Discovery
Discovery Activities in DTP
The Developmental Therapeutics Program (DTP) within DCTD has supported the development of hundreds of new agents since its inception in 1955. The drug discovery resources and capabilities of DTP are exemplified by the Biological Testing Branch, Toxicology and Pharmacology Branch, and Biological Resources Branch. DTP also facilitates anticancer drug discovery by maintaining open chemical repositories and providing screening services.
The Open Chemical Repository Collection (free)
The Open Chemical Repository is an extensive collection of synthetic compounds and pure natural products maintained by DTP and available to investigators throughout the world for non-clinical research purposes. The collection contains more than 200,000 compounds that have been submitted directly to DTP or synthesized under its auspices. The compounds are classified into different categories with unique characteristics such as source (natural product or synthetic), whether they have been characterized in the NCI-60 cell line screen, and whether they are approved by the FDA. Of specific interest to researchers performing combination studies, FDA-approved agents are available in pre-cast 96-well plates. The request for these compounds can be submitted via the Compound Request site.
NCI-60 Human Cancer Cell Line Screen (free)
DTP provides both extramural and intramural investigators with a screening service for in vitro compound activity using the NCI-60 panel of 60 cancer cell lines. NCI-60 cell lines were derived from different human cancer types including melanoma, leukemia, and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney and have been verified by extensive molecular and genetic characterization. IVCLSP has the capacity to screen up to 3,000 compounds each year. Investigators can submit compounds for screening through the NCI-60 Screening Request site.
Biological Testing Branch
The Biological Testing Branch (BTB) provides animal models to support preclinical screening and evaluation of new agents in the drug discovery and development pipeline. More than 70 distinct, quality-controlled xenograft and allograft models (including subcutaneous and orthotopic implants) as well as the hollow fiber-based screening model are used to assess activity, confirm efficacy, and provide samples for assessing drug effect on a molecular target. Information from these models can be used to aid in the validation of the “clinical readiness” of pharmacodynamic assays.
Toxicology and Pharmacology Branch
Preclinical toxicology and pharmacology are required for informed decision making throughout the drug discovery and development process and for preparing an IND filing to support clinical trials. Toxicological and pharmacological data can inform clinical trial design in aspects of dosing, drug administration regimen, and biomarker studies.
The resources and expertise of the Toxicology and Pharmacology Branch (TPB) can support several steps in the NExT Stage Gate process:
| Exploratory Screen Development | Screening/ Hit-to-Lead |
Lead Development |
Candidate Selection |
Preclinical Evaluation |
|---|---|---|---|---|
|
Prepare project |
Evaluate PK and PD using best available tools Determine acute toxicity profile in vitro |
Determine safety issues Develop PD and toxicology biomarker assays Assess achievability of human PK/PD profile |
Evaluate biopharmaceutical properties (absorption in rodents and non-rodents, clearance, and bioavailability) Evaluate biodistribution Evaluate clinical readiness of PK/PD assay(s) and specimen handling SOPs Evaluate safety issues (most sensitive species) in range-finding toxicology studies |
Conduct IND-directed toxicology studies including toxicokinetics Determine preclinical MTD, DLTs, and clinical starting dose Validate PK/PD assay(s) and specimen handling SOPs Prepare and file IND |
Biological Resources Branch
The Biological Resources Branch (BRB) supports research in biological therapies and provides resources to explore potential leads for cancer treatment through grants and contracts. Two BRB programs directly support the NExT Program: the NCI Preclinical Repository distributes selected agents for peer-reviewed preclinical studies performed by both extramural and intramural investigators, while the Biopharmaceutical Development Program (BDP) manufactures biologic agents and a variety of clinical-grade biopharmaceuticals for clinical trials in a multiproduct current Good Manufacturing Practices (cGMP) facility at the Frederick National Laboratory for Cancer Research.