011-10-05T21:06:00.000-05:00

On September 19^th, the Journal of Clinical Oncology published online a St Jude original report on the molecular analysis of diffuse intrinsic pontine gliomas entitled:

Genomic-Wide Analyses Identify Recurrent Amplification of Receptor Tyrosine Kinase and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma.

A press release from Memphis heralded this landmark event as “the largest study ever of a rare childhood brain tumor”.

http://www.eurekalert.org/pub_releases/2011-09/sjcr-krg091911.php

Other news articles highlight “possible new treatment targets for diffuse intrinsic pontine gliomas” and speculates that (this research) “may tip the scales in the current debate about tumor biopsies.” http://www.marketwatch.com/story/key-regulatory-genes-often-amplified-in-aggressive-childhood-tumor-of-the-brainstem-2011-09-19

So what is the big news from this study?

First, DIPGs are a distinct subclass of gliomas. They are different from their counterparts not only in location but also in tumor molecular biology in some ways. In comparing DIPGs to other pediatric and adult gliomas they found “higher expression of particular HOX gene family members in DIPGs compared to non-brainstem gliomas.”   These HOX genes play an important part in the development of the hindbrain.    Suzanne Baker, St Jude senior developmental biologists said “those differences offer clues about where DIPGs begin and suggest the HOX family of genes might be involved.”

What does this mean?

Well, it would seem to explain the reason that other high grade glioma (HGG) research can not be reliably translated to DIPGs as we have seen with the recurrent dismal results with temozolomide in DIPGs despite it being a first line treatment with adult glioblastoma.     Even HGG pediatric studies might not be comparable.   Thus, DIPG will need to have its own research and clinical trials.

Secondly, it gives another point to start in trying to unravel the development of DIPGs… the HOX genes. This seems somewhat novel in DIPG literature; however, there are researchers in other areas that are working on HOX genes and hindbrain development.

Thirdly, this is only the beginning.   To truly understand DIPG, there will need to be more samples and more studies.

Please join us on September 17, 2011 as we celebrate Childhood Cancer Awareness Month along with the life of Alicia Marie Martin

2011-08-06T16:50:00.001-05:00

Bowl for the Gold ~ Strike Back Against Childhood Cancer

2010-08-24T14:35:00.000-05:00

Join us September 11, 2010 as we celebrate Childhood Cancer Awareness Month along with the life of Alicia Marie Martin

2010-08-21T17:20:00.000-05:00

French Present DIPG Biopsy Data at ISPNO

2010-07-13T22:12:00.000-05:00

Back in the summer of 2005 the Institut Gustave Roussy started a study with upfront stereotactic biopsy in children with diffuse intrinsic pontine gliomas.

http://clinicaltrial.gov/ct2/show/NCT00418327?term=Tarceva+and+brainstem+glioma&rank=1

In the July 2007 edition of The Journal of Neurosurgery, the results neurosurgical results of 24 children who underwent biopsy were published. In this there was no mortality and transient morbidity in two patients.
http://www.ncbi.nlm.nih.gov/pubmed/17647306

At the 2010 International Society of Pediatric Neuro-Oncology in Vienna, the French group presented pathologic data regarding the upfront biopsy results with pediatric DIPG. There were 60 children who underwent biopsy and which there were 35 frozen sample in which they could undertake array comparative genomic hybridization or gene expression profiles. The median age of the children was 7.3 years and the overall survival was 10.5 months. Histopathologically, there were 10 grade II, 14 grade III, 10 grade IV and one that could not be graded.

Neither the MRI characteristics or the tumor grade were correlated with survival.

Two patterns were found by genetic analysis. One pattern showed enrichment for neural patterning genes (particularly regarding PDGFRa). The other had angiogenic and adhesion genes. The patterns did not relate to tumor grade. The first group had a worse prognosis with a majority of children in this group having overall survival less than the median survival.

The authors concluded that they have found two DIPG molecular subgroups ‘characterized by chromosomal regions and potentially therapeutic targets’.
These results seem to dovetail well with the previously reported post-mortem study in March in JCO from Sick Kids in Toronto.

References-
Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets
J Clin Oncol. 2010 Mar 10;28(8):1337-44. Epub 2010 Feb 8.

From "Brain Tomour" World Edition 2010. International Brain Tomour Alliance

2010-07-11T20:28:00.000-05:00

DIFFUSE INTRINSIC PONTINE GLIOMA: COLLABORATION IS LEADING TO CHANGE
By Dr Loice Swisher

Dr Loice Swisher whose daughter Tori is a ten year medulloblastoma survivor. Loice is an FDA Patient Representative and emergency medicine physician. She is pictured here on a family vacation in Utah.

“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 24 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.

Compassionate Access Act Capital House Briefing

2010-06-08T12:25:00.000-05:00

Abigail was 21 when she ran out of options for her cancer. Her oncologist urged the family to try to get access to an experimental drug targeted at EGFR called C225 (now called Erbitux). Contacting the pharmaceutical companies, congressional representatives, the media and other influential people was to no avail. Abigail died on June 9, 2001. Ten hours after the greatest tragedy in his life, Frank Burroughs, decided to dedicate his life to furthering the cause of expanded access. In November 2001, a foundation was started bearing his daughter’s name- Abigail’s Alliance for the Better Access to Developmental Drugs.
http://www.abigail-alliance.org/story.php

Now there is a House Bill (H.R. 4732) called The Compassionate Access Act of 2010 which seeks expanded access to drugs in development for patients with serious disease. A summary of the bill is at-
http://www.govtrack.us/congress/bill.xpd?bill=h111-4732&tab=summary

On Thursday June 10th there will be a Capital House Briefing on the Compassionate Access Act held in room 122 of the Cannon House Building. Abigail Alliance cofounder, Steven Walker, will be giving a Power Point presentation. Interested persons are invited to attend.

Those who can’t attend can still support this bill. Contact the Rep's office in DC. Ask for the health care aide. Request the aide to go to the Congressional Briefing on June 10 at 9 (122 House Cannon Building- Rep Diane Watson is sponsor and her office may know more details if they need) Ask for the Rep to consponsor the bill. To find your representative’s office
http://www.house.gov/

Journal Watch (continued)

2010-06-02T23:42:00.000-05:00

“The lack of tumour tissue has led to stagnation in biological and genetic studies.”

The paper’s main focus was in understanding problems in overcoming the lack of specimens for analysis of DIPGs. The authors did identify that recent reports indicate “that biopsies in DIPG are safe and performed with acceptable low and only transient morbities while accomplishing meaningful analysis.” However, they also felt that using living tissue is ‘most defensible’ once there are therapeutic options in which the patient will benefit from in obtaining such samples.
The authors report on post-mortem tumor examination to try to get out of this catch 22 situation (one can only do a biopsy if there is benefit to the individual however one will not uncover those things that might be of benefit without tissue).
In regards to the 9 donations-

Eight of the children died at home.
Two children (age 10 and 11) expressed their own wish to donate.
No parent expressed regret in donation.
All families were offered disclosure of the autopsy result.

Although the numbers are very small, the paper is of significance in highlighting that such a program can be untaken— even with such logistical difficulties as serving an area of 1 million square kilometers with the children dying at home. Not only can such research happen but it can also uncover important biologic/genetic findings. For example, 2 of the 9 tumors were PNETs instead of gliomas.
It is interesting that the authors concluded with a statement indication for such a program to work there has to be cooperation of the primary neuro-ocnologists with the palliative care team, the pathology department and hospital management. This cooperation is critical in overcoming barriers and logistical issues.

Reference:

J Neurooncol. 2010 May 16
Post mortem Examination in diffuse intrinsic pontine glioma: challenges and chances.
Angelini P, Hawkins, C, Laperriere N, Bouffet E, Bartels U.
Division of Paediatric Haematology and Oncology, The Hospital for Sick Children, Toronto, Canada

Journal Watch

2010-05-27T18:02:00.000-05:00

Sick Kids is becoming a powerhouse for diffuse intrinsic pontine glioma research.
This past February, Sick Kids hosted an International Think Tank with approximately 45 researchers, clinicians and advocates to specifically address issues regarding this tumor. In February, this same team published the first whole genomic profiling of DIPG tumors highlighting platelet derived growth factor receptor alpha as a potential target for therapy. In the May issue of the Journal of Neuro-oncology, the same team published their six year experience with post-mortem examination of diffuse intrinsic pontine gliomas.

Between July 2002 and June 2008, 27 children were diagnosed by a combination of clinical symptoms and radiographic appearance to have a diffuse intrinsic pontine glioma. The clinical symptoms included cranial nerve palsies, ataxia and long tract signs lasting less 6 months. The radiographic criteria included that the mass was at least 2/3 of the pons without an exophytic component.
Here are some of the statistics that were presented regarding these 27 children

There was an even gender split- 13 male and 14 female.
The median age at diagnosis was 7.1 years (range - 0 days to 16.9 years) .
Twenty- four children had radiation. The three that did not have radiation were of a very young age.
Sixty three percent of the children had a partial or complete clinical response to radiation.
The media time to progression at the end of radiation was 3.9 months (range – 0.8 to 13. 6 months).
The median time from diagnosis to death was 10.1 months (range – 0.3- 26.3 months).

Autopsy tumor donation was discussed with 21 of the families. Ten consented. Regarding the six families where this was not discussed- 4 children had transferred care to another provider and with two families the physicians felt that the family was too overwhelmed.

Due to logistical issues only nine of the ten consented donations were obtained. All specimens were adequate for nucleic acid. Interestingly, two of the nine samples were found to be primitive neurectodermal tumors (PNETs). The other seven were glioblastomas.

Reference:

J Neurooncol. 2010 May 16
Post mortem Examination in diffuse intrinsic pontine glioma: challaneges and chances.
Angelini P, Hawkins, C, Laperriere N, Bouffet E, Bartels U.
Division of Paediatric Haematology and Oncology, The Hospital for Sick Children, Toronto, Canada

Treatment Upon Progression

2010-03-20T17:11:00.004-05:00

Trials for Children with Recurrent DIPG

The following information was gathered by Sue Rooney, mother of Quinn Rooney and JOMD Board member. Sue attempted to contact at least one institution for each open clinical trial to determine both whether a child with DIPG is eligible to participate in the study and to ensure the study is still open. If you find that any of this information is incorrect, please email info@JustOneMoreDay.org so that the list may be corrected. Further, if you are aware of an open trial that is not listed, please email us that information as well.

This list is provided for the sole purpose of helping individuals research. No assessment of the efficacy or advisability of any of the treatments listed has been made or is implied by inclusion in this list. Please note that the order listed was purely random! Please consult your own medical practitioners to determine appropriate medical treatment. Thank you!

1) A Phase I Study of MK-0752 in Pediatric Patients With Recurrent or Refractory CNS Malignancies

Please refer to this study by its ClinicalTrials.gov identifier: NCT00572182

2) ABT-888 and Temozolomide in Treating Young Patients With Recurrent or Refractory CNS Tumors

3) Study of Peptide Vaccination With Tumor Associated Antigens Mixed With Montanide in Patients With CNS Tumors
ClinicalTrials.gov Identifier: NCT00935545
sharon.gardner@nyumc.org

4) An Open Label Dose Escalation Safety Study of Convection-Enhanced Delivery of IL13-PE38QQR in Patients With Progressive Pediatric Diffuse Infiltrating Brainstem Glioma and Supratentorial High-grade Glioma

5) AZD2171 in Treating Young Patients With Recurrent, Progressive, or Refractory Primary CNS Tumors
Mark Kieran, MD, PhD, Protocol chair Ph: 617-632-4907;Â 866-790-4500

(close to being full per Dr. Kieran)

6) Enzastaurin in Treating Young Patients With Refractory Primary CNS Tumors

(this will be closing soon per Dr. Blaney (2/15/10))

7) Antineoplaston Therapy in Treating Children With Brain Tumors
info@burzynskiclinic.com

8) Topotecan in Treating Young Patients With Neoplastic Meningitis Due to Leukemia, Lymphoma, or Solid Tumors
(DIPG not technically excluded but may not qualify per Dr. Susan Blaney)

9) Karenitecin in Pediatric Patients With Refractory or Recurrent Solid Tumors N10010) (KTN10010)

Susan Blaney, MD 832-822-4586 smblaney@txccc.edu

10) Phase 2 Study of Nimotuzumab in Pediatric Recurrent Diffuse Intrinsic Pontine Glioma
ClinicalTrials.gov Identifier: NCT00600054

11) Ixabepilone in Treating Young Patients With Solid Tumors or Leukemia That Haven't Responded to Therapy

12) Valproate and Etoposide for Patients with Progressive, Relapsed or Refractory Neuronal tumors and Brain Metastases, Phase I clinical trial

Dr. Johannes Wolff 800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

jwolff@mdanderson.org

13) Phase I Study Of Single Agent Perifosine For Recurrent Pediatric Solid Tumors
For more information and to inquire about eligibility for this study, please contact

Dr. Oren Becher at 212-639-2152 or Dr. Ira Dunkel at 212-639-2153.

14) Sunitinib in Treating Young Patients With Refractory Solid Tumors

15) PF-02341066 in Treating Young Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma

16) Intracerebral Clysis in Treating Patients With Recurrent Primary Brain Tumors
Jeffrey Bruce, MD jnb2@columbia.edu (reference NCT 00452959)

17) A Trial of RAD001 and Avastin in Children With Recurrent Solid Tumors

18) PF-02341066 in Treating Young Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma

19) Perifosine With Temsirolimus for Recurrent Pediatric Solid Tumors
Please refer to this study by its ClinicalTrials.gov identifier: NCT01049841
Contact Dr. Oren Becher at 212-639-2152 or Dr. Ira Dunkel at 212-639-2153

20) Pazopanib Hydrochloride in Treating Young Patients With Solid Tumors That Have Not Responded to Treatment
(This trial is temporarily closed with an expected date of reopening in mid March 2010)

21) Trabectedin in Treating Young Patients With Solid Tumors That Have Relapsed or Not Responded to Treatment

22) Cixutumumab and Temsirolimus in Treating Young Patients With Solid Tumors That Have Recurred or Not Responded to Treatment

23) Doxercalciferol in Recurrent Pediatric Solid Tumors

24) Immunotherapy for Patients With Brain Stem Glioma and Glioblastoma
Email: Marites.Francisco@cshs.org

Finding Hope--Are There Survivors?

2010-02-17T09:41:00.004-06:00

Parents new to DIPG often ask, "Are there survivors?"

The children below--though treated very differently--have one thing in common; they have beaten the odds. Their stories provide hope for families who come after them.

Annabelle-dx 9/2005

Benny-dx 1/2008

Bridget-dx 8/2006

Clay-dx 12/2007

Connor-dx 9/2003

Cooper-dx 8/2007

Dasia-dx 3/2005

Dylan-dx 1/2004

Emily-dx 1/2007

Erica-dx 4/2005

JohnRobert-dx 4/2007

Kayla-dx 8/2006

Kayla-dx 8/2005

Laurel-dx 9/1999
Well 1/2010

Nikki-dx 1998

Nina Rose-dx 3/2006

Quinn-dx 5/2007
Well 2/2010

Ross-dx 10/2001
Well 1/2010

Sam-dx 9/2000
Well 1/2010

Tori-dx 8/1998

Survey of DIPG Parents

2010-02-07T21:02:00.006-06:00

We are reaching out to all parents of children who have been diagnosed with DIPG to seek information regarding each family's experience after the DIPG diagnosis.

We have been asked to gather information from families for consideration by clinicians and researchers who are focused on DIPG. To that end, we've prepared a survey which seeks information regarding individual experiences, thoughts and feelings, as well as suggestions for changes and improvements. The input of parents who have traveled the path will be invaluable help to those who, unfortunately, will certainly come behind us. (Both parents of a child who has been diagnosed with DIPG are encouraged to complete the survey -- each parent is certain to have a different perspective, even with regard to experiences with the same child.)

The survey results will be compiled in a report which will be shared at the end of February. The hope is that this will assist the medical community in better meeting the needs of children and families. (We also plan to make the information available to the DIPG community as a whole.)

We know the DIPG journey is difficult, no matter where you are on the path. Please accept our apologies if you are reading this at a particularly painful or difficult time. We would never want to hurt you or cause you additional pain, and you should feel no pressure or obligation to participate in this project.

Because we are on a short time frame, there is also a short time for completing this survey. Please note that the survey will close at midnight on February 14, 2010. We sincerely hope you will be able to find time during the next week to share your thoughts and experiences and we thank you for contemplating participating in this effort.

Please contact us at info@JustOneMoreDay.org if there is anything at all we can do to support you and your family.

Click here to begin the survey.

Again, thank you.

Medical News

2010-01-29T15:46:00.009-06:00

The Cancer Genome Atlas Identifies Distinct Subtypes of Deadly Brain Cancer That May Lead to New Treatment Strategies

St. Jude Children's Research Hospital and Washington University team to unravel genetic basis of childhood cancers

Scientists Show How Brain Tumors Outsmart Drugs

PI EGFRvIII Peptide Vaccination After Radiation in Children with Diffuse Intrinsic Pontine Gliomas
Vaccine Trial for Newly Diagnosed -- pre-planning is required for this trial at Stanford University. Criteria include requirements that radiation must have been completed 14-28 days prior to beginning the trial and that no other experimental drugs have been used for any reason.

*******

Remembering 2009

2010-01-09T18:50:00.020-06:00

We seize hope as we enter 2010 in the world of DIPG. There are new clinical trials on the horizon and exciting research is on the way. There seem to be more researchers and clinicians focused on DIPG and our children

In the meantime, we shall not forget the brave children who were taken from their families by DIPG in 2009. There are 66 names on this list, and we certainly are not aware of every child who died because of diffuse intrinsic pontine glioma during the last year.

With much hope that this number will be significantly lower in 2010, we honor and remember:

Ella B. (12/29/09)
Nadia Smith (12/27/09)
Lovis Tews (12/20/09)
Peyton Ricker (12/15/09)
Carter Harris (12/14/09)
Andrew Smith (12/4/09)
Claire McColloch (12/2/09)
Delaney Starcher (12/1/09)
Finnegan Grady (11/24/09)
Caden Safer (11/22/09)
Shanade Tellintire (11/18/09)
Claudia Smith (11/13/09)
Colton Thurman (10/31/09)
Melana Matson (10/27/09)
Katie Seaman (10/21/09)
Makael Shaw (10/11/09)
Tyler Magnuson (10/9/09)
Luke Pollok (9/30/09)
Mia Shand (9/20/09)
Dominic Horns (9/20/09)
Monisha Nalini Prasad (9/15/09)
Nicole Lee (9/2/09)
Viviana Cora Perez (9/2/09)
Caleb Bradford (8/30/09)
Elizabeth Kulikowski (8/28/09)
Samuel Watson (8/23/09)
Sasitaya Sriprayoonsakul ("Ing") (8/20/09)
Fabian Burke-Georgiou (8/17/09)
Joshua Solomon (8/14/09)
Christopher Sliker (8/8/09)
Derric Williams (8/3/09)
Brianna Sharp (7/25/09)
Caleb Spady (7/21/09)
Mei Margaret Pohly (7/15/09)
Ravyn Finch (7/11/09)
Zac Talley (7/8/09)
Max Lacewell (7/4/09)
Caleb Crosby (7/4/09)
Kelly-Anne Bouchard (7/4/09)
Kira Cundiff (7/2/09)
Morgan Pritchett (6/30/09)
Sadie Huish (6/25/09)
Jasmine-Eva Schubert (6/23/09)
Liam Reilly (6/22/09)
Ari Noelle Rich (6/10/09)
Chris Jones Jr. (5/31/09)
Max Scotti (4/21/09)
Andrew Helms (4/10/09)
Tyler Marx (4/5/09)
Ryan Summer (3/31/09)
Amy Pedersen (3/31/09)
Eric Kelly (3/28/09)
Amanda Gonzales (3/13/09)
Ellie Willaert (2/19/09)
Ian Henderson (2/19/09)
Miguel Garcia (2/17/09)
Rishabh Goel (2/13/09)
Milan Maria Capobianco (2/12/09)
Cal Daniel (2/10/09)
Kyle Roger (2/7/09)
Katie McKerracher (1/27/09)
Cristian Rivera (1/25/09)
Morgan Palmer (1/20/09)
Asiyyah Moore (1/16/09)
Dylan Jewett (1/8/09)
Ethan Perkins (1/8/09)