The CCR Center for Advanced Preclinical Research (CAPR) is developing a comprehensive preclinical trial framework for evaluating the anti-tumor efficacy and selectivity, biodistribution, and metabolism of early-stage candidate drugs using genetically engineered mouse (GEM) models.
Mission: To facilitate the improvement of preclinical evaluation for effective cancer diagnosis and treatment.
Rationale for need: Recent advances have been made in developing treatments that target specific molecular pathway aberrations associated with a given cancer. Where successful, such targeted therapies have revolutionized the treatment of a few specific cancers, such as leukemia, certain stomach tumors and a subset of breast cancers. Yet, despite the promise of these "targeted therapies," only five percent of cancer drugs under development are actually approved. The majority of new cancer treatments fail due to lack of efficacy in patients, indicating that the current preclinical methods of testing cancer drug efficacy (i.e., xenograft and cell-based tests) have limited accuracy. Such failure comes at an estimated average cost of $1.2 billion per drug, not to mention the human toll exacted in the process.
The following objectives are within the purview of CAPR:
Resouces: Towards More Predictive Mouse Models for Preclinical Drug Development
Currently, drug efficacy studies are conducted almost exclusively in xenograft models that use transformed human cell lines to initiate tumor growth after injection into immunocompromised animals. Though easily derived, these models feature multiple intrinsic constraints that limit the predictability of outcome drug testing data. Xenograft tumors are developed from a genetically heterogeneous cell population that has been maintained in vitro for multiple passages. In addition, tumor growth occurs in an ectopic, non-physiological environment in the absence of both immune surveillance and systemic interactions with the vascular system. As an alternative source of experimental tumors, animal models of spontaneous carcinogenesis have also been used, but these models generally lack reproducibility in timing of tumor onset and feature(s) due to considerable genetic "background noise" caused by the non-inbred strain.
The drawbacks of these two systems are largely ameliorated in genetically engineered mouse (GEM) tumor models that provide preclinical researchers with the ability to study naturally occurring tumors in the context of an appropriate tissue environment in immunocompetent animals. CAPR will use GEM models exclusively in the preclinical testing phase. This strategy will not only provide an opportunity to combine, in transgenic animals, multiple genetic aberrations closely matching those detected in human patients, but also the potential to interfere with cancer-related molecular pathways in both a tissue-restricted and time-specific manner, providing genetic evidence for drug target legitimacy.
CAPR will serve as a national resource for the comprehensive preclinical testing of early stage candidate drugs. Candidate compounds will be primarily assessed for anti-tumor efficacy and selectivity in genetically engineered animal models.
The Center will implement an innovative approach to preclinical drug characterization as well as molecular drug target identification, validation, and the discovery of prognostic/diagnostic biomarkers for clinical oncology. On the one hand, CAPR will develop the infrastructure required for preclinical evaluation of anti-cancer drug leads in an existing collection of GEM models for high-occurrence cancers such as brain astrocytomas, lung and prostate tumors. On the other hand, CAPR will also continuously search the dynamic knowledge base on mechanisms of carcinogenesis to seek additional molecular targets related to the tumor formation process. Appropriate GEM strains will be designed, derived, or adapted both to address CAPR’s internal demand for novel tumor models and also to share these resources with other scientific and industrial communities involved in anti-cancer drug discovery and development.
A service of the National Cancer Institute