|By: Dr. Akira Nakagawara, MD, PhD|
|CEO of the Saga Medical Center KOSEIKAN and President Emeritus, Chiba Cancer Center|
|26 Sep 2017|
The Help Fight Childhood Cancer researchers discuss how they’re moving forward with data analysis and continuing their search for pharmaceutical partners.
The Help Fight Childhood Cancer (HFCC) project was created to look for better treatments for neuroblastoma, which is refractory among childhood cancers (meaning that it is resistant to treatment). The project’s goal was to target certain cell proteins regulating cancer cell growth—such as TrkB tyrosine kinase receptor, ALK tyrosine kinase receptor, N - CYM protein and others—with the help of World Community Grid’s enormous computing power, which is donated by an international community of volunteers.
Our research team conducted in-silico (computer simulation-based) drug discovery screening using World Community Grid to search through a library of three million small molecular compounds. We discovered a small molecule compound which competitively binds to the TrkB protein pocket to which BDNF (a specific growth factor) binds. The discovered molecule can thus prevent BDNF from binding to the TrkB protein and diminish cancer cell growth. This could lead to a new and improved treatment for neuroblastoma.
Subsequently, the anti-tumor effect of the compound was examined using cultured cancer cells, or human neuroblastoma transplanted into mice, and this laboratory research confirmed that this small molecular compound and possibly some others could be candidates for anticancer drugs targeting TrkB. We announced this breakthrough and published our findings in the peer-reviewed, English language journal, Cancer Medicine, in 2014.
Currently, we are conducting research to develop even more potent inhibitors by synthesizing small molecular compounds similar in structure to the compounds found using the screening. The road to developing commercial, approved new drugs is a tough task. We must find a pharmaceutical company that will conduct joint research and development and create a patentable compound so that this expensive effort is profitable. If any of you have contacts with a pharmaceutical company that may be interested in pursuing this venture, please introduce us.
Additionally, using World Community Grid to screen drug candidates, we found other small molecular compounds showing the ability to inhibit the ligand BDNF. These results were presented it in another English language journal (Neurochem International, 2016, abstract here). These compounds also look promising as a remedy for depression and dementia, and similarly, we are seeking a pharmaceutical company to cooperate in research and development of these.
The N-CYM is a new protein we discovered which is implicated in neuroblastoma. A published paper about this can be found here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879166/. Before we can screen for drug candidates, we must determine this protein's three-dimensional structure. Therefore, we are currently working on the difficult task of crystallizing the N-CYM protein so that we can perform X-ray analysis to determine the protein’s three-dimensional structure. Once the three-dimensional structure of the protein is determined, we will screen to find inhibiting compounds in the Smash Childhood Cancer project, which is building on the work from this project.
Regarding the development of ALK inhibitors (see article https://www.ncbi.nlm.nih.gov/pubmed/15972965), candidate compounds as inhibitors were found in the in-silico screening, and analysis on cultured cancer cells was completed. Because of the lack of research personnel, unfortunately preclinical tests have not yet progressed.
We thank all volunteers who supported this project, and look forward to keeping you updated on the progress of this project as well as the Smash Childhood Cancer project.