One of the longstanding questions for DIPG has been."Why doesn't chemo work?"
There have been dozens of trials using all kinds of agents and all of them have virtually the identical Kaplan Meier Curve. The think we don't know is why that is. Often times one hears about something in the blood brain barrier that limits chemotherapy effectiveness. Other times one wonders if it is something in the glioma cells themselves that make them more resistant. The Netherlands paper tried to answer one part of this in better defining ABC transporters in pediatric glioma.
ABC transporters essentially function as little door ways in the cell's membrane either usher substances into the cell (importers) or out of the cells (exporters). The exporters are tone ones that are a problem withe drug resistance. The transporters pump drugs and toxins out of the cells.
There have been 3 different ABC transporters found that escort drugs out of cells. These include P-glcyoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance associated proteins (MRPs, ABCC1).
This Netherlands study looked at the above 3 ABC transporters in each of the glioma cell lines. All cell lines were negative for P-gp. Only one supratentorial pediatric glioma cell line had BRCP1. High levels of MRP1 was found in 4 of the 9 glioma cell lines. That included 2 of 3 of the DIPG cell lines.
The researchers then looked at actual tumor sample sections to try to determine the amount of ABC transporters in the glioma cells versus the blood vessels. They found that P-gp was not present in most of the glioma cells but was presesnt moderately in the tumor's blood vessels. BCRP1 was not present in the glioma cells but was highly pressent in the blood vessels. Only MRP1 was seen in both the glioma cells and the blood vessels. A chart on the cell lines tested (including 2 of the 3 DIPG samples) is available (click here to see chart).
So, what does this mean for DIPG now?
That is hard to say. So far tying to inhibit the ABC transporters with different agents have been problematic because of significant toxic side effects. These ABC transporters are meant to protect normal cells as well. However, since most of the ABC transporters seem to be in the blood vessels a way around this blood-brain barrier could be direct tumor delivery (i.e., convenction enhanced delivery). The researchers also suggest developing drugs that are not a substract for these transporters could also increase chemotherapy effectiveness.
It does tell us that in trying to find a cure for DIPG that we can not just focus on finding targets within the cancer biology but also need to work on finding ways for new agents to be able reach these targets.
Note: The ATP-binding cassette transporters issue was featured in a recent blogspot regarding a new abstract out of Oren Becher's lab in Duke.
This work was funded by KiKa "Stichting Kinderen Kankervrij"- Dutch Children Cancer-free Foundation.
References:
In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma
PLoS One. 2013 Apr 29;8(4):e61512. doi: 10.1371/journal.pone.0061512. Print 2013.
Free Full Text- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639279/
KiKa Stichting Kinderen Kankervrij- Dutch Children Cancer-free Foundation
http://www.kika.nl/
ABC transporters limit dansantinib efficacy in mice
http://dipg.blogspot.com/2013/04/abc-transported-limit-dasatinib.html
Tuesday, May 7, 2013
Monday, May 6, 2013
New Publication- Are DIPGs just resistant to chemo? No!
Last week the highly productive, DIPG-focused Netherlands group from VU University Medical Center in Amsterdam put forth another publication which happens to have free full text available!
This research focuses on unravelling the reasons why chemotherapy has not been beneficial against DIPGs and pediatric high-grade gliomas. Are DIPGs just resistant to the agents? Or, is it that something is protecting the cells which causes an otherwise good option to be ineffective?
Part 1- Are glioma cells just resistant to chemotherapy?
To look at the first question, the researchers evaluated 9 pediatric glioma cell lines to eliminate questions of adequate drug delivery. Three of these cell lines were from children with DIPGs and 6 were from supratentorial high grade gliomas. Of the 3 DIPG cell lines, all were of different histologic grades- one GBM, one anaplastic astrocytoma and one diffuse fibrillary asrocytomas. Two of these DIPG cell lines came from children who had not had any treatment. The other cell line came from an autopsy donation done approximately 2 hours after death.
In the screening of these cell lines, several agents had high level of killing tumor cells.
When looking at targeted small molecule agents, these did not fare as well as classical chemotherapies. Some did show some efficacy . The best of these was bortezomib which resulted in more than 50% reduction in cell line surival in 6/9 cell lines. There was little or no effect with erlotinib and everolimus. A hypothesis for this result include that the cell lines were not checked for the targets. If there was a matching of targets and agents the results might have been better. Also since there are multiple messed up pathways combined therapy is generally thought to be needed and a single agents is very unlikely to be effective.
In looking at classic chemotherapy agents, melphalan was the only drug that had significiant toxicity in all cell lines. Interestly that is the exact agent of the new intra-arterial Hopkins DIPG trial!
Other agents that were found to have a signficant effect included doxorubicin, mitoxantrone and BCNU. The next level included etoposide, thiotepa and carboplatin. Carboplatin was of special note since that is what the UK in their CED report.
What this means for DIPG is that DIPG is not necessarily resistant to chemotherapy! Effective drgus might not be the biggest hurdle for a cure for DIPG. It might be getting them to the tumor cells.
This work was funded by KiKa "Stichting Kinderen Kankervrij"- Dutch Children Cancer-free Foundation.
Tomorrow.....
Part 2- Do the efflux transporters protect the glioma cells?
References:
In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma
PLoS One. 2013 Apr 29;8(4):e61512. doi: 10.1371/journal.pone.0061512. Print 2013.
Free Full Text- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639279/
KiKa Stichting Kinderen Kankervrij- Dutch Children Cancer-free Foundation
http://www.kika.nl/
This research focuses on unravelling the reasons why chemotherapy has not been beneficial against DIPGs and pediatric high-grade gliomas. Are DIPGs just resistant to the agents? Or, is it that something is protecting the cells which causes an otherwise good option to be ineffective?
Part 1- Are glioma cells just resistant to chemotherapy?
To look at the first question, the researchers evaluated 9 pediatric glioma cell lines to eliminate questions of adequate drug delivery. Three of these cell lines were from children with DIPGs and 6 were from supratentorial high grade gliomas. Of the 3 DIPG cell lines, all were of different histologic grades- one GBM, one anaplastic astrocytoma and one diffuse fibrillary asrocytomas. Two of these DIPG cell lines came from children who had not had any treatment. The other cell line came from an autopsy donation done approximately 2 hours after death.
In the screening of these cell lines, several agents had high level of killing tumor cells.
When looking at targeted small molecule agents, these did not fare as well as classical chemotherapies. Some did show some efficacy . The best of these was bortezomib which resulted in more than 50% reduction in cell line surival in 6/9 cell lines. There was little or no effect with erlotinib and everolimus. A hypothesis for this result include that the cell lines were not checked for the targets. If there was a matching of targets and agents the results might have been better. Also since there are multiple messed up pathways combined therapy is generally thought to be needed and a single agents is very unlikely to be effective.
In looking at classic chemotherapy agents, melphalan was the only drug that had significiant toxicity in all cell lines. Interestly that is the exact agent of the new intra-arterial Hopkins DIPG trial!
Other agents that were found to have a signficant effect included doxorubicin, mitoxantrone and BCNU. The next level included etoposide, thiotepa and carboplatin. Carboplatin was of special note since that is what the UK in their CED report.
What this means for DIPG is that DIPG is not necessarily resistant to chemotherapy! Effective drgus might not be the biggest hurdle for a cure for DIPG. It might be getting them to the tumor cells.
This work was funded by KiKa "Stichting Kinderen Kankervrij"- Dutch Children Cancer-free Foundation.
Tomorrow.....
Part 2- Do the efflux transporters protect the glioma cells?
References:
In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma
PLoS One. 2013 Apr 29;8(4):e61512. doi: 10.1371/journal.pone.0061512. Print 2013.
Free Full Text- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639279/
KiKa Stichting Kinderen Kankervrij- Dutch Children Cancer-free Foundation
http://www.kika.nl/
Sunday, May 5, 2013
More than 2 Million- DC Race for Hope!
Today was the 16th year for the DC Race for Hope. It drew over 11,000 people and raised more than 2 million dollars! The facebook page says that the count is more than 2.3 million and counting. Check out the pictures on their page. It is heartening to see the street with people filled supporting the fight against brain tumors.
One of the teams for the past several years has been David Cook. He is the Season 7 winner of American Idol. He also lost his brother to a 10 year battle with brain cancer. This week he was back on the Idol stage and specific mention was made of his passion for supporting brain tumor research. (Click here to see the video)
In it's history the DC Race for Hope has raised more than 17 million for brain tumor research. The funds go to the National Brain Tumor Society and Accelerated Brain Cancer Cure (ABC2). These foundations are fighting all brain tumors- many kinds and all ages.
Perhaps at one time pediatric brain tumors seemed to be off on their own but not anymore. To me, it definitely seems that DIPG research has matured in the past few years that it has now naturally melded into other glioma research.
I was taken by surprised when ABC2 decided not only to provide funds for the DIPG Preclinical Consortium (initiated at the first DIPG Collaborative Symposium) but also provided strategic advice "to help the research consortium preform DNA (exon) sequencing of all DIPG cell lines, their primary tumor and paired normal DNA via the laboratory of Dr Paul Spellman at OHSU.
And the National Brain Tumor Society sponsored and attended the DIPG Collaborative Symposium. Their Pediatric Research Initiative seems to be exactly what are top priorities for DIPG- molecular profiling and neuordevelopmental biology (gliomagenesis). The National Brain Tumor Society grants in 2010 funded the ground-breaking work DIPG genomic work of both Cynthia Hawkins in Toronto and Suzanne Baker of St. Jude which has reported some of the most exciting results for DIPG- particularly the histone/K27M findings.
Times are changing. Just a few years ago there was no preclinical DIPG research. Now DIPG research has garnered the interest and inclusion from larger brain tumor organizations. DIPG does have alot in common with adult GBMs- particularly poor statistics, invasiveness and the blood brain barrier. The combined efforts with these other organizations seems to be a great thing in fighting DIPG.
Reference:
DC Race for Hope-
http://www.braintumorcommunity.org/site/PageServer?pagename=RFH_DC_Homepage
One of the teams for the past several years has been David Cook. He is the Season 7 winner of American Idol. He also lost his brother to a 10 year battle with brain cancer. This week he was back on the Idol stage and specific mention was made of his passion for supporting brain tumor research. (Click here to see the video)
In it's history the DC Race for Hope has raised more than 17 million for brain tumor research. The funds go to the National Brain Tumor Society and Accelerated Brain Cancer Cure (ABC2). These foundations are fighting all brain tumors- many kinds and all ages.
Perhaps at one time pediatric brain tumors seemed to be off on their own but not anymore. To me, it definitely seems that DIPG research has matured in the past few years that it has now naturally melded into other glioma research.
I was taken by surprised when ABC2 decided not only to provide funds for the DIPG Preclinical Consortium (initiated at the first DIPG Collaborative Symposium) but also provided strategic advice "to help the research consortium preform DNA (exon) sequencing of all DIPG cell lines, their primary tumor and paired normal DNA via the laboratory of Dr Paul Spellman at OHSU.
And the National Brain Tumor Society sponsored and attended the DIPG Collaborative Symposium. Their Pediatric Research Initiative seems to be exactly what are top priorities for DIPG- molecular profiling and neuordevelopmental biology (gliomagenesis). The National Brain Tumor Society grants in 2010 funded the ground-breaking work DIPG genomic work of both Cynthia Hawkins in Toronto and Suzanne Baker of St. Jude which has reported some of the most exciting results for DIPG- particularly the histone/K27M findings.
Times are changing. Just a few years ago there was no preclinical DIPG research. Now DIPG research has garnered the interest and inclusion from larger brain tumor organizations. DIPG does have alot in common with adult GBMs- particularly poor statistics, invasiveness and the blood brain barrier. The combined efforts with these other organizations seems to be a great thing in fighting DIPG.
Reference:
DC Race for Hope-
http://www.braintumorcommunity.org/site/PageServer?pagename=RFH_DC_Homepage
Saturday, May 4, 2013
Dr Souweidane CED Trial on 8th Patient
The Cristian Rivera Foundation, a significant support of the Cornell convection enhanced delivery (CED) trial for newly diagnosed children with DIPG, announced in their April 2013 newsletter that the primary investigator, Dr. Mark Souweidane, is now up to his 8th patient in this trial that opened at the end of 2012.
This is a very exciting, innovative trial for DIPG where a catheter is placed from the top of the head down in to the brainstem. A few weeks after traditional radiation, a radiolabelled antibiody is infused directly in to the pons. Thus, the blood brain barrier is no longer a problem in getting an agent into the tumor.
This is different than other DIPG CED trials in that it uses a radiolabelled antibody. The antibody is
8H9 which has been found in several different tumors. This is linked to 124I which is radioactive. Since radiation has been the only thing that has made a dent in survival statistics the hope seems that this targeted radiation will clean up some of the cancer cells that have thus far been radioresistant with routine radiation.
This trial is the culmination of more than a decade of research utlitizing CED in the brainstem undertaken by Dr Souweidane and his team at Cornell. Below is a video illustrating how CED is performed.
For more information about this trial, about the trial and contact information for Dr. Soweidane click here.
Related Blog Post:
UK Gives CED a Go
http://dipg.blogspot.com/2013/04/uk-gives-ced-go.html
This is a very exciting, innovative trial for DIPG where a catheter is placed from the top of the head down in to the brainstem. A few weeks after traditional radiation, a radiolabelled antibiody is infused directly in to the pons. Thus, the blood brain barrier is no longer a problem in getting an agent into the tumor.
This is different than other DIPG CED trials in that it uses a radiolabelled antibody. The antibody is
8H9 which has been found in several different tumors. This is linked to 124I which is radioactive. Since radiation has been the only thing that has made a dent in survival statistics the hope seems that this targeted radiation will clean up some of the cancer cells that have thus far been radioresistant with routine radiation.
This trial is the culmination of more than a decade of research utlitizing CED in the brainstem undertaken by Dr Souweidane and his team at Cornell. Below is a video illustrating how CED is performed.
Related Blog Post:
UK Gives CED a Go
http://dipg.blogspot.com/2013/04/uk-gives-ced-go.html
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