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

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/

The TIssue Issue- Molecular Biology of DIPG

DIPG as a chapter section regarding new molecular targets and treatments for brain tumors! 

Chapter 20: New Molecular Targets and Treatment for Pediatric Brain Tumors by James T. Rutka

in Evolution of Molecular Biology of Brain Tumors and the Therapeutic Implications edited by Terry Lichtor and published on February 27, 2013

The main reason for lack of advancement on DIPG has been the lack of tumor tissue (not lack of funding, not lack of interest and not lack of trying).  The almost total absence of tumor tumor tissue meant there was no feasible way to develop specific research on this devastating pediatric tumor.  Let me emphasize that again--    All basic science research with DIPG was essentially impossible without tissue.  However, the past half decade has seen rapid changes and unprecedented collaboration to get tissue both by biopsy and autopsy.

Timeline-
* 2004- the French  decided it the molecular age of tumor biology has reached a stage to reinstitute biopsies.  Simultaneously in North America several hospitals (Sick Kids, St Jude, NIH) made a concerted effort to obtain post-mortem samples.
* Jauary 2009- Dylan Jewett's tumor was donated to Standford.
* February 2010, the first ever DIPG genomic study was published by Sick Kids.
* March 2011, Stanford released news that they had developed a first pediatric DIPG cell line and animal model from the previously donated tumor.
* Today there are more than 30 DIPG cell lines, several institutions that have developed animal models and a handful of DIPG molecular biology papers have been published.

Chapter Highlightss

• From  recent studies it has become common knowledge that pediatric brain tumor (including DIPG) are different from similarly appearing adult tumors.   Not only are pediatric tumors different than adults, but also DIPG are genetically different from other pediatric gliomas

• A growing list of different pathways and factors are being described.   DIPG discussions are soon going to routinely contain a confusing concoction of letters,number, factors and receptors-  EGFR, PDGFA, recetpor tyorosine kinase, retinoblastoma protein, PARP-1, MET and insulin-like growth factor receptor 1.    All these are parts of pathways driving tumors and all have been found in a percentage of DIPGs.

• Drugable targets in DIPG tumors have been found in the molecular biology evaluation of DIPGs.  The paper lists the overall survival and references for seven different clinical trials since 2007 using different targeted drugs- imatinib, tififanib, genfitinib, vandetanib, erlotinib and nimozumab.  In some cases, a subset of patients have been found to survive longer than expected.  Most of these trials though were done blindly so individual patient's molecular biology is not known.

• Recently the first mutated oncogene in DIPG was described- P13KCA.

• The chapter also highlights the challenge of getting these agents into the pons.  The blood brain barrier seems to severely limit access to the pons.   Convection-enhanced delivery and nanoparticles were specifically mentioned as techniques to consider in DIPG.

Five years ago, few would have foreseen a chapter section on DIPG molecular biology!  Looking into near future for DIPG, tumor molecular biology and new therapeutic approaches to get around the blood brain barrier are likely to take center stage.

Chapter Author: James T Rutka- Division of Neurosurgery and Labatt Brain Tumor Centre, The Hospital for Sick Children, University of Toronto, Canada

References:
Claudia C. Faria, Christian A. Smith and James T. Rutka (2013). New Molecular Targets and Treatments for Pediatric Brain Tumors, Evolution of the Molecular Biology of Brain Tumors and the Therapeutic Implications, Dr. Terry Lichtor (Ed.), ISBN: 978-953-51-0989-1, InTech, DOI: 10.5772/53300. Available from:   http://www.intechopen.com/books/evolution-of-the-molecular-biology-of-brain-tumors-and-the-therapeutic-implications/new-molecular-targets-and-treatments-for-pediatric-brain-tumors

Dylan Warriors- a pivotal change for DIPG

The last two posts about the sonic hedgehog pathway have been quite medical.   When trying to decipher the medical terms it is easy to miss the amazing lengths families have gone to try to make a difference in the course of DIPG.   In this instance, we actually know a specific child and family that started it all- the Jewett family.  This is a remarkable story of a family and a researcher joining forces to completely change the world for DIPG.  Through the donation of Dylan's tumor to Stanford the entire landscape for DIPG research has changed.

The thinking has changed from "it isn't possible" to "it is possible"!

*It is possible that parents will want to donate tumor after their child has died.
*It is possible that we can grow cell lines and make animal models from this donated tissue.
*It is possible from that information we can chose new ways to try to fight DIPG.
*It is possible for families, foundations and researchers to come together to make a difference.

Thank you Jewett family, Dylan's Warriors, Michelle Monje and the doctors at Stanford.

Note:  We now not only do we have that one cell line but more than 30 others DIPG cell lines!

Please watch their story at-
https://www.youtube.com/watch?v=pdFfWhQ9964

References:
Dylan's Warriors- http://curedipg5.com/ or www.facebook.com/CureDIPG

Dylan's Story- http://www.kidsvcancer.org/tissue-donation/information-for-families/donation-stories/dylan/

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