Corporate Banner
Satellite Banner
Stem Cells, Cellular Therapy & Biobanking
>
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Chemical Screen Points to New Line of Attack Against Neuroblastoma

Published: Monday, June 10, 2013
Last Updated: Monday, June 10, 2013
Bookmark and Share
In the war on neuroblastoma, the current chemical weaponry is reaching its limit.

Kimberly Stegmaier, a physician-scientist who treats children with cancer, describes having reached a ceiling in terms of treating this type of tumor with classical chemotherapy drugs. Such drugs are designed to kill cancer cells, but they also destroy many healthy cells in the process. Children with high-risk neuroblastoma may receive multiple cycles of chemotherapy over a six-month period, in addition to stem-cell transplantation, radiation, surgery, and immunotherapy. But for many patients, this is still not enough: the majority of patients with high-risk neuroblastoma are not cured with current treatment regimens.

For many years, Stegmaier and her colleagues have been pursuing a new approach: instead of looking for drugs that will directly kill cancer cells, they are on the hunt for drugs that will, in simple terms, make cancer cells grow up. This approach, known as differentiation therapy, is based on the concept that cancer cells are stuck in – or have regressed to – an immature state. In this state, they multiply unchecked. By using chemical compounds to coax cancer cells to mature, or differentiate, researchers have successfully treated certain forms of cancer, such as acute promyelocytic leukemia. Several lines of evidence suggest that differentiation therapy could also be used to treat patients with high-risk neuroblastoma. But finding compounds that have this maturing effect has not been easy.

In a paper published in Chemistry & Biology, Stegmaier and her colleagues at the Broad Institute, the Dana-Farber Cancer Institute, and Boston Children’s Hospital report important progress in developing a strategy to pinpoint promising compounds. Using a new method, the team uncovered a probe compound that causes neuroblastoma cells to differentiate. Although not a drug, the compound points to a new way of targeting neuroblastoma cells.

“We know that in many ways, these cells are poised to differentiate if we could only figure out the trigger,” said Stegmaier, a Broad associate member and a member of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “The hope is that differentiation therapy offers an alternative mechanism [for attacking neuroblastoma], and that the toxicity won’t be as great as with standard cytotoxins.”

Stegmaier, whose connection to the Broad dates back to her time as a postdoctoral fellow in the laboratory of Broad core member Todd Golub, teamed up with the Broad’s Therapeutics Platform to search for compounds of interest. While a postdoc, Stegmaier had developed a gene expression profile, or signature, of differentiated neuroblastoma cells. This unique signature of active genes would give the researchers a signal they could look for to identify the most promising compounds.

Rather than screening all of the chemical compounds in the Therapeutics Platform’s extensive collection, the team decided to use a subset of molecules with a particular focus. These compounds – built at the Broad through a process known as diversity-oriented synthesis (DOS) – were specifically developed to focus on genome-organizing complexes known as chromatin.

“There were a couple of things that were intriguing right off of the bat with that data,” said Jeremy Duvall, manager of DOS chemistry in the Therapeutics Platform. The results of the screen pointed to a DOS compound known simply as BRD8430, could induce neuroblastoma cells to mature, while closely related structures could not. “There seemed to be a preferred stereochemical relationship that affected its activity. That was exciting: that’s what we look for when we look at these datasets.”

BRD8430 is part of a class of compounds known as HDAC inhibitors. These compounds target histone deacetylases (HDACs), which are a type of gene-regulating protein with lots of effects. HDAC inhibitors have been connected to a variety of diseases, including sickle cell anemia, psychiatric diseases, metabolic diseases, and other forms of cancer. There are a number of different kinds of HDACs, and some inhibitors hit more than one of these targets. Broad associate member Jay Bradner, who has studied HDAC inhibitors in the context of sickle cell anemia, helped Stegmaier determine that BRD8430 selectively targets HDACs 1 and 2.

Duvall recalls the meeting where Stegmaier showed the team data suggesting that BRD8430 targeted HDACs 1 and 2. “When we saw the data, we realized that a door had opened,” he said. “We told her, you need to talk to the HDAC experts at the Broad: there’s a wealth of knowledge we could tap into right here.”

Ed Holson, director of medicinal chemistry for the Broad’s Stanley Center for Psychiatric Research, has been assembling a toolkit of selective HDAC inhibitors for the last four years, looking for cognitive enhancers that could be used to treat Alzheimer’s disease or post-traumatic stress disorder. When Holson heard about the neuroblastoma results, he immediately offered up the toolkit of compounds. These probe compounds helped the team confirm its results and validate its findings.

“We’re happy to share these compounds,” said Holson who has shared the toolkit with several other research groups. “The whole idea is to leverage the domain expertise that we have in the Stanley Center across [the Broad’s] platforms, programs, and wherever they might be applicable. HDACs have been implicated in a lot of different diseases, and the point of the toolkit is to get to a finer resolution about which HDACs are important in certain indications.”

Stegmaier and her colleagues also did a series of genetic experiments to turn off, or knock down, HDACs 1 and 2. These experiments also confirmed that these enzymes could play a key role in neuroblastoma differentiation. They then treated cells with both BRD8430 and cis-retinoic acid, a treatment already being given to patients with neuroblastoma, and found that the compound enhanced activity of the existing treatment, suggesting a possible role for combination therapy. But a long path to the clinic may lie ahead.

“While there are tool compounds that selectively target HDAC 1 and 2, there is not yet a commercially available compound with good drug-like properties,” said Stegmaier. “From a clinical perspective, that’s an important next step.”

But Stegmaier adds that if it is possible to develop a drug that selectively inhibits HDACs 1 and 2, but not the other HDACs, it could minimize toxicity. “We don’t know yet for certain, but there’s hope,” she said. “Companies have shown interest in pursuing selective inhibitors in the past – maybe these findings will reinvigorate that work.”


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,000+ scientific posters on ePosters
  • More than 4,500+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Targeting Cancer’s “Queen Bees” with Better Tissue Modeling
In many types of cancer, standard chemotherapy cures only a fraction of patients.
Wednesday, October 30, 2013
Rewinding the Clock with Epigenomics
How does a single cell give rise to a fully formed organism? Insights from induced pluripotent stem (iPS) cells have helped scientists develop a deeper understanding of this process.
Wednesday, April 03, 2013
Gene Mismatch Influences Success of Bone Marrow Transplants
Missing gene in donor found to increase recipient's chances of graft-versus-host disease, a common complication of bone marrow transplantation.
Monday, November 30, 2009
A Peek Under the Hood of Embryonic Stem Cells
Scientists discover unique molecular imprints coupled to DNA in mouse embryonic stem cells.
Tuesday, May 02, 2006
Scientific News
Turning Skin Cells into Heart, Brain Cells
In a major breakthrough, scientists at the Gladstone Institutes transformed skin cells into heart cells and brain cells using a combination of chemicals.
Stem Cells Know How to Unwind
Research led by the Babraham Institute with collaborators in the UK, Canada and Japan has revealed a new understanding of how an open genome structure supports the long-term and unrestricted developmental potential in embryonic stem cells.
Growing Stem Cells More Safely
Nurturing stem cells atop a bed of mouse cells works well, but is a non-starter for transplants to patients – Brown University scientists are developing a synthetic bed instead.
Cell Transplant Treats Parkinson’s in Mice
A University of Wisconsin—Madison neuroscientist has inserted a genetic switch into nerve cells so a patient can alter their activity by taking designer drugs that would not affect any other cell.
Skin Cells Turned into Heart Cells and Brain Cells Using Drugs
In a scientific first, Gladstone researchers have used chemical drugs to convert skin cells into heart cells and brain cells, without adding any external genes.
Shape Of Tumor May Affect Whether Cells Can Metastasize
Illinois researchers found that the shape of a tumor may play a role in how cancer cells become primed to spread.
‘Mini-Brains’ to Study Zika
Novel tool expected to speed research on brain and drug development.
Cytokine Triggers Immune Response at Expense of Blood Renewal
Research highlights promise of Anti-IL-1 drugs to treat chronic inflammatory disease.
AstraZeneca to Sequence 2 Million Genomes in Search for New Drugs
Company launches integrated genomics approach which aims to transform drug discovery and development.
Improving Engineered T-Cell Cancer Treatment
Purdue University researchers may have figured out a way to call off a cancer cell assassin that sometimes goes rogue and assign it a larger tumor-specific "hit list."
SELECTBIO

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,500+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!