The Office of Cancer Genomics (OCG) Cancer Target Discovery and Development or CTD2 initiative was established by the National Cancer Institute (NCI) to accelerate the “translation” of high-throughput, high-content genomic data to the bedside through functional genomics. The CTD2 initiative is a collaborative network of 13 different research teams, or Centers. The goal of this Network is to develop novel bioinformatics and functional genomics approaches to identify biomarkers, therapeutic targets and perturbagens that affect the targets thereby impeding survival of the cancer cells. The success of the CTD2 Network has prompted us to take a look back at what the program has accomplished so far.
A major characteristic of the initiative is intra-Network collaboration because there is a continuous communication among the Centers. In addition to conducting individual research projects, the CTD2 awardees also contributed to trans-network activities, including participation in joint pilot research projects. Most of the trans-Network collaborations are fruitful and are generating high-value publications.
The CTD2 Network Centers have used multiple platforms to share ideas, data, and resources. All data and tools developed as part of the CTD2 initiative are made available to the scientific community in a format that can be easily utilized. The examples below demonstrate how CTD2 broadly shares community resources, confirmation of important scientific concepts, or clinical impact.
- Publications: The CTD2 Network has been very productive, to date 257 manuscripts have been published and more are submitted. Ten papers have been cited over 100 times.
- Data Portal: NCI and CTD2 Centers developed a Data Portal for deposition of the primary raw/analyzed data. Currently there are 38 diverse datasets in the Data Portal. The Data Portal has an average of 400 unique users per month.
- CTD2 Dashboard: The massive amounts of primary data stored in large databases are often difficult to navigate without bioinformatics expertise and it is also challenging for researchers to determine the significance and reproducibility of a result from the primary data alone. To address this challenge, the Network developed CTD2 Dashboard which allows easy data navigation and use by a range of scientists, from computational scientists to cancer experts. The Dashboard gives access to conclusions along with the supporting evidence generated by CTD2 investigators. To understand more about the Dashboard functionalities, please read the article “CTD2 Dashboard: A Platform to Explore Evidence-based Observations”. There are currently 132 submissions associated with 45 projects (related submissions are grouped together) in the Dashboard. The CTD2 Dashboard has over 200 unique users per month.
- Strength of evidence: Because of the multiplicity of approaches Network Centers use it is beneficial that the data be presented in a manner that connects results from various approaches to a conclusion. To address this issue, CTD2 Network developed a multi-Tier framework which defines what constitutes sufficient computational or experimental evidence to support a biologically relevant finding. The Network published a manuscript, “Transforming Big Data into Cancer-Relevant Insight: An Initial, Multi-Tier Approach to Assess Reproducibility and Relevance”, which defines the Tiers framework. The multi-Tier framework is being applied to results in the CTD2 Dashboard.
- Analytical tools: To date, the Network has generated nineteen novel algorithms, each with its own function, including the identification of therapeutic targets, gene and molecular networks, driver mutations, and chemical sensitivities. These tools are widely used by hundreds of users each month and can be found at this link.
- CTD2 supported reagents: The Network has made available to the community the reagents it has generated, including CRISPR libraries, protein-protein interaction reagents, etc. These reagents foster growth of genomics and precision medicine science. More information on these reagents can be found here.
- Clinical impact: The CTD2 Network has been highly successful in generating multiple projects with preclinical and clinical relevance. Many of the hypotheses generated have been tested in mouse models or organoid cultures that represent in vivo systems (fulfilling one of the aims articulated in RFA(s)). The results have provided supporting evidence for the initiation of clinical trials: in breast cancer (NCT02066532, NCT02632071), head and neck cancer (NCT02508246), and in KRAS mutant non-small cell lung cancer (NCT03095612).
There are still more challenges to address to enable rapid conversion of molecular data to precision oncology as new data sets and types (cancers from underrepresented minorities, children, data from clinical trials, etc.) are becoming available. Because of the accomplishments, some of which are highlighted above and the collaborative nature of the current Network, the Board of Scientific Advisors approved a new phase of the CTD2 initiative . The new CTD2 Network will explore cancer complexity in terms of inter-patient and intra-tumor heterogeneities and their impacts, e.g., on innate or acquired resistance to chemo and immunotherapies. One focus of the new Network will be to take advantage of novel patient-derived cancer models being developed as part of the Human Cancer Models Initiative (HCMI) for high-throughput functional studies to define biologically relevant targets, modulators and biomarkers.
In summary, the Network strives to integrate large-scale genomic data with systems biology analyses and high-throughput molecular modulation (small-molecules/CRISPR/RNAi) of the cancer phenotype. The Network accelerates the discovery process by sharing knowledge and resources. The Network has made great accomplishments through collaborations and looks forward to making more discoveries by ensuring that the new Network analyzes the data expeditiously and integrates into the body of knowledge the initiative has already amassed.