At a poster session for the 3rd biennial Pediatric Neuro-Oncology Basic and Translational Research Conference next month, physicians from St Jude Research Hospital will be presenting a retrospective review of their patients who had prolonged survival despite being given a diagnosis of diffuse intrinsic pontine glioma.
These physicians reviewed the records of DIPG patients at St Jude from October 1, 192 to May 31, 2011. Of the 191 patients there were 5 long time survivors with a median time from diagnosis being 9.3 years! It seems 4 out of 5 of these patients had some atypical clinical or imaging features that put them on the side of potentially better outcomes than the average.
All these survivors underwent neurocognitive testing. Interestingly, and unfortunately like so many other children who undergo brain radiation, cognitive function was impacted in 4 of 5 patients- two falling in the range of borderline/mild mental retardation. These findings will become increasingly important when there is better survival statistics for DIPG.
The researcher point out that prolonged survival does not equal cure. Two of the patients had progression years after their initial treatment with radiation.
It will be interesting to see what comes of this. Certainly the DIPG Registy could become very important to bring the information on all long term survivors together at one place.
Reference:
Clinico-radiologic characteristics and neurocognitive assessment of long-term survivors of diffuse intrinsic pontine glioma
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=738281
Friday, April 12, 2013
Thursday, April 11, 2013
Focus on Research- Mitochondria and DIPG (New Australian Abstract)
The 3rd biennial Pediatric Neuro-Oncology Basic and Translational Research Conference jointly sponsored by the Society of Neuro-Oncology and the Children's Brain Tumor Foundation will be held on May 16th and 17th in Fort Lauderdale Florida. Several of the already available abstracts are several on DIPG. One of the ones that caught my eye will be a poster presentation from Australian researchers entitled " Targeting mitochondria and metabolism as a novel therapeutic approach in the treatment of Diffuse Intrinsic Pontine Glioma".
The interest in cellular metabolism in cancer goes back the early 1900's with Otto Heinrich Warburg. The Warburg Hypothesis says "the prime cause of cancer is the replacement of the respiratory of oxygen in normal body cells by a fermentation of sugar." He speculated that tumor development is driven by insults to the mitochondria which affects cellular respiration. Mitochondria have become a potential target for cancer therapy. One of the key mitochondrial proteins implicated in cancer has been adenine nucleotide translocase (ANT).
In this abstract, the researchers used DIPG neurospheres to evaluate the effectiveness of an ANT inhibitor PENAO. This agent appears to have first hit the internet in 2011, when some of the authors unveiled this novel compound at AACR in an abstract " PENAO: A small molecule tumor metabolism inhibitor". In the AACR abstract PENAO led arrest of proliferation and apoptosis of tumors cells. It was well tolerated by IV and subcutaneously in mice.
In this study, the use of PENAO on DIPG neurospheres was found to be a "promising therapeutic strategy" to treat DIPG. In addition, combination with a MRP1 ( multidrug resistance-associated protein ), Reversan, increased the effect. Effectiveness of PENAO was also increased by 3-bromopyruvate.
This is interesting research with a different approach to DIPG in utilizing mitochondrial small molecule inhibitors. Now, the challenge would seem to be in the steps to translate this from bench to bedside. The great thing now compared to just a few years ago is that several institutions have been able to developed DIPG animal models to be able to preform the necessary translational research.
Reference:
Targeting mitochondria and metabolism as a novel therapeutic approach in the treatment of Diffuse Intrinsic Pontine Glioma
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=740145
Mitochondria and Cancer: Past, Present, and Future
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581248/
Adenine nucleotide translocase 2 is a key mitochondrial protein in cancer
http://www.ncbi.nlm.nih.gov/pubmed/20950584
Inhibition of Glycolysis in Cancer Cells: A Novel Strategy to Overcome Drug Resistance Associated with Mitochondrial Respiratory Defect and Hypoxia
http://cancerres.aacrjournals.org/content/65/2/613.full
The interest in cellular metabolism in cancer goes back the early 1900's with Otto Heinrich Warburg. The Warburg Hypothesis says "the prime cause of cancer is the replacement of the respiratory of oxygen in normal body cells by a fermentation of sugar." He speculated that tumor development is driven by insults to the mitochondria which affects cellular respiration. Mitochondria have become a potential target for cancer therapy. One of the key mitochondrial proteins implicated in cancer has been adenine nucleotide translocase (ANT).
In this abstract, the researchers used DIPG neurospheres to evaluate the effectiveness of an ANT inhibitor PENAO. This agent appears to have first hit the internet in 2011, when some of the authors unveiled this novel compound at AACR in an abstract " PENAO: A small molecule tumor metabolism inhibitor". In the AACR abstract PENAO led arrest of proliferation and apoptosis of tumors cells. It was well tolerated by IV and subcutaneously in mice.
In this study, the use of PENAO on DIPG neurospheres was found to be a "promising therapeutic strategy" to treat DIPG. In addition, combination with a MRP1 ( multidrug resistance-associated protein ), Reversan, increased the effect. Effectiveness of PENAO was also increased by 3-bromopyruvate.
This is interesting research with a different approach to DIPG in utilizing mitochondrial small molecule inhibitors. Now, the challenge would seem to be in the steps to translate this from bench to bedside. The great thing now compared to just a few years ago is that several institutions have been able to developed DIPG animal models to be able to preform the necessary translational research.
Reference:
Targeting mitochondria and metabolism as a novel therapeutic approach in the treatment of Diffuse Intrinsic Pontine Glioma
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=740145
Mitochondria and Cancer: Past, Present, and Future
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581248/
Adenine nucleotide translocase 2 is a key mitochondrial protein in cancer
http://www.ncbi.nlm.nih.gov/pubmed/20950584
Inhibition of Glycolysis in Cancer Cells: A Novel Strategy to Overcome Drug Resistance Associated with Mitochondrial Respiratory Defect and Hypoxia
http://cancerres.aacrjournals.org/content/65/2/613.full
Wednesday, April 10, 2013
DIPG- Adults versus Kids
Adult diffuse pontine lesions have a median survival range of 4.9 to 7.3 years!
There seems to be a bimodal type of distribution of diffuse brainstem lesions. The first peak is generally in the the 4-9 year olds and the second is in the 20-50 year olds. Like children, diffuse brainstem gliomas are the most frequent type of brainstem tumor in adults. Unlike children who tend to have high grade lesions with a prognosis on average of about 1 year, young adults with similarly appearing lesions when biopsied are low grade and may have a much greater life expectancy.
Although adult and pediatric DIPG patients might present with similar symptoms (such as ataxia and cranial nerve palsies), is important to realize that despite potentially similar appearances of the diffuse pontine lesions on MRI this is not the same disease process. This is made clear in the review (full text link) published last year in The Oncologist. For those interested the read is not near as difficult as the recent molecular tumor biology publications. In addition, there are three MRI series of adult patients with diffuse pontine lesions. One of these survivors' MRIs is shown 10 years out.
I highly recommend a peak at these MRIs (which is easier to do on pub med if one doesn't want to read the entire publication.) It is amazing how the MR imaging is so similar to what we see in pediatric patients, yet the course can be so much different.
No one know yet why the tumors are so different in different ages.
Reference:
Adult Brainstem Glioma
Oncologist. 2012;17(3):388-97. doi: 10.1634/theoncologist.2011-0335. Epub 2012 Mar 1.
Full Free Text
http://theoncologist.alphamedpress.org/content/17/3/388.long
There seems to be a bimodal type of distribution of diffuse brainstem lesions. The first peak is generally in the the 4-9 year olds and the second is in the 20-50 year olds. Like children, diffuse brainstem gliomas are the most frequent type of brainstem tumor in adults. Unlike children who tend to have high grade lesions with a prognosis on average of about 1 year, young adults with similarly appearing lesions when biopsied are low grade and may have a much greater life expectancy.
Although adult and pediatric DIPG patients might present with similar symptoms (such as ataxia and cranial nerve palsies), is important to realize that despite potentially similar appearances of the diffuse pontine lesions on MRI this is not the same disease process. This is made clear in the review (full text link) published last year in The Oncologist. For those interested the read is not near as difficult as the recent molecular tumor biology publications. In addition, there are three MRI series of adult patients with diffuse pontine lesions. One of these survivors' MRIs is shown 10 years out.
I highly recommend a peak at these MRIs (which is easier to do on pub med if one doesn't want to read the entire publication.) It is amazing how the MR imaging is so similar to what we see in pediatric patients, yet the course can be so much different.
No one know yet why the tumors are so different in different ages.
Reference:
Adult Brainstem Glioma
Oncologist. 2012;17(3):388-97. doi: 10.1634/theoncologist.2011-0335. Epub 2012 Mar 1.
Full Free Text
http://theoncologist.alphamedpress.org/content/17/3/388.long
Tuesday, April 9, 2013
Focus on Research: 3 New DIPG Abstract This Week!
One of the frustrating things about medical research is the delay between when research is presented at a scientific meeting and when it actually gets to publication. Unfortunately, sometimes the gap is more than a year. For this reason, I trawl around the meeting abstracts which might have potential. One such meeting is the American Association of Cancer Research (AACR) concluding it's five-day Annual Meeting tomorrow. I am thrilled to report there are DIPG presentations at this meeting.
Here are the citations for the three presented abstracts:
1) Nathalene Truffaux, Ludivine Le Dret, Stephanie Puget, Gilles Vassal, Birgit Geoerger, Jacques Grill.
Activity of dasatinib and potential escape mechanisms in diffuse intrinsic pontine glioma (DIPG) models
In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013 {Abstract 2763}
2) Sridevi Yadavilli, Madhuri Kambhampati, Oren J. Becher, Tobey MacDonald, Ravi Bellamkonda, Roger J. Packer, Javad Nazarian.
NG2 upregulation and its defective asymmetric distribution in pediatric brainstem glioma and diffuse intrinsic pontine glioma
In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. {Abstract 5004}
3) Marianne Hutt, Wendy Goldstein, Javad Nazarian, Antoinette Price, Kah Jing Lim, Katherine Warren, Howard Chang, Charles Eberhart, Eric Raabe.
Targeting the Notch and mTOR pathways in diffuse intrinsic pontine glioma
In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. {Abstract 5049}
The first abstract is from the French researchers that have pioneered the way for biopsies. The second is from National Children's in DC, Duke and Emory/Georgia Institute of Technology. The third is from the Mid Atlantic DIPG Consortium (MADC). The MADC abstract appears to be an extension of the abstract we highlighted here on March 23this year.
As the abstracts are meant for a group of researchers, they are most definitely highly scientific. Here is one thing to take away- it is possible to establish cell lines from freshly biopsied DIPG material. The French group has been able to establish 12 lines in this way!
Here are the citations for the three presented abstracts:
1) Nathalene Truffaux, Ludivine Le Dret, Stephanie Puget, Gilles Vassal, Birgit Geoerger, Jacques Grill.
Activity of dasatinib and potential escape mechanisms in diffuse intrinsic pontine glioma (DIPG) models
In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013 {Abstract 2763}
2) Sridevi Yadavilli, Madhuri Kambhampati, Oren J. Becher, Tobey MacDonald, Ravi Bellamkonda, Roger J. Packer, Javad Nazarian.
NG2 upregulation and its defective asymmetric distribution in pediatric brainstem glioma and diffuse intrinsic pontine glioma
In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. {Abstract 5004}
3) Marianne Hutt, Wendy Goldstein, Javad Nazarian, Antoinette Price, Kah Jing Lim, Katherine Warren, Howard Chang, Charles Eberhart, Eric Raabe.
Targeting the Notch and mTOR pathways in diffuse intrinsic pontine glioma
In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. {Abstract 5049}
The first abstract is from the French researchers that have pioneered the way for biopsies. The second is from National Children's in DC, Duke and Emory/Georgia Institute of Technology. The third is from the Mid Atlantic DIPG Consortium (MADC). The MADC abstract appears to be an extension of the abstract we highlighted here on March 23this year.
As the abstracts are meant for a group of researchers, they are most definitely highly scientific. Here is one thing to take away- it is possible to establish cell lines from freshly biopsied DIPG material. The French group has been able to establish 12 lines in this way!
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