Fast-Track proposals will be accepted.
Direct to Phase II will not be accepted.
Number of anticipated awards: 3-4
Budget (total costs, per award): Phase I: up to $225,000 for up to 9 months
Phase II: up to $1,500,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
The generation and dynamic interplay of redox effector molecules (e.g., oxygen, free radicals, peroxides, nitrogen oxides, and hydrogen sulfide) are fundamental features underlying the genomic, structural, metabolic and functional alterations observed in cancers. Alterations in redox balance impact all phases of disease including carcinogenesis, disease progression, response to treatment and prevention. For example, the DNA damaging effects of free radicals can mutagenize key oncogenic sites. Redox imbalances occur by abnormalities commonly associated with cancers including mutations in p53, myc and ras pathways. Redox effectors operate to modify protein function at the post-translational level, which plays a significant mechanistic role in the phenotypic plasticity cancer cells demonstrate in the face of oxidative and reductive (hypoxia) stresses. Redox tone is a key regulator of the self-renewal properties of stem-like cancer cells, which has been shown to contribute to tumor resistance to current therapies.
Progress in the cancer biology and pre-clinical space has been limited by the lack of tools that can accurately measure redox parameters in animal models with sufficient spatio-temporal resolution and minimal perturbation of the system. NCI seeks input from the small business community to develop and optimize a new generation of quantitative and specific technologies that will enable and accelerate basic research aimed at understanding basic redox effector mechanisms and the roles they play in the cellular adaptations and complex biology of tumors.
Supporting the development of these technologies will allow researchers to validate and benchmark data obtained across different 3D cell culture platforms and pre-clinical animal model systems with the goal of accurately mimicking tumor environments experienced by patients with cancer. Moreover, an enhanced ability to screen, manipulate, or analyze redox dynamics is an invaluable index in the evaluation of cancer cell-tumor responses to therapeutic interventions in the critical pre-clinical testing phase. These redox data have potential to significantly improve our understanding of tumor biology and ability to better predict treatment responses and long-term efficacy when translated into patients.
There is an unmet need in basic cancer research for probes or technologies that can better measure, characterize, profile, or resolve the spatiotemporal dynamics of redox effectors at the subcellular to cellular levels. Genomic profiles, for instance, cannot capture post-translational redox regulation that occurs with changes in the tumor microenvironment. Redox probes have been traditionally reliant on organic dyes that experience spectral shifts with redox. The current state of the art is genetically encoded redox indicators that couple redox responsive enzyme motifs with indicator proteins. These genetically engineered redox probes have improved response kinetics, but may have limited optical qualities. Given the critical role played by redox effectors, developing a range of new tools will help us better understand how redox effectors regulate cell phenotypes in functional tumor populations.
The goal of this FOA is to develop quantitative tools to measure redox dynamics in biological systems. Ideally, probes or biosensor tools should be minimally invasive as to not significantly perturb the system. The technical approach should: (1) allow for in vivo measurements of redox effector spatiotemporal dynamics; and/or (2) be useable in high throughput systems, for example to allow the screening of cellular response to experimental perturbations, such as exposure to cytotoxic agents. The long term goal is that the technologies developed through this contract can help validate whether data gathered in model experimental systems faithfully represents the redox dynamics of human tumors.
To successfully meet this goal, offerors shall develop a technology for the minimally to non-invasive measurement of one or more redox effectors, including but not limited to oxygen, free radicals, reactive oxygen species, peroxides, nitrogen oxides, and hydrogen sulfide. Phase I studies should focus on developing the technology and demonstrating proof of concept in an in vitro system. Phase II studies further refine the technology and demonstrate the use of the technology to measure redox effectors. Offerors shall justify their choice of approach with respect to the scientific utility and commercial potential, and specify quantitative milestones that can be used to evaluate the success of the technology being developed.
It is anticipated that offerors shall develop a probe or similar agent that facilitates the measurement of redox effectors by one or more imaging modalities; however, offerors are not restricted to any particular technical approach and label or probe free approaches that can meet the requirements of this contract are welcome.
Offerors are not restricted to any particular technical approach and can propose resource and tool development that incorporates high-risk/high-impact technologies. Examples can include, but are not limited to:
Technologies that have the potential for in vivo use, especially those with potential clinical applications in the long term will be of particular interest, but methods that will be restricted to pre-clinical research applications are also of interest.
The goal of the Phase II product is an optimized commercial resource, product, reagent, kit or device that can allow researchers to measure the relevant redox effector molecules in their laboratory. Decisions for continued project development into Phase II will be based on probes, biosensors, assays or systems that:
Deliverables for the Phase II projects are: