(Fast-Track proposals will be accepted.)
Number of anticipated awards: 3–5
Budget (total costs):
Phase I: $300,000 for 9 months;
Phase II: $2,000,000 for 2 years
It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.
The deadline for receipt of all contract proposals submitted in response to this solicitation has expired. It was: November 13, 2012 by 5 p.m. EST.
There is a critical need to improve the accuracy of preclinical drug efficacy screening and testing through the development of in vitro culture systems that more effectively mimic the in vivo environment. Currently, two-dimensional (2D) in vitro culture systems or in vivo animal models are the primary tools used to test cancer cell responses to drugs. However, drug sensitivity data obtained via 2D culture systems can be misrepresentative, while animal models are expensive, time-consuming, and not always predictive of the effects on human tumors in their native environment. Three-dimensional (3D) culture systems that mimic the tumor microenvironment using human tissue could be a better tool for drug screening by providing a more accurate, in vivo-like structure and organization than 2D culture systems, without the cost and time associated with using animal models. In addition, culture systems using human tissue may produce responses more predictive of humans than animal models. Advances in bioengineering and 3D cell culture models have led to in vitro systems that better replicate the structure, physiology, and function of tissues seen in vivo. 3D models more accurately mimic the in vivo milieu than current 2D in vitro culture systems by recreating the morphology and arrangement of individual cells, concentration gradients of signaling molecules and therapeutic agents, and the composition, structure, and mechanical forces of extracellular matrix around cells. The use of 3D systems that recreate the human tumor microenvironment could improve drug development in at least two ways: 1) speed decision-making for whether a particular therapeutic agent is worth pursuing in an animal model, reducing the time and cost of development; 2) lead to fewer clinical trial failures because of earlier, more relevant results from human tissue.
Properly representing the tumor microenvironment is particularly critical for testing the effectiveness of anti-cancer therapeutic agents. For example, extravascular transport in solid tumors is a fundamental determinant of the efficacy of both locally and systemically administered cancer agents. Large diffusion distances in tumor tissues, elevated interstitial fluid pressure, and interactions between anti-cancer drugs, tumor tissue, and normal tissue are factors that significantly limit drug diffusion in the extravascular compartment. Additionally, due to rapid proliferation and poor blood supply to tumor cells, the tumor microenvironment is often acidic and hypoxic, which can lead to the resistance of tumor cells to both drug and radiation therapy. Thus, systems to properly recreate the tumor microenvironment are essential to advance the discovery and development of effective anti-cancer agents.
The focus of this topic is the development of 3D human tissue model culture systems that accurately mimic the tumor microenvironment, including factors affecting tumor cell responses such as vascularization and interactions with heterogeneous cell types. The project goal is to produce a system that is validated against known effective anti-cancer agents to demonstrate the system's utility as a predictive tool and screening assay. It is anticipated that the development of 3D systems representative of human tumor microenvironments will lead to an increase in the quality of and reduction in the timelines and costs associated with screening drugs, and enhancement in efficacy information for regulatory decisions.
Essential characteristics of an in vitro tumor microsystem should include all or some of the following features: 1) multicellular architecture that represents physiologically relevant characteristics of the tumor and tissue of origin; 2) reproducible and viable operation with simple and clear protocols; 3) ability to examine multiple aspects of cancer, such as tumor growth, angiogenesis, cell proliferation, migration, and/or invasion; and 4) compatibility with high content screening platforms that include multiple molecular read-outs, such as genomic, proteomic, metabolomic, or epigenomic analyses. System development should permit scale-up production such that the system can be reliably reproduced at a cost with reasonable expectation for market success. An eventual goal for such systems may include the ability to incorporate individual patient tumor biopsies to test patient-specific responses to available agents.
It is important to note that full 3D tumor microenvironment systems will consist of more than just an extracellular matrix containing tumor cells and will facilitate the inclusion of various cell types to mimic tumor cell interaction with surrounding normal cells and their effects on cancer aggressiveness and response to anti-cancer drugs. Examples include stromal cells that can induce chemoresistance and encourage metastasis, as well as endothelial cells that can carry therapeutics to the cancer. This topic is not intended to fund microphysiological organ systems for the study of toxicity, though tumor culture systems developed under this topic may be combined as a module with systems such as those being developed through the collaborative program between NIH, FDA, and DARPA: http://www.ncats.nih.gov/research/reengineering/tissue-chip/tissue-chip.html