In 2014, Help Fight Childhood Cancer, which ran on World Community Grid, identified several potential treatments for neuroblastoma, a common type of cancer among infants and young children. Building on their success so far, the scientists behind the project are expanding their team to include researchers across Asia, and expanding their focus to look for treatments for additional forms of childhood cancer.
Leading Disease-Related Cause of Childhood Death
Cancer remains the number one cause of death by disease in children. According to data from the International Agency for Research on Cancer, the global occurrence of childhood cancer may be significantly higher than previously thought. Drawing on data from more than 100 cancer registries in 68 countries from 2001-2010, the International Agency for Research on Cancer reported in 2016 that approximately 300,000 cases of cancer are diagnosed in children and teens under the age of 19 every year, and there are an estimated 80,000 deaths annually from childhood cancer worldwide.
Few New Treatments and Lack of Research Funding
In the past 20 years, only three new drugs that were specifically developed to treat childhood cancer have been approved by the US Food and Drug Administration. Half of all the chemotherapy treatments used for children with cancer have been in existence for 25 years or longer. And the National Cancer Institute spends only four percent of its annual research budget to fund studies on childhood cancer.
Searching for New Treatments for the Most Common Types of Childhood Cancer
This project will expand on the work of Help Fight Childhood Cancer (which addressed the need for new neuroblastoma treatments) to include other forms of childhood cancer as well as further research into neuroblastoma treatments. These include:
- Brain tumors
- Wilms' tumor - a malignant tumor of the kidney
- Germ cell tumors
- Hepatoblastoma - cancer of the liver
- Osteosarcoma - bone cancer
Like neuroblastoma, the cancers listed above are among the most common forms of childhood cancer. It is possible that the project will expand to include other childhood cancers in the future.
Discovering and Designing New Childhood Cancer Treatments
Cancers are usually caused by a problem with molecules that regulate cell growth. For example, if there are too many or too few of certain molecules present, this could cause uncontrolled growth of cells (cancer).
As cancers grow, they can undergo additional mutations and evolve in ways that make them even more difficult to stop. Researchers study cancers to find out which molecules, proteins, genes, DNA, RNA and other regulating molecules are usually involved in each cancer. Then they try to find ways to block one or more of the mechanisms that are responsible for the cancer. Often, they identify a specific protein which plays a key role in a specific cancer, either positive (stopping cancer growth) or negative (enabling cancer growth). That protein thus becomes the target molecule they want to disable or enable. The researchers for this project have identified several such molecular targets for various forms of childhood cancer. These molecular targets are important because controlling any one of them may have an impact on how multiple types of cancer (both childhood and adult cancer) can be treated.
The molecular regulatory processes involved in cancer research can be quite complex. Thanks to gene sequencing, studies about protein structure and function, and big data investigations in disease data, scientists are learning more about how cancers form and spread in the body. Because of this complexity, it is important to investigate approaches for treating these cancers at the molecular level.
The researchers for Smash Childhood Cancer already have extensive experience with various childhood cancers and aim to identify potential drug candidates to treat these diseases.
The Projected Solution
The Smash Childhood Cancer project's approach is to find ligands (chemical compounds or molecules) that bind to specific target proteins involved in the childhood cancers to be addressed. In some cases, the ligands may be chemical antagonists, suppressing or blocking the normal activity of the target protein. In other cases, the ligands may be agonists, activating or increasing the activity of the target protein.
The Challenges of Finding New Treatments
To find promising ligand-protein matches (which might lead to potential childhood cancer treatments), scientists need to test millions of chemical compounds. Conducting research on this scale in a laboratory is nearly impossible because of the amount of time and expense involved. That is where World Community Grid can help - by allowing researchers to use virtual screening techniques to systematically evaluate millions of compounds against specific molecular targets associated with a cancer. This large-scale virtual screening process, which is only possible through massive computing power, allows the researchers to predict the effectiveness of a large number of drugs as potential cancer treatments.
The Project's Target Molecules
The following target molecules are ones the researchers will be addressing first. These molecules have been identified by the project researchers, as well as other scientists, as the most likely to be involved in the growth of childhood and some adult cancers.
- TrkB (Tropomyosin receptor kinase B, pronounced "track B") are proteins which control growth in certain types of cells in the body, primarily neurons. NCYM (MYCNOS) is an RNA molecule which regulates neural cell survival. One of the research groups in this project has discovered that this RNA molecule encodes the recently identified protein N-CYM. TrkB, N-CYM and the protein encoded by the LIN28B gene are involved in childhood cancers, such as neuroblastoma (a cancer that often arises in or near the adrenal gland) and Wilms' tumors (malignant tumors of the kidney). Research also has shown that TrkB may play a role in Alzheimer's disease and in other cancers commonly found in adults such as lung cancer, pancreatic cancer, colon cancer, liver cancer, breast cancer, and ovarian cancer. Furthermore, LIB28B is involved in hepatoblastoma (a deadly liver cancer in children), germ cell tumor, and other cancers in general.
- Beta-Catenin is another protein that has more than one function. It is involved in regulating cell-to-cell adhesion and gene transcription (the first step in creating proteins). When too much beta-catenin is produced, this can lead to a number of cancers, including childhood hepatoblastoma and osteosarcoma (a childhood bone cancer). The protein is also involved in adult cancers such as colorectal cancer, lung cancer, gastric cancer, pancreatic cancer, renal cancer, liver cancer, nasopharyngeal cancer, prostate cancer, and more.
These molecules are the initial focus of the Smash Childhood Cancer team to treat various childhood cancers. Finding ligands that bind with these molecules will help further research in understanding their exact roles in these complex diseases and enable testing various therapeutic approaches. There are usually several regulatory processes at the molecular level involved in these cancers, and having specific ligands to manipulate each regulatory molecule will let researchers better understand the complex interactions that lead to uncontrolled cell growth and the spread of these cells to other parts of the body (metastasis).
As the project progresses, and new data are found through this project and other studies, the researchers may expand or shift their focus to new target molecules.
World Community Grid volunteers will be performing virtual chemistry experiments to determine which of about three million ligands bind well to the target molecules. The molecular structure of each ligand and target molecule, showing where all of the atoms are positioned, are run through a research software tool called AutoDock VINA. This tool, developed by The Scripps Research Institute, evaluates how two molecules may interact or fit together, a process called 'docking' the ligand molecule to the target molecule. The tool calculates the expected binding energy for each orientation of the pair of molecules. The ligands with the best scoring binding energy are the molecules that will be further evaluated by the researchers in laboratory tests. The computational power of World Community Grid will greatly accelerate this research by making it possible for the researchers to evaluate millions of potential drug candidates.
The specific goals of Smash Childhood Cancer are:
- To use the computing power donated by World Community Grid volunteers to search for ligand molecules that bind to the selected target molecules.
- To test the most promising results in the laboratory for effectiveness in controlling the respective types of childhood cancers.
- To make the computational data and research findings publically available to other scientists.