The USCF pediatric neurosurgical department this week had a publication come out electronically ahead of print regarding biopsy issues for intrinsic brainstem lesions. These doctors note that the situation with pediatric brainstem tumors is "virtually unlike any other location in the brain" because for these other areas the first step is obtaining a tissue diagnosis to devise an appropriate treatment course. The reason for the lack of biopsy has been the perception of excessive risk of pediatric brainstem biopsy. The article also notes that the current approach of investigating a wide array of chemotherapeutic options in multitudinous trials without biologic tumor analysis has not lead to any increased survival in the last two decade. The authors evaluated the feasibility and safety of pediatric brainstem biopsy at their institution.
Nine children ( 4 male and 5 female witht he average age of 5.7 years) underwent brainstem biopsy between 2000 and 2011 under approval from the Committee for Human Research. Children were exlcuded from the study if the tumor originated from the cerebellum or cerebral hemispheres, were exophytic or well defined lesions. All included children had typical DIPG imaging features. The included children presented with cranial nerve palsies (7/9), ataxia (5/9) and headache (3/9). Rarer symptoms included head tilt, nausea, weakness on one side and respiratory distress.
The authors did discuss target selection. All children had stereotactic biospies via a transcerebellar approach. The course was chosen to minimize passing through the brainstem avoiding the lateral edge of the 4th ventical, pontine tegmentum and ventral corticospinal tracts. In some cases diffusion tensor imaging was used to locate the corticospinal tracts. Unless there was an obviously enhancing, aggressive area the site selection was just deep to the middle cerebellar penduncle. One to four specimens were taken.
All cases were gliomas. Five of the children had high grade gliomas and four were low grade. None of the children suffered intraoperative complications. One of hte children developed seizures and hypercephalus postoperative which was treated with a shunt. Seven of the patients underwent radiation and chemotherapy and two underwent chemotherapy only. All children did experience the natural progresssion of DIPG with decline in neurologic and functional status. At the time of the publication writing 4 children had died- 2 high grade at 12 months and 2 low grade at 6 and 11 months.
The authors point out the the tremendous lack of progress with DIPG statitics has lead to "therapeutic nihilism". However, they point out ther are many targeted biologic agents that might have potential on the horizon. The problem is for phase II trials there will "certainly require tissue in order to determine molecular pheontype prior to treatment assignement".
It seems that this publication is looking specificially forward to those biologic agent trials so that DIPG children will not be excluded just on the basis of not having a tissue analysis. Although biopsy did not aid the children in this study, it did outline that biopsy can be preformed safely in children with DIPG and gives some tips on the approach of such biospies.
With biospy and convection enhanced delivery I would hope that more pediatric neurosurgeons will become increasingly interested in options for children with DIPG.
References:
Feasibility, safety and indications for surgical biopsy of intrinsic brainstem tumors in children
http://www.ncbi.nlm.nih.gov/pubmed/23666401
Friday, May 17, 2013
Thursday, May 9, 2013
Stanford's Big News- Anti CD47
Recently there has been quite a bit of press over Stanford's research on an anti-CD 47 drug because of a recent publication and potential of upcoming clinical trials. Now it seems that the FDA has approved this- human clinical trials. Because I am primarily interested in pediatric brain tumors, I rarely get excited about this type of news as in the past it often has taken years to go from first in man studies to our kids. However, this might not be the case with this new agent. It seems that DIPG has been on the minds of the developers of this anti- CD47 antibody already. Stanford already lists this as a topic in their pediatric brain tumor research program!
So what is so special about this anti-CD47 antibody that it has been called the "Holy Grail" of cancer research?
Apparently cells have these proteins on them called CD47 which tell a person's body "don't eat me". Those things that are foreign don't have these proteins so the idea is that the immune system will get destroy them. Cancer cells have alot of these CD47 proteins on them which allows them to continue to survive by tricking the immune system.
A decade ago a Stanford researcher, Irving Weissman, found that leukemia cells had more CD47 on them than normal healthy cells. Later the researchers found that every type of cancer they tested had high levels of CD47 than healthy cells. They developed an anti-CD 47 antibody and tested it on tumor cells in petri dishes. Without the antibody the macrophages (those cells which eating up stuff that shouldn't be there) ignored the cancer cells. However, when the samples had the anit-CD47 antibody included the macrophages destroyed all types of cancer cells. They then tested the agent on mice with similar effects.
There has been some concern that since all cells have CD47 that there could be some significant side effects in normal tissue. Although there has been some transient decreases in blood counts other effects were not seen in mice. The hope is that this will hold true in people as well.
The Stanford team has recieved a four-year $20 million grant for California Institute for Regenerative Medicine to translate these findings from mice to humans. Since Stanford seems to have the funding, the approval and the interest in DIPG this might be research to watch as sometime in the future this agent might become a clinical trial option for kids with DIPG.
Names to Know: It seems the Stanford researchers involved in this project and interested in pediatric DIPG included Michelle Monje, Hans Vogel, Paul Fisher, Albert Wong, Irving Weissman and Phillip Beachy as well as David Rowitch (UCSF).
References:
Antidote: On Cancer and CD47
http://www.mmm-online.com/antidote-on-cancer-and-cd47/article/291840/
CD47 Antibody treatment shrinks or eliminate human cancer tumors in mice (Stanford Video)
https://www.youtube.com/watch?v=EyGWZbmjeR0
So what is so special about this anti-CD47 antibody that it has been called the "Holy Grail" of cancer research?
Apparently cells have these proteins on them called CD47 which tell a person's body "don't eat me". Those things that are foreign don't have these proteins so the idea is that the immune system will get destroy them. Cancer cells have alot of these CD47 proteins on them which allows them to continue to survive by tricking the immune system.
A decade ago a Stanford researcher, Irving Weissman, found that leukemia cells had more CD47 on them than normal healthy cells. Later the researchers found that every type of cancer they tested had high levels of CD47 than healthy cells. They developed an anti-CD 47 antibody and tested it on tumor cells in petri dishes. Without the antibody the macrophages (those cells which eating up stuff that shouldn't be there) ignored the cancer cells. However, when the samples had the anit-CD47 antibody included the macrophages destroyed all types of cancer cells. They then tested the agent on mice with similar effects.
The Stanford team has recieved a four-year $20 million grant for California Institute for Regenerative Medicine to translate these findings from mice to humans. Since Stanford seems to have the funding, the approval and the interest in DIPG this might be research to watch as sometime in the future this agent might become a clinical trial option for kids with DIPG.
Names to Know: It seems the Stanford researchers involved in this project and interested in pediatric DIPG included Michelle Monje, Hans Vogel, Paul Fisher, Albert Wong, Irving Weissman and Phillip Beachy as well as David Rowitch (UCSF).
References:
Antidote: On Cancer and CD47
http://www.mmm-online.com/antidote-on-cancer-and-cd47/article/291840/
CD47 Antibody treatment shrinks or eliminate human cancer tumors in mice (Stanford Video)
https://www.youtube.com/watch?v=EyGWZbmjeR0
Wednesday, May 8, 2013
Their Ultimate Last Stand- McKenna Claire Foundation
When the beautiful, green-eyed, blond 7 year-old California kid, McKenna Claire Wetzel, started to throw up in January 2011 it was just thought to be the flu that had been going around. After of week of illness and a couple visits to the doctor, her parents started to notice a wandering left eye. The CT Scan that followed found the DIPG.
Good friends and good times- two of life's greatest gifts. MckKenna's parents worked hard for both. They had been told that this tumor was not survivable. Thus, they told their oldest child that they were doing thing to make Mckenna feel better- sadly not to cure her. She traveled to Hawaii, to tapings of both American Idol and Dancing with the Stars and sat on the floor at the Laker's game. She continued to go to second grade and every Tuesday night was "homework parties" at her house. The parties were more about community and friendship than homework. As things worsened her friend, Katie, would sit for hours holding McKenna's hand in silence.
Just six months from hearing DIPG, McKenna passed away. As devastating as this was, the Wetzel's were making one "last stand" against the tumor. They decided to donate Mckenna's tumor to Michele Monje's lab at Stanford. A lab tech from Stanford flew down as a guardian for this precious gift as it came to a new home- a place striving to learn how get rid of "that stupid tumor".
However, the Wetzel's realized that funded research would be able to do more. To honor McKenna and "perpetuate the sense of community", the McKenna Claire Foundation was born. In less than 2 years the foundation has raised approximately a half million dollars. One amazing thing was last May (Brain Cancer Awareness Month) the Chevron Corporation raised $292,466 at some of their California convenience stores.
These funds have been provided to Michele Monje's lab at Stanford which had grown a cell line from McKenna's tumor. And although cell lines haven't been easy to transport, Michele Monje's lab seems to have overcome this hurdle. McKenna's tumor now is also being studied by researchers in England and Australia!
Some of that funding had gone to fund the position of "tumor cell line guardian". OK, Anitha Pannuswami's official title is laboratory manager at Monje’s lab at Stanford. Often times salary funding is not part of grants, but I believe this has been a important factor in being able to do more in DIPG research. Anitha Pannuswami's job is to watch over McKenna's tumor as well as 5 other children's at the Monje lab. She also handles shipping them in ice to any researcher in the world who wishes to study DIPG. This is defnitely increasing DIPG reasearch internationally.
This May's Brain Cancer Awareness Month, the Chevron Corporation has expanded their support through their convenience stores throughout California. The Mckenna Claire Foundation has several other events already planned for 2013.
McKenna's tumor is flying like a butterfly around the world. Without a doubt, the McKenna Claire Foundation and the targeted partnership with Stanford is changing the landscape for DIPG Research. I predict both will be well worth watching.
References:
Tumor that killed girl could keep others alive
http://www.bendbulletin.com/article/20130427/NEWS0107/304270355/
Chevron customers raise $292,466 for McKenna Clair Foundation fight against pediatric cancer
http://www.orangecounty.com/articles/chevron-41266-foundation-claire.html#
Mckenna Claire Foundation
http://mckennaclairefoundation.org/
Good friends and good times- two of life's greatest gifts. MckKenna's parents worked hard for both. They had been told that this tumor was not survivable. Thus, they told their oldest child that they were doing thing to make Mckenna feel better- sadly not to cure her. She traveled to Hawaii, to tapings of both American Idol and Dancing with the Stars and sat on the floor at the Laker's game. She continued to go to second grade and every Tuesday night was "homework parties" at her house. The parties were more about community and friendship than homework. As things worsened her friend, Katie, would sit for hours holding McKenna's hand in silence.
Just six months from hearing DIPG, McKenna passed away. As devastating as this was, the Wetzel's were making one "last stand" against the tumor. They decided to donate Mckenna's tumor to Michele Monje's lab at Stanford. A lab tech from Stanford flew down as a guardian for this precious gift as it came to a new home- a place striving to learn how get rid of "that stupid tumor".
However, the Wetzel's realized that funded research would be able to do more. To honor McKenna and "perpetuate the sense of community", the McKenna Claire Foundation was born. In less than 2 years the foundation has raised approximately a half million dollars. One amazing thing was last May (Brain Cancer Awareness Month) the Chevron Corporation raised $292,466 at some of their California convenience stores.
These funds have been provided to Michele Monje's lab at Stanford which had grown a cell line from McKenna's tumor. And although cell lines haven't been easy to transport, Michele Monje's lab seems to have overcome this hurdle. McKenna's tumor now is also being studied by researchers in England and Australia!
Some of that funding had gone to fund the position of "tumor cell line guardian". OK, Anitha Pannuswami's official title is laboratory manager at Monje’s lab at Stanford. Often times salary funding is not part of grants, but I believe this has been a important factor in being able to do more in DIPG research. Anitha Pannuswami's job is to watch over McKenna's tumor as well as 5 other children's at the Monje lab. She also handles shipping them in ice to any researcher in the world who wishes to study DIPG. This is defnitely increasing DIPG reasearch internationally.
This May's Brain Cancer Awareness Month, the Chevron Corporation has expanded their support through their convenience stores throughout California. The Mckenna Claire Foundation has several other events already planned for 2013.
McKenna's tumor is flying like a butterfly around the world. Without a doubt, the McKenna Claire Foundation and the targeted partnership with Stanford is changing the landscape for DIPG Research. I predict both will be well worth watching.
References:
Tumor that killed girl could keep others alive
http://www.bendbulletin.com/article/20130427/NEWS0107/304270355/
Chevron customers raise $292,466 for McKenna Clair Foundation fight against pediatric cancer
http://www.orangecounty.com/articles/chevron-41266-foundation-claire.html#
Mckenna Claire Foundation
http://mckennaclairefoundation.org/
Tuesday, May 7, 2013
Part 2- Do the efflux transporters protect the glioma cells?
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
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
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