Developed with the input of the Foundation’s Scientific Advisory Board, the Research Roadmap is a concrete set of objectives the Foundation is pursuing to advance the development of effective treatments for chordoma.
1. Provide research-enabling resources
Create and distribute models, biospecimens and data that are required for nearly all basic and translational chordoma research.
- Develop disease models including cell lines, patient derived xenografts, genetically engineered mouse models, and zebrafish models
- Create repositories of chordoma disease models to make them easily accessible to the research community
- Create a Biobank to provide a centralized source of high-quality biospecimens linked to clinical data
2. Determine the molecular drivers of chordoma
Identify altered genes and pathways critical for chordoma development which could represent therapeutic targets.
- Comprehensively catalogue all genomic alterations through whole genome sequencing, transcriptome sequencing and methylation analysis
- Identify aberrantly activated signaling pathways through proteomic analysis
3. Test drugs in preclinical models of chordoma
Identify drugs most likely to be effective in chordoma patients, and provide rationale for clinical trials.
- Conduct empirical in-vitro screens of diverse compound libraries – including all approved drugs, preclinical pharmaceutical collections, and publically available compound collections – and test the most active compounds in in-vivo models.
- Rationally test agents that inhibit identified therapeutic targets in in-vitro and in-vivo models.
4. Develop therapeutics targeting brachyury
Pursue therapeutic approaches to inhibit the activity of brachyury, a gene now known to play a critical role in the development of chordoma.
- Determine what activates brachyury
- Genetically silence brachyury in chordoma animal models
- Develop a brachyury reporter assay (a test to measure the effectiveness of drugs) suitable for high throughput drug screening
- Screen large compound libraries against brachyury reporter assay
5. Fund investigator-initiated research
Incentivize and enable researchers to bring their expertise and ideas to bear on chordoma by offering peer-reviewed seed grants to test hypotheses, and generate preliminary data needed to garner larger, sustained funding sources.
The Foundation is currently focused on carrying out the following projects which are ready to begin immediately. Each of these projects has been thoroughly vetted, contactors or grantees have been identified, and exact costs are known. These projects will commence as soon as funds are raised.
|Chordoma Genome Project||Why?|
|Uncovering all of the genetic changes responsible for driving chordoma||Modern cancer drugs target and kill cells that harbor specific genetic changes. Knowing what changes are present in the DNA of chordoma tumors is critical to finding effective treatments. Now that we know that a change in brachyury loads the gun for developing chordoma, it is important to know what other genetic events actually pull the trigger.|
|Goal: Whole genome and transcriptome (RNA) sequencing of 10 chordoma tumors||Status: Completed exome (part of the genome) sequencing of 25 chordoma tumors|
|Funding need: $47,000 (matched by $400K from the Sanger Institute)|
|Start-up funding to enable researchers to begin studying chordoma and generate preliminary data needed to leverage additional funding sources||Recent developments, including the creation of new mouse models and the discovery of a gene that contributes substantially to the development of chordoma, have created numerous opportunities for high-impact research. Plans will be made at the next research workshop to pursue those opportunities and researchers will need funding to carry out those plans.|
|Goal: Award 5-7 seed grants of up to $50,000 each
||Status: Funding permitting, we will release a request for proposals in January 2013
|Funding need: $250,000
|Drug Repurposing Project||Why?|
|Determining whether an effective treatment for chordoma already exists by testing FDA-approved drugs in cell lines and mouse models||There are over 2,800 FDA-approved drugs available to patients today. Cell-line testing has revealed that over 40 of these drugs are promising candidates for chordoma treatments. Now mouse model testing is needed before embarking on human clinical trials.|
|Goal: Test top 20 FDA approved drugs in 3 mouse models||Status: Completed exome (part of the genome) sequencing of 25 chordoma tumors|
|Funding need: $369,000
|International Chordoma Research Workshop||Why?|
|Convene a multi-disciplinary group of researchers to share the latest discoveries and build partnerships with colleagues around the world||Information exchange and collaboration are critical to advancing research; studies have shown that increasing the number relationships within a network of researchers increases innovation. The workshop provides a rare opportunity to exchange unpublished data and connect the world leaders in chordoma with experts in related disciplines.|
|Goal: Spark new relationships and collaborations, recruit new researchers into the field||Status: Workshop scheduled for March 2013 in Boston, MA|
|Funding need: $75,000
|Cell Line Repository||Why?|
|A one-stop easy-to-access source of valid chordoma cell lines available to the research community.||Cell lines are required for many of the most important cancer research experiments, such as drug testing. Providing chordoma cell lines to scientists enables research that otherwise would not be possible. Often, chordoma cell lines can be included in ongoing projects for other cancers at no cost to the Foundation.|
|Goal: 10 cell lines||Status: 3 cell lines
|Funding need: $200,000 (cell line prizes, characterization, and banking)
Once the projects listed above are funded the Foundation will begin soliciting proposals for the following objectives recommended by the Scientific Advisory Board:
- Develop a chordoma patient derived xenograft repository
- Develop a genetically engineered mouse model of chordoma
- Develop a zebrafish model of chordoma
- Carry out proteomic analysis of chordoma
- Genetically silence brachyury in chordoma xenograft models
- Develop a brachyury activity reporter assay
- Carry out high-throughput small molecule screening against brachyury reporter assay
- Additional investigator initiated grants