Help defeat childhood cancer
Results of the Help Fight Childhood Cancer project
discover new ways to fight neuroblastoma
Maxim Malakhovsky, distributed.org.ua based on the materials of the World Community Grid:
Surprising new prospects help advance the fight against neuroblastomaThe head of research, Dr. Akira Nakagawara, CEO of the KOSEIKAN Medical Center in Saga and Honorary President of the Cancer Center in Chiba (Japan), talks about new prospects for using the results of the distributed computing project "Help Fight Childhood Cancer" (Help Fight Childhood Cancer).
As it turned out, as a result of processing the results of the project, even more potential mechanisms for the treatment of neuroblastoma were discovered than initially thought. Also in the near future, the second phase of the project will be launched, in which it is expected to expand the list of childhood cancers.
Last year was marked by great success in the Help Fight Childhood Cancer (HFCC) project (implemented with the help of the World Community Grid association), the scientific part of which is promoted by the efforts of the research teams of the Cancer Center in Chiba (Chiba Cancer Center Research Institute), which is headed by Prof. Nakagawara, and Chiba University (Chiba University), under the supervision of Dr. Hoshino (Hoshino) and Tamura (Tamura). The main goal of the project was to search for small chemical compounds aimed at specific sites of one of the proteins of the nerve growth factor receptor family – tropomyosin receptor kinase B (Tropomyosin receptor kinase B, TrkB), which are involved in the regulation of tumor cells and are responsible for their aggressiveness. These compounds should lead to the destruction of neuroblastoma tumor cells in vitro and in animal experiments. The second goal was to develop new drugs for the treatment of patients with aggressive neuroblastoma, based on the obtained structural information about the discovered candidate chemical compounds.
Thanks to the help of the project participants, the researchers have made significant progress towards achieving both goals. So, last year an article was published in the journal Cancer Medicine (Nakamura et al., Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma, in open access), which describes in detail the current results of the project.
However, this article highlights only part of the results obtained. As it turned out, the anti-cancer potential of the detected small chemical compounds can work in three different ways:
1. TrkB receptor antagonistsThis topic was the subject of the above scientific article in the journal Cancer Medicine.
The researchers used AutoDock calculations and were able to find among the library of 3 million. chemical compounds of 7 candidate substances, which showed very low values of IC 50 (low values indicate greater efficiency), contributing to the destruction of neuroblastoma cells in vitro.
IC 50, or the concentration of semi–maximal inhibition, is an indicator of the effectiveness of a ligand (a substance binding to a target molecule), which shows how much an inhibitor ligand is needed to suppress the biological process by 50%.
Then 2 compounds with the lowest IC50 values were selected, which confirmed their effectiveness in suppressing tumor growth in experiments on mice.
Models of binding of two candidate small molecules to the TrkB protein
(here and below are drawings from an article in Cancer Medicine).
Dr. Hoshino's group at Chiba University is currently generating new small chemical compounds based on the structure of candidate compounds found in the HFCC project, which are chemical compounds with much lower IC50 values.
The main challenge for this aspect of research is finding a pharmaceutical company that will cooperate in turning these promising compounds into medicines. This is problematic, because although neuroblastoma is a terrible disease, it is not too common, representing a small-capacity pharmaceutical market. Therefore, only a few companies can be interested in allocating resources for its development.
2. TrkB receptor agonistsAs a side result of the HFCC project, agonists of TrkB receptors were accidentally found that function similarly to the brain-derived neurotrophic factor (BDNF), which is the physiological ligand of TrkB.
This could be a new way to fight neuroblastoma. Researchers are currently analyzing data in this area.
A model of specific binding between TrkB (yellow) and BDNF (blue) on the cell membrane (white).
The inset shows amino acids potentially involved in the interaction.
3. Antagonists inhibiting binding sites of ALK receptors and ShcC protein adapterPreviously, researchers found that the receptors of ALK (anaplastic lymphoma kinase, anaplastic lymphoma kinase, an enzyme also belonging to the tyrosine kinase class) and the associated signaling protein ShcC are markers of neuroblastoma aggressiveness.
Work has been done to identify small chemical compounds that can block the binding sites of these proteins. Calculations carried out using the World Community Grid found several promising compounds with low IC 50 values. The molecular mechanism by which these compounds kill tumor cells is currently being analyzed. The group of Dr. Sakai from the National Cancer Research Institute in Tokyo (National Cancer Center Research Institute in Tokyo) helps in this work.
The scientific team of the project is now collecting data for a new article. In the meantime, he discusses the results at scientific conferences in Japan and Germany.
The second phase of the Help Fight Childhood Cancer project is also being developed, where the list of investigated childhood cancers will expand. A new team from Hong Kong University, led by pediatric oncologist Dr. Godfrey C.F. Chan, was involved in the development of the project.
To all participants of the Help Fight Childhood Cancer project, the organizers once again express their great gratitude for the invaluable contribution to the research of methods of treatment of a severe childhood disease – neuroblastoma.
Portal "Eternal youth" http://vechnayamolodost.ru22.01.2015